307 results on '"Gow, AJ"'
Search Results
2. GWAS for executive function and processing speed suggests involvement of the CADM2 gene
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Ibrahim-Verbaas, CA, Bressler, J, Debette, S, Schuur, M, Smith, AV, Bis, JC, Davies, G, Trompet, S, Smith, JA, Wolf, C, Chibnik, LB, Liu, Y, Vitart, V, Kirin, M, Petrovic, K, Polasek, O, Zgaga, L, Fawns-Ritchie, C, Hoffmann, P, Karjalainen, J, Lahti, J, Llewellyn, DJ, Schmidt, CO, Mather, KA, Chouraki, V, Sun, Q, Resnick, SM, Rose, LM, Oldmeadow, C, Stewart, M, Smith, BH, Gudnason, V, Yang, Q, Mirza, SS, Jukema, JW, deJager, PL, Harris, TB, Liewald, DC, Amin, N, Coker, LH, Stegle, O, Lopez, OL, Schmidt, R, Teumer, A, Ford, I, Karbalai, N, Becker, JT, Jonsdottir, MK, Au, R, Fehrmann, RSN, Herms, S, Nalls, M, Zhao, W, Turner, ST, Yaffe, K, Lohman, K, van Swieten, JC, Kardia, SLR, Knopman, DS, Meeks, WM, Heiss, G, Holliday, EG, Schofield, PW, Tanaka, T, Stott, DJ, Wang, J, Ridker, P, Gow, AJ, Pattie, A, Starr, JM, Hocking, LJ, Armstrong, NJ, McLachlan, S, Shulman, JM, Pilling, LC, Eiriksdottir, G, Scott, RJ, Kochan, NA, Palotie, A, Hsieh, Y-C, Eriksson, JG, Penman, A, Gottesman, RF, Oostra, BA, Yu, L, DeStefano, AL, Beiser, A, Garcia, M, Rotter, JI, Nöthen, MM, Hofman, A, Slagboom, PE, Westendorp, RGJ, Buckley, BM, Wolf, PA, Uitterlinden, AG, Psaty, BM, Grabe, HJ, Bandinelli, S, and Chasman, DI
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Biological Psychology ,Clinical and Health Psychology ,Psychology ,Human Genome ,Neurosciences ,Genetics ,Clinical Research ,Aging ,Aetiology ,2.1 Biological and endogenous factors ,Aged ,Aged ,80 and over ,Cell Adhesion Molecules ,Cognition ,Cohort Studies ,Executive Function ,Female ,Genetic Association Studies ,Genetic Variation ,Genome-Wide Association Study ,Genomics ,Humans ,Introns ,Male ,Middle Aged ,Neuropsychological Tests ,Polymorphism ,Single Nucleotide ,White People ,gamma-Aminobutyric Acid ,Generation Scotland ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Clinical sciences ,Biological psychology ,Clinical and health psychology - Abstract
To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.
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- 2016
3. Inhaled nitric oxide in premature infants: effect on tracheal aspirate and plasma nitric oxide metabolites
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Posencheg, MA, Gow, AJ, Truog, WE, Ballard, RA, Cnaan, A, Golombek, SG, and Ballard, PL
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Paediatrics ,Biomedical and Clinical Sciences ,Preterm ,Low Birth Weight and Health of the Newborn ,Pediatric ,Clinical Trials and Supportive Activities ,Clinical Research ,Perinatal Period - Conditions Originating in Perinatal Period ,Lung ,Infant Mortality ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Good Health and Well Being ,Bronchopulmonary Dysplasia ,Gestational Age ,Humans ,Infant ,Newborn ,Infant ,Premature ,Nitrates ,Nitric Oxide ,Nitrites ,Respiratory Therapy ,Trachea ,nitrite ,bronchopulmonary dysplasia ,NO CLD trial ,NO CLD Investigators ,Clinical Sciences ,Paediatrics and Reproductive Medicine ,Pediatrics - Abstract
ObjectiveInhaled nitric oxide (iNO) is a potential new therapy for prevention of bronchopulmonary dysplasia and brain injury in premature infants. This study examined dose-related effects of iNO on NO metabolites as evidence of NO delivery.Study designA subset of 102 premature infants in the NO CLD trial, receiving 24 days of iNO (20 p.p.m. decreasing to 2 p.p.m.) or placebo, were analyzed. Tracheal aspirate (TA) and plasma samples collected at enrollment and at intervals during study gas were analyzed for NO metabolites.ResultiNO treatment increased NO metabolites in TA at 20 and 10 p.p.m. (1.7- to 2.3-fold vs control) and in plasma at 20, 10, and 5 p.p.m. (1.6- to 2.3-fold). In post hoc analysis, treated infants with lower metabolite levels at entry had an improved clinical outcome.ConclusioniNO causes dose-related increases in NO metabolites in the circulation as well as lung fluid, as evidenced by TA analysis, showing NO delivery to these compartments.
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- 2010
4. The Holocene-Younger Dryas Transition Recorded at Summit, Greenland
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Taylor, KC, Mayewski, PA, Alley, RB, Brook, EJ, Gow, AJ, Grootes, PM, Meese, DA, Saltzman, ES, Severinghaus, JP, Twickler, MS, White, JWC, Whitlow, S, and Zielinski, GA
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Climate Action ,General Science & Technology - Abstract
Analysis of ice from Dye-3, Greenland, has demonstrated that the transition between the Younger Dryas and Holocene climate periods occurred over a 40-year period. A near annually resolved, multiparameter record of the transition recorded in the GISP2 core from Summit, Greenland, shows that most of the transition occurred in a series of steps with durations of about 5 years. Some climate proxies associated with mid-latitude sources appear to have changed about 15 years before climate proxies associated with more northern regions. Changes in atmospheric water vapor are likely to have played a large role in the climate transition.
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- 1997
5. Cerebral Small Vessel Disease Burden and Longitudinal Cognitive Decline from age 73 to 82: the Lothian Birth Cohort 1936
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Hamilton, OKL, primary, Cox, SR, additional, Okely, JA, additional, Conte, F, additional, Ballerini, L, additional, Bastin, ME, additional, Corley, J, additional, Taylor, AM, additional, Page, D, additional, Gow, AJ, additional, Muñoz Maniega, S, additional, Redmond, P, additional, Valdés-Hernández, M del C, additional, Wardlaw, JM, additional, and Deary, IJ, additional
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- 2021
- Full Text
- View/download PDF
6. Associations between total MRI-visible small vessel disease burden and domain-specific cognitive abilities in a community-dwelling older-age cohort
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Hamilton, OKL, primary, Cox, SR, additional, Ballerini, L, additional, Bastin, ME, additional, Corley, J, additional, Gow, AJ, additional, Muñoz Maniega, S, additional, Redmond, P, additional, M del C, Valdés-Hernández, additional, Wardlaw, JM, additional, and Deary, IJ, additional
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- 2021
- Full Text
- View/download PDF
7. Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits (vol 50, pg 1412, 2018)
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Evangelou, E, Warren, HR, Mosen-Ansorena, D, Mifsud, B, Pazoki, R, Gao, H, Ntritsos, G, Dimou, N, Cabrera, CP, Karaman, I, Fu, LN, Evangelou, M, Witkowska, K, Tzanis, E, Hellwege, JN, Giri, A, Edwards, DRV, Sun, YV, Cho, K, Gaziano, JM, Wilson, PWF, Tsao, PS, Kovesdy, CP, Esko, T, Magi, R, Milani, L, Almgren, P, Boutin, T, Debette, S, Ding, J, Giulianini, F, Holliday, EG, Jackson, AU, Li-Gao, R, Lin, W-Y, Luan, J, Mangino, M, Oldmeadow, C, Prins, BP, Qian, Y, Sargurupremraj, M, Shah, N, Surendran, P, Theriault, S, Verweij, N, Willems, SM, Zhao, J-H, Amouyel, P, Connell, J, De Mutsert, R, Doney, ASF, Farrall, M, Menni, C, Morris, AD, Noordam, R, Pare, G, Poulter, NR, Shields, DC, Stanton, A, Thom, S, Abecasis, G, Amin, N, Arking, DE, Ayers, KL, Barbieri, CM, Batini, C, Bis, JC, Blake, T, Bochud, M, Boehnke, M, Boerwinkle, E, Boomsma, DI, Bottinger, EP, Braund, PS, Brumat, M, Campbell, A, Campbell, H, Chakravarti, A, Chambers, JC, Chauhan, G, Ciullo, M, Cocca, M, Collins, F, Cordell, HJ, Davies, G, De Borst, MH, De Geus, EJ, Deary, IJ, Deelen, J, Del Greco, FM, Demirkale, CY, Dorr, M, Ehret, GB, Elosua, R, Enroth, S, Erzurumluoglu, AM, Ferreira, T, Franberg, M, Franco, OH, Gandin, I, Gasparini, P, Giedraitis, V, Gieger, C, Girotto, G, Goel, A, Gow, AJ, Gudnason, V, Guo, X, Gyllensten, U, Hamsten, A, Harris, TB, Harris, SE, Hartman, CA, Havulinna, AS, Hicks, AA, Hofer, E, Hofman, A, Hottenga, J-J, Huffman, JE, Hwang, S-J, Ingelsson, E, James, A, Jansen, R, Jarvelin, M-R, Joehanes, R, Johansson, A, Johnson, AD, Joshi, PK, Jousilahti, P, Jukema, JW, Jula, A, Kahonen, M, Kathiresan, S, Keavney, BD, Khaw, K-T, Knekt, P, Knight, J, Kolcic, I, Kooner, JS, Koskinen, S, Kristiansson, K, Kutalik, Z, Laan, M, Larson, M, Launer, LJ, Lehne, B, Lehtimaki, T, Liewald, DCM, Lin, L, Lind, L, Lindgren, CM, Liu, Y, Loos, RJF, Lopez, LM, Lu, Y, Lyytikainen, L-P, Mahajan, A, Mamasoula, C, Marrugat, J, Marten, J, Milaneschi, Y, Morgan, A, Morris, AP, Morrison, AC, Munson, PJ, Nalls, MA, Nandakumar, P, Nelson, CP, Niiranen, T, Nolte, IM, Nutile, T, Oldehinkel, AJ, Oostra, BA, O'Reilly, PF, Org, E, Padmanabhan, S, Palmas, W, Palotie, A, Pattie, A, Penninx, BWJH, Perola, M, Peters, A, Polasek, O, Pramstaller, PP, Quang, TN, Raitakari, OT, Ren, M, Rettig, R, Rice, K, Ridker, PM, Ried, JS, Riese, H, Ripatti, S, Robino, A, Rose, LM, Rotter, JI, Rudan, I, Ruggiero, D, Saba, Y, Sala, CF, Salomaa, V, Samani, NJ, Sarin, A-P, Schmidt, R, Schmidt, H, Shrine, N, Siscovick, D, Smith, AV, Snieder, H, Sober, S, Sorice, R, Starr, JM, Stott, DJ, Strachan, DP, Strawbridge, RJ, Sundstrom, J, Swertz, MA, Taylor, KD, Teumer, A, Tobin, MD, Tomaszewski, M, Toniolo, D, Traglia, M, Trompet, S, Tuomilehto, J, Tzourio, C, Uitterlinden, AG, Vaez, A, Van der Most, PJ, Van Duijn, CM, Vergnaud, A-C, Verwoert, GC, Vitart, V, Volker, U, Vollenweider, P, Vuckovic, D, Watkins, H, Wild, SH, Willemsen, G, Wilson, JF, Wright, AF, Yao, J, Zemunik, T, Zhang, W, Attia, JR, Butterworth, AS, Chasman, DI, Conen, D, Cucca, F, Danesh, J, Hayward, C, Howson, JMM, Laakso, M, Lakatta, EG, Langenberg, C, Melander, O, Mook-Kanamori, DO, Palmer, CNA, Risch, L, Scott, RA, Scott, RJ, Sever, P, Spector, TD, Van der Harst, P, Wareham, NJ, Zeggini, E, Levy, D, Munroe, PB, Newton-Cheh, C, Brown, MJ, Metspalu, A, Hung, AM, O'Donnell, CJ, Edwards, TL, Psaty, BM, Tzoulaki, I, Barnes, MR, Wain, LV, Elliott, P, and Caulfield, MJ
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Genetics & Heredity ,Science & Technology ,Million Veteran Program ,06 Biological Sciences ,Life Sciences & Biomedicine ,11 Medical and Health Sciences ,Developmental Biology - Abstract
Correction to: Nature Genetics https://doi.org/10.1038/s41588-018-0205-x, published online 17 September 2018.
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- 2018
8. Sitting time, fidgeting and all-cause mortality in the UK Women's Cohort Study
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Hagger-Johnson, G, Gow, AJ, Burley, VJ, Greenwood, DC, and Cade, JE
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Introduction: Sedentary behaviours (including sitting) may increase risk of mortality independently of physical activity level. Little is known about how fidgeting behaviours might modify the association. Methods: Data were drawn from the UK Women’s Cohort Study. In 1999/2002, 12,778 women (age 37 to 78) provided data on average daily sitting time, overall fidgeting (irrespective of posture), and a range of relevant covariates including physical activity, diet, smoking status and alcohol consumption. Participants were followed for mortality over a mean of 12 years. Proportional hazards Cox regression models were used to estimate the relative risk of mortality in the high (vs. low) and medium (vs. low) sitting time groups. Results: Fidgeting modified the risk associated with sitting time (p value for interaction = 0.04), leading us to separate groups for analysis. Adjusting for a range of covariates, sitting for 7+ hours/day (vs.
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- 2016
9. Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans
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Huffman, JE, Albrecht, E, Teumer, A, Mangino, M, Kapur, K, Johnson, T, Kutalik, Z, Pirastu, N, Pistis, G, Lopez, LM, Haller, T, Salo, P, Goel, A, Li, M, Tanaka, T, Dehghan, Abbas, Ruggiero, D, Malerba, G, Smith, AV, Nolte, IM (Ilja), Portas, L, Phipps-Green, A, Boteva, L, Navarro, P, Johansson, A, Hicks, AA, Polasek, O, Esko, T, Peden, JF, Harris, SE, Murgia, F, Wild, SH, Tenesa, A, Tin, A, Mihailov, E, Grotevendt, A, Gislason, GK, Coresh, J, d'Adamo, P, Ulivi, S, Vollenweider, P, Waeber, G, Campbell, S, Kolcic, I, Fisher, K, Viigimaa, M, Metter, JE, Masciullo, C, Trabetti, E, Bombieri, C, Sorice, R, Doring, A, Reischl, E, Strauch, K, Hofman, Bert, Uitterlinden, André, Waldenberger, M, Wichmann, HE, Davies, G, Gow, AJ, Dalbeth, N, Stamp, L, Smit, JH, Kirin, M, Nagaraja, R, Nauck, M, Schurmann, C, Budde, K, Farrington, SM, Theodoratou, E, Jula, A, Salomaa, V, Sala, C, Hengstenberg, C, Burnier, M, Magi, R, Klopp, N, Kloiber, S, Schipf, S, Ripatti, S, Cabras, S, Soranzo, N, Homuth, G, Nutile, T, Munroe, PB, Hastie, N, Campbell, H, Rudan, I, Cabrera, C, Haley, C, Franco Duran, OH, Merriman, TR, Gudnason, V, Pirastu, M, Penninx, BW, Snieder, H, Metspalu, A, Ciullo, M, Pramstaller, PP, Duijn, Cornelia, Ferrucci, L, Gambaro, G, Deary, IJ, Dunlop, MG, Wilson, JF, Gasparini, P, Gyllensten, U, Spector, TD, Wright, AF, Hayward, C, Watkins, H, Perola, M, Bochud, M, Kao, WHL, Caulfield, M, Toniolo, D, Volzke, H, Gieger, C, Kottgen, A, Vitart, V, Huffman, Jennifer E., Albrecht, Eva, Teumer, Alexander, Mangino, Massimo, Kapur, Karen, Johnson, Toby, Kutalik, Zoltán, Pirastu, Nicola, Pistis, Giorgio, Lopez, Lorna M., Haller, Tooma, Salo, Perttu, Goel, Anuj, Li, Man, Tanaka, Toshiko, Dehghan, Abba, Ruggiero, Daniela, Malerba, Giovanni, Smith, Albert V., Nolte, Ilja M., Portas, Laura, Phipps Green, Amanda, Boteva, Lora, Navarro, Pau, Johansson, Asa, Hicks, Andrew A., Polasek, Ozren, Esko, Tõnu, Peden, John F., Harris, Sarah E., Murgia, Federico, Wild, Sarah H., Tenesa, Albert, Tin, Adrienne, Mihailov, Evelin, Grotevendt, Anne, Gislason, Gauti K., Coresh, Josef, D'Adamo, ADAMO PIO, Ulivi, Sheila, Vollenweider, Peter, Waeber, Gerard, Campbell, Susan, Kolcic, Ivana, Fisher, Krista, Viigimaa, Margu, Metter, Jeffrey E., Masciullo, Corrado, Trabetti, Elisabetta, Bombieri, Cristina, Sorice, Rossella, Döring, Angela, Reischl, Eva, Strauch, Konstantin, Hofman, Albert, Uitterlinden, Andre G., Waldenberger, Melanie, Wichmann, H. Erich, Davies, Gail, Gow, Alan J., Dalbeth, Nicola, Stamp, Lisa, Smit, Johannes H., Kirin, Mirna, Nagaraja, Ramaiah, Nauck, Matthia, Schurmann, Claudia, Budde, Kathrin, Farrington, Susan M., Theodoratou, Evropi, Jula, Antti, Salomaa, Veikko, Sala, Cinzia, Hengstenberg, Christian, Burnier, Michel, Mägi, Reedik, Klopp, Norman, Kloiber, Stefan, Schipf, Sabine, Ripatti, Samuli, Cabras, Stefano, Soranzo, Nicole, Homuth, Georg, Nutile, Teresa, Munroe, Patricia B., Hastie, Nichola, Campbell, Harry, Rudan, Igor, Cabrera, Claudia, Haley, Chri, Franco, Oscar H., Merriman, Tony R., Gudnason, Vilmundur, Pirastu, Mario, Penninx, Brenda W., Snieder, Harold, Metspalu, Andre, Ciullo, Marina, Pramstaller, Peter P., Van Duijn, Cornelia M., Ferrucci, Luigi, Gambaro, Giovanni, Deary, Ian J., Dunlop, Malcolm G., Wilson, James F., Gasparini, Paolo, Gyllensten, Ulf, Spector, Tim D., Wright, Alan F., Hayward, Caroline, Watkins, Hugh, Perola, Marku, Bochud, Murielle, Linda Kao, W. H., Caulfield, Mark, Toniolo, Daniela, Völzke, Henry, Gieger, Christian, Köttgen, Anna, Vitart, Veronique, Life Course Epidemiology (LCE), Institute for Molecular Medicine Finland, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Quantitative Genetics, Complex Disease Genetics, Epidemiology, Public Health, and Internal Medicine
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Genetics and Molecular Biology (all) ,Male ,Gout ,lcsh:Medicine ,Biochemistry ,Body Mass Index ,Risk Factors ,GWAS ,ATP Binding Cassette Transporter, Subfamily G, Member 2 ,Settore MED/14 - NEFROLOGIA ,Oxidoreductases Acting on Sulfur Group Donors ,lcsh:Science ,METABOLIC SYNDROME ,INSULIN-RESISTANCE ,Membrane Glycoproteins ,PLASMA N-GLYCANS ,Edar Receptor ,Medicine (all) ,Antigens, Nuclear ,Neoplasm Proteins ,Female ,Medical Genetics ,Research Article ,Genotype ,Nerve Tissue Proteins ,Polymorphism, Single Nucleotide ,BMI ,SDG 3 - Good Health and Well-being ,Humans ,Agricultural and Biological Sciences (all) ,Biochemistry, Genetics and Molecular Biology (all) ,Obesity ,GENOME-WIDE ASSOCIATION ,Medicinsk genetik ,ENVIRONMENT ,lcsh:R ,TRANSPORTER ,serum urate levels ,genetic associations ,Overweight ,Uric Acid ,ALKALINE-PHOSPHATASE ,Genetic Loci ,RISK-FACTORS ,Linear Models ,lcsh:Q ,ATP-Binding Cassette Transporters ,3111 Biomedicine ,URIC-ACID LEVELS ,Genome-Wide Association Study - Abstract
We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, P-inter= 2.6 x 10(-8)). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDAR-ADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10(-8)), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10(-8)), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10(-4)). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.
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- 2015
10. Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations
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Okada, Y, Sim, X, Go, Mj, Wu, Jy, Gu, D, Takeuchi, F, Takahashi, A, Maeda, S, Tsunoda, T, Chen, P, Lim, Sc, Wong, Ty, Liu, J, Young, Tl, Aung, T, Seielstad, M, Teo, Yy, Kim, Yj, Lee, Jy, Han, Bg, Kang, D, Chen, Ch, Tsai, Fj, Chang, Lc, Fann, Sj, Mei, H, Rao, Dc, Hixson, Je, Chen, S, Katsuya, T, Isono, M, Ogihara, T, Chambers, Jc, Zhang, W, Kooner, Js, Kidneygen, Consortium, Ckdgen, Consortium, Albrecht, E, Gugc, Consortium, Yamamoto, K, Kubo, M, Nakamura, Y, Kamatani, N, Kato, N, He, J, Chen, Yt, Cho, Ys, Tai, Es, Tanaka, T., Lord, Gm, van der Harst, P, Lawlor, Da, Sehmi, Js, Gale, Dp, Wass, Mn, Ahmadi, Kr, Bakker, Sj, Beckmann, J, Bilo, Hj, Bochud, M, Brown, Mj, Caulfield, Mj, Connell, Jm, Cook, Ht, Cotlarciuc, I, Smith, Gd, de Silva, R, Deng, G, Devuyst, O, Dikkeschei, Ld, Dimkovic, N, Dockrell, M, Dominiczak, A, Ebrahim, S, Eggermann, T, Farrall, M, Ferrucci, L, Floege, J, Forouhi, Ng, Gansevoort, Rt, Han, X, Hedblad, B, van der Heide JJ, Hepkema, Bg, Hernandez Fuentes, M, Hypponen, E, Johnson, T, de Jong PE, Kleefstra, N, Lagou, V, Lapsley, M, Li, Y, Loos, Rj, Luan, J, Luttropp, K, Maréchal, C, Melander, O, Munroe, Pb, Nordfors, L, Parsa, A, Peltonen, L, Penninx, Bw, Perucha, E, Pouta, A, Prokopenko, I, Roderick, Pj, Ruokonen, A, Samani, Nj, Sanna, S, Schalling, M, Schlessinger, D, Schlieper, G, Seelen, Ma, Shuldiner, Ar, Sjögren, M, Smit, Jh, Snieder, H, Soranzo, N, Spector, Td, Stenvinkel, P, Sternberg, Mj, Swaminathan, R, Tanaka, T, Ubink Veltmaat LJ, Uda, M, Vollenweider, P, Wallace, C, Waterworth, D, Zerres, K, Waeber, G, Wareham, Nj, Maxwell, Ph, Mccarthy, Mi, Jarvelin, Mr, Mooser, V, Abecasis, Gr, Lightstone, L, Scott, J, Navis, G, Elliott, P, Köttgen, A, Pattaro, C, Böger, Ca, Fuchsberger, C, Olden, M, Glazer, Nl, Gao, X, Yang, Q, Smith, Av, O'Connell, Jr, Li, M, Schmidt, H, Isaacs, A, Ketkar, S, Hwang, Sj, Johnson, Ad, Dehghan, A, Teumer, A, Paré, G, Atkinson, Ej, Zeller, T, Lohman, K, Cornelis, Mc, Probst Hensch NM, Kronenberg, F, Tönjes, A, Hayward, C, Aspelund, T, Eiriksdottir, G, Launer, Lj, Harris, Tb, Rampersaud, E, Mitchell, Bd, Arking, De, Boerwinkle, E, Struchalin, M, Cavalieri, M, Singleton, A, Giallauria, F, Metter, J, de Boer IH, Haritunians, T, Lumley, T, Siscovick, D, Psaty, Bm, Zillikens, Mc, Oostra, Ba, Feitosa, M, Province, M, de Andrade, M, Turner, St, Schillert, A, Ziegler, A, Wild, Ps, Schnabel, Rb, Wilde, S, Munzel, Tf, Leak, Ts, Illig, T, Klopp, N, Meisinger, C, Wichmann, He, Koenig, W, Zgaga, L, Zemunik, T, Kolcic, I, Minelli, C, Hu, Fb, Johansson, Å, Igl, W, Zaboli, G, Wild, Sh, Wright, Af, Campbell, H, Ellinghaus, D, Schreiber, S, Aulchenko, Ys, Felix, Jf, Rivadeneira, F, Uitterlinden, Ag, Hofman, A, Imboden, M, Nitsch, D, Brandstätter, A, Kollerits, B, Kedenko, L, Mägi, R, Stumvoll, M, Kovacs, P, Boban, M, Campbell, S, Endlich, K, Völzke, H, Kroemer, Hk, Nauck, M, Völker, U, Polasek, O, Vitart, V, Badola, S, Parker, An, Ridker, Pm, Kardia, Sl, Blankenberg, S, Liu, Y, Curhan, Gc, Franke, A, Rochat, T, Paulweber, B, Wang, W, Gudnason, V, Coresh, J, Schmidt, R, Shlipak, Mg, van Duijn CM, Borecki, I, Krämer, Bk, Rudan, I, Gyllensten, U, Wilson, Jf, Witteman, Jc, Pramstaller, Pp, Rettig, R, Hastie, N, Chasman, Di, Kao, Wh, Heid, Im, Fox, Cs, Krumsiek, J, Hundertmark, C, Pistis, G, Ruggiero, D, O'Seaghdha, M, Haller, T, Kutalik, Z, Shi, J, Middelberg, Ps, Gaffo, Al, Pirastu, N, Li, G, Huffman, J, Yengo, L, Zhao, Jh, Demirkan, A, Feitosa, Mf, Liu, X, Malerba, Giovanni, Lopez, Lm, Li, X, Kleber, Me, Hicks, Aa, Nolte, Im, Johansson, A, Murgia, F, Peden, Jf, Steri, M, Tenesa, A, Salo, P, Mangino, M, Rose, Lm, Lehtimäki, T, Woodward, Om, Tin, A, Müller, C, Oldmeadow, C, Putku, M, Czamara, D, Kraft, P, Frogheri, L, Thun, Ga, Grotevendt, A, Gislason, Gk, Mcardle, P, Schallert, M, Martin, Ng, Montgomery, Gw, Jacobs DR Jr, Liu, K, D'Adamo, P, Ulivi, S, Rotter, Ji, Navaro, P, Balkau, B, Froguel, P, Esko, T, Salumets, A, Khaw, Kt, Langenberg, C, Kraja, A, Zhang, Q, Scott, Rj, Holliday, Eg, Org, E, 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Boerwinkle, E, Struchalin, M, Cavalieri, M, Singleton, A, Giallauria, F, Metter, J, de Boer, Ih, Haritunians, T, Lumley, T, Siscovick, D, Psaty, Bm, Zillikens, Mc, Oostra, Ba, Feitosa, M, Province, M, de Andrade, M, Turner, St, Schillert, A, Ziegler, A, Wild, P, Schnabel, Rb, Wilde, S, Munzel, Tf, Leak, T, Illig, T, Klopp, N, Meisinger, C, Wichmann, He, Koenig, W, Zgaga, L, Zemunik, T, Kolcic, I, Minelli, C, Hu, Fb, Johansson, Å, Igl, W, Zaboli, G, Wild, Sh, Wright, Af, Campbell, H, Ellinghaus, D, Schreiber, S, Aulchenko, Y, Felix, Jf, Rivadeneira, F, Uitterlinden, Ag, Hofman, A, Imboden, M, Nitsch, D, Brandstätter, A, Kollerits, B, Kedenko, L, Mägi, R, Stumvoll, M, Kovacs, P, Boban, M, Campbell, S, Endlich, K, Völzke, H, Kroemer, Hk, Nauck, M, Völker, U, Polasek, O, Vitart, V, Badola, S, Parker, An, Ridker, Pm, Kardia, Sl, Blankenberg, S, Liu, Y, Curhan, Gc, Franke, A, Rochat, T, Paulweber, B, Wang, W, Gudnason, V, Coresh, J, Schmidt, R, Shlipak, Mg, van Duijn, Cm, Borecki, I, Krämer, Bk, Rudan, I, Gyllensten, U, Wilson, Jf, Witteman, Jc, Pramstaller, Pp, Rettig, R, Hastie, N, Chasman, Di, Kao, Wh, Heid, Im, Fox, C, Krumsiek, J, Hundertmark, C, Pistis, G, Ruggiero, D, O'Seaghdha, M, Haller, T, Kutalik, Z, Shi, J, Middelberg, P, Gaffo, Al, Pirastu, Nicola, Li, G, Huffman, J, Yengo, L, Zhao, Jh, Demirkan, A, Feitosa, Mf, Liu, X, Malerba, G, Lopez, Lm, Li, X, Kleber, Me, Hicks, Aa, Nolte, Im, Johansson, A, Murgia, F, Peden, Jf, Steri, M, Tenesa, A, Salo, P, Mangino, M, Rose, Lm, Lehtimäki, T, Woodward, Om, Tin, A, Müller, C, Oldmeadow, C, Putku, M, Czamara, D, Kraft, P, Frogheri, L, Thun, Ga, Grotevendt, A, Gislason, Gk, Mcardle, P, Schallert, M, Martin, Ng, Montgomery, Gw, Jacobs DR, Jr, Liu, K, D'Adamo, ADAMO PIO, Ulivi, S, Rotter, Ji, Navaro, P, Balkau, B, Froguel, P, Esko, T, Salumets, A, Khaw, Kt, Langenberg, C, Kraja, A, Zhang, Q, Scott, Rj, Holliday, Eg, Org, E, Viigimaa, M, Bandinelli, S, Metter, Je, Lupo, A, Trabetti, E, Sorice, R, Döring, A, Lattka, E, 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D.P., Wass, M.N., Ahmadi, K.R., Bakker, S.J., Beckmann, J., Bilo, H.J., Bochud, M., Brown, M.J., Caulfield, M.J., Connell, J.M., Cook, H.T., Cotlarciuc, I., Smith, G.D., de Silva, R., Deng, G., Devuyst, O., Dikkeschei, L.D., Dimkovic, N., Dockrell, M., Dominiczak, A., Ebrahim, S., Eggermann, T., Farrall, M., Ferrucci, L., Floege, J., Forouhi, N.G., Gansevoort, R.T., Han, X., Hedblad, B., van der Heide, J.J., Hepkema, B.G., Hernandez-Fuentes, M., Hypponen, E., Johnson, T., de Jong, P.E., Kleefstra, N., Lagou, V., Lapsley, M., Li, Y., Loos, R.J., Luan, J., Luttropp, K., Maréchal, C., Melander, O., Munroe, P.B., Nordfors, L., Parsa, A., Peltonen, L., Penninx, B.W., Perucha, E., Pouta, A., Prokopenko, I., Roderick, P.J., Ruokonen, A., Samani, N.J., Sanna, S., Schalling, M., Schlessinger, D., Schlieper, G., Seelen, M.A., Shuldiner, A.R., Sjögren, M., Smit, J.H., Snieder, H., Soranzo, N., Spector, T.D., Stenvinkel, P., Sternberg, M.J., Swaminathan, R., Tanaka, T., Ubink-Veltmaat, L.J., Uda, M., Vollenweider, P., Wallace, C., Waterworth, D., Zerres, K., Waeber, G., Wareham, N.J., Maxwell, P.H., McCarthy, M.I., Jarvelin, M.R., Mooser, V., Abecasis, G.R., Lightstone, L., Scott, J., Navis, G., Elliott, P., Kooner, J.S., Köttgen, A., Pattaro, C., Böger, C.A., Fuchsberger, C., Olden, M., Glazer, N.L., Gao, X., Yang, Q., Smith, A.V., O'Connell, J.R., Li, M., Schmidt, H., Isaacs, A., Ketkar, S., Hwang, S.J., Johnson, A.D., Dehghan, A., Teumer, A., Paré, G., Atkinson, E.J., Zeller, T., Lohman, K., Cornelis, M.C., Probst-Hensch, N.M., Kronenberg, F., Tönjes, A., Hayward, C., Aspelund, T., Eiriksdottir, G., Launer, L.J., Harris, T.B., Rampersaud, E., Mitchell, B.D., Arking, D.E., Boerwinkle, E., Struchalin, M., Cavalieri, M., Singleton, A., Giallauria, F., Metter, J., de Boer, I.H., Haritunians, T., Lumley, T., Siscovick, D., Psaty, B.M., Zillikens, M.C., Oostra, B.A., Feitosa, M., Province, M., de Andrade, M., Turner, S.T., Schillert, A., Ziegler, A., Wild, P.S., Schnabel, R.B., Wilde, S., Munzel, T.F., Leak, T.S., Illig, T., Klopp, N., Meisinger, C., Wichmann, H.E., Koenig, W., Zgaga, L., Zemunik, T., Kolcic, I., Minelli, C., Hu, F.B., Johansson, Å., Igl, W., Zaboli, G., Wild, S.H., Wright, A.F., Campbell, H., Ellinghaus, D., Schreiber, S., Aulchenko, Y.S., Felix, J.F., Rivadeneira, F., Uitterlinden, A.G., Hofman, A., Imboden, M., Nitsch, D., Brandstätter, A., Kollerits, B., Kedenko, L., Mägi, R., Stumvoll, M., Kovacs, P., Boban, M., Campbell, S., Endlich, K., Völzke, H., Kroemer, H.K., Nauck, M., Völker, U., Polasek, O., Vitart, V., Badola, S., Parker, A.N., Ridker, P.M., Kardia, S.L., Blankenberg, S., Liu, Y., Curhan, G.C., Franke, A., Rochat, T., Paulweber, B., Wang, W., Gudnason, V., Coresh, J., Schmidt, R., Shlipak, M.G., van Duijn, C.M., Borecki, I., Krämer, B.K., Rudan, I., Gyllensten, U., Wilson, J.F., Witteman, J.C., Pramstaller, P.P., Rettig, R., Hastie, N., Chasman, D.I., Kao, W.H., Heid, I.M., Fox, C.S., Albrecht, E., Krumsiek, J., Hundertmark, C., Pistis, G., Ruggiero, D., O'Seaghdha, M., Haller, T., Kutalik, Z., Shi, J., Middelberg, P.S., Gaffo, A.L., Pirastu, N., Li, G., Huffman, J., Yengo, L., Zhao, J.H., Demirkan, A., Feitosa, M.F., Liu, X., Malerba, G., Lopez, L.M., Li, X., Kleber, M.E., Hicks, A.A., Nolte, I.M., Johansson, A., Murgia, F., Peden, J.F., Steri, M., Tenesa, A., Salo, P., Mangino, M., Rose, L.M., Lehtimäki, T., Woodward, O.M., Okada, Y., Tin, A., Müller, C., Oldmeadow, C., Putku, M., Czamara, D., Kraft, P., Frogheri, L., Thun, G.A., Grotevendt, A., Gislason, G.K., McArdle, P., Schallert, M., Martin, N.G., Montgomery, G.W., Kubo, M., Nakamura, Y., Jacobs, D.R., Liu, K., D'Adamo, P., Ulivi, S., Rotter, J.I., Navaro, P., Balkau, B., Froguel, P., Esko, T., Salumets, A., Khaw, K.T., Langenberg, C., Kraja, A., Zhang, Q., Scott, R.J., Holliday, E.G., Org, E., Viigimaa, M., Bandinelli, S., Metter, J.E., Lupo, A., Trabetti, E., Sorice, R., Döring, A., Lattka, E., Strauch, K., Theis, F., Waldenberger, M., Davies, G., 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Jer-Yuarn, Gu, Dongfeng, Takeuchi, Fumihiko, Takahashi, Atsushi, Maeda, Shiro, Tsunoda, Tatsuhiko, Chen, Peng, Lim, Su-Chi, Wong, Tien-Yin, Liu, Jianjun, Young, Terri L., Aung, Tin, Seielstad, Mark, Teo, Yik-Ying, Kim, Young Jin, Lee, Jong-Young, Han, Bok-Ghee, Kang, Daehee, Chen, Chien-Hsiun, Tsai, Fuu-Jen, Chang, Li-Ching, Cathy Fann, S. -J. C., Mei, Hao, Rao, Dabeeru C., Hixson, James E., Chen, Shufeng, Katsuya, Tomohiro, Isono, Masato, Ogihara, Toshio, Chambers, John C., Zhang, Weihua, Kooner, Jaspal S., Albrecht, Eva, Yamamoto, Kazuhiko, Kubo, Michiaki, Nakamura, Yusuke, Kamatani, Naoyuki, Kato, Norihiro, He, Jiang, Chen, Yuan-Tsong, Cho, Yoon Shin, Tai, E-Shyong, Tanaka, Toshihiro, de Silva, R Deng G, Hernandez-Fuentes, M, Ubink-Veltmaat, Lj, Probst-Hensch, Nm, Giallauria, Francesco, Pirastu, N, D'Adamo, P, Gasparini, P, and Bouatia-Naji, N
- Subjects
Asian Continental Ancestry Group ,kidney ,Population ,Renal function ,Genome-wide association study ,Biology ,Kidney ,Polymorphism, Single Nucleotide ,Article ,Blood Urea Nitrogen ,Cohort Studies ,chemistry.chemical_compound ,SDG 3 - Good Health and Well-being ,Asian People ,loci ,Asian ,medicine ,Humans ,genetics ,Genetic Predisposition to Disease ,Renal Insufficiency, Chronic ,education ,meta-analysis ,Genome-Wide Association Study ,Genetic association ,Genetics ,Creatinine ,education.field_of_study ,ta3121 ,medicine.disease ,Uric Acid ,Asian Continental Ancestry Group/genetics ,Creatinine/blood ,Glomerular Filtration Rate/genetics ,Kidney/physiology ,Renal Insufficiency, Chronic/genetics ,Uric Acid/blood ,medicine.anatomical_structure ,chemistry ,Genetic epidemiology ,Cohort Studie ,Human ,Kidney disease ,Glomerular Filtration Rate - Abstract
Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genomewide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 x 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of similar to 110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.
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- 2012
11. Harmonization of Neuroticism and Extraversion phenotypes across inventories and cohorts in the Genetics of Personality Consortium: an application of Item Response Theory
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van den Berg, SM, de Moor, MHM, McGue, M, Pettersson, E, Terracciano, A, Verweij, KJH, Amin, Najaf, Derringer, J, Esko, T, Van Grootheest, G, Hansell, NK, Huffman, J, Konte, B, Lahti, J, Luciano, M, Matteson, LK, Viktorin, A, Wouda, J, Agrawal, A, Allik, J, Bierut, L, Broms, U, Campbell, H, Smith, GD, Eriksson, JG, Ferrucci, L, Franke, B, Fox, JP, de Geus, EJC, Giegling, I, Gow, AJ, Grucza, R, Hartmann, AM, Heath, AC, Heikkila, K, Iacono, W, Janzing, J, Jokela, M, Kiemeney, L, Lehtimaki, T, Madden, PAF, Magnusson, PKE, Northstone, K, Nutile, T, Ouwens, KG, Palotie, A, Pattie, A, Pesonen, AK, Polasek, O, Pulkkinen, L, Pulkki-Raback, L, Raitakari, OT, Realo, A, Rose, RJ, Ruggiero, D, Seppala, I, Slutske, WS, Smyth, DC, Sorice, R, Starr, JM, Sutin, AR, Tanaka, T, Verhagen, J, Vermeulen, Shanna, Vuoksimaa, E, Widen, E, Willemsen, G, Wright, M, Zgaga, L, Rujescu, D, Metspalu, A, Wilson, JF, Ciullo, M, Hayward, C, Rudan, I, Deary, IJ, Raikkonen, K, Vasquez, AA, Costa, PT, Keltikangas-Jarvinen, L, Duijn, Cornelia, Penninx, BWJH, Krueger, RF, Evans, DM, Kaprio, J, Pedersen, NL, Martin, NG, Boomsma, DI, van den Berg, SM, de Moor, MHM, McGue, M, Pettersson, E, Terracciano, A, Verweij, KJH, Amin, Najaf, Derringer, J, Esko, T, Van Grootheest, G, Hansell, NK, Huffman, J, Konte, B, Lahti, J, Luciano, M, Matteson, LK, Viktorin, A, Wouda, J, Agrawal, A, Allik, J, Bierut, L, Broms, U, Campbell, H, Smith, GD, Eriksson, JG, Ferrucci, L, Franke, B, Fox, JP, de Geus, EJC, Giegling, I, Gow, AJ, Grucza, R, Hartmann, AM, Heath, AC, Heikkila, K, Iacono, W, Janzing, J, Jokela, M, Kiemeney, L, Lehtimaki, T, Madden, PAF, Magnusson, PKE, Northstone, K, Nutile, T, Ouwens, KG, Palotie, A, Pattie, A, Pesonen, AK, Polasek, O, Pulkkinen, L, Pulkki-Raback, L, Raitakari, OT, Realo, A, Rose, RJ, Ruggiero, D, Seppala, I, Slutske, WS, Smyth, DC, Sorice, R, Starr, JM, Sutin, AR, Tanaka, T, Verhagen, J, Vermeulen, Shanna, Vuoksimaa, E, Widen, E, Willemsen, G, Wright, M, Zgaga, L, Rujescu, D, Metspalu, A, Wilson, JF, Ciullo, M, Hayward, C, Rudan, I, Deary, IJ, Raikkonen, K, Vasquez, AA, Costa, PT, Keltikangas-Jarvinen, L, Duijn, Cornelia, Penninx, BWJH, Krueger, RF, Evans, DM, Kaprio, J, Pedersen, NL, Martin, NG, and Boomsma, DI
- Abstract
Mega- or meta-analytic studies (e.g. genome-wide association studies) are increasingly used in behavior genetics. An issue in such studies is that phenotypes are often measured by different instruments across study cohorts, requiring harmonization of measures so that more powerful fixed effect meta-analyses can be employed. Within the Genetics of Personality Consortium, we demonstrate for two clinically relevant personality traits, Neuroticism and Extraversion, how Item-Response Theory (IRT) can be applied to map item data from different inventories to the same underlying constructs. Personality item data were analyzed in > 160,000 individuals from 23 cohorts across Europe, USA and Australia in which Neuroticism and Extraversion were assessed by nine different personality inventories. Results showed that harmonization was very successful for most personality inventories and moderately successful for some. Neuroticism and Extraversion inventories were largely measurement invariant across cohorts, in particular when comparing cohorts from countries where the same language is spoken. The IRT-based scores for Neuroticism and Extraversion were heritable (48 and 49 %, respectively, based on a meta-analysis of six twin cohorts, total N = 29,496 and 29,501 twin pairs, respectively) with a significant part of the heritability due to non-additive genetic factors. For Extraversion, these genetic factors qualitatively differ across sexes. We showed that our IRT method can lead to a large increase in sample size and therefore statistical power. The IRT approach may be applied to any mega- or meta-analytic study in which item-based behavioral measures need to be harmonized.
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- 2014
12. Childhood socioeconomic position and objectively measured physical capability levels in adulthood: A systematic review and meta-analysis
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Birnie, K, Cooper, R, Martin, RM, Kuh, D, Sayer, AA, Alvarado, BE, Bayer, A, Christensen, K, Cho, S, Cooper, C, Corley, J, Craig, L, Deary, IJ, Demakakos, P, Ebrahim, S, Gallacher, J, Gow, AJ, Gunnell, D, Haas, S, Hemmingsson, T, Inskip, H, Jang, S, Noronha, K, Osler, M, Palloni, A, Rasmussen, F, Santos-Eggimann, B, Spagnoli, J, Starr, J, Steptoe, A, Syddall, H, Tynelius, P, Weir, D, Whalley, LJ, Zunzunegui, MV, Ben-Shlomo, Y, Hardy, R, Birnie, K, Cooper, R, Martin, RM, Kuh, D, Sayer, AA, Alvarado, BE, Bayer, A, Christensen, K, Cho, S, Cooper, C, Corley, J, Craig, L, Deary, IJ, Demakakos, P, Ebrahim, S, Gallacher, J, Gow, AJ, Gunnell, D, Haas, S, Hemmingsson, T, Inskip, H, Jang, S, Noronha, K, Osler, M, Palloni, A, Rasmussen, F, Santos-Eggimann, B, Spagnoli, J, Starr, J, Steptoe, A, Syddall, H, Tynelius, P, Weir, D, Whalley, LJ, Zunzunegui, MV, Ben-Shlomo, Y, and Hardy, R
- Abstract
Background Grip strength, walking speed, chair rising and standing balance time are objective measures of physical capability that characterise current health and predict survival in older populations. Socioeconomic position (SEP) in childhood may influence the peak level of physical capability achieved in early adulthood, thereby affecting levels in later adulthood. We have undertaken a systematic review with meta-analyses to test the hypothesis that adverse childhood SEP is associated with lower levels of objectively measured physical capability in adulthood. Methods and Findings Relevant studies published by May 2010 were identified through literature searches using EMBASE and MEDLINE. Unpublished results were obtained from study investigators. Results were provided by all study investigators in a standard format and pooled using random-effects meta-analyses. 19 studies were included in the review. Total sample sizes in meta-analyses ranged from N = 17,215 for chair rise time to N = 1,061,855 for grip strength. Although heterogeneity was detected, there was consistent evidence in age adjusted models that lower childhood SEP was associated with modest reductions in physical capability levels in adulthood: comparing the lowest with the highest childhood SEP there was a reduction in grip strength of 0.13 standard deviations (95% CI: 0.06, 0.21), a reduction in mean walking speed of 0.07 m/s (0.05, 0.10), an increase in mean chair rise time of 6% (4%, 8%) and an odds ratio of an inability to balance for 5s of 1.26 (1.02, 1.55). Adjustment for the potential mediating factors, adult SEP and body size attenuated associations greatly. However, despite this attenuation, for walking speed and chair rise time, there was still evidence of moderate associations. Conclusions Policies targeting socioeconomic inequalities in childhood may have additional benefits in promoting the maintenance of independence in later life.
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- 2011
13. Genome-wide association studies establish that human intelligence is highly heritable and polygenic
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Davies, G, Tenesa, A, Payton, A, Yang, J, Harris, SE, Liewald, D, Ke, X, Le Hellard, S, Christoforou, A, Luciano, M, McGhee, K, Lopez, L, Gow, AJ, Corley, J, Redmond, P, Fox, HC, Haggarty, P, Whalley, LJ, McNeill, G, Goddard, ME, Espeseth, T, Lundervold, AJ, Reinvang, I, Pickles, A, Steen, VM, Ollier, W, Porteous, DJ, Horan, M, Starr, JM, Pendleton, N, Visscher, PM, Deary, IJ, Davies, G, Tenesa, A, Payton, A, Yang, J, Harris, SE, Liewald, D, Ke, X, Le Hellard, S, Christoforou, A, Luciano, M, McGhee, K, Lopez, L, Gow, AJ, Corley, J, Redmond, P, Fox, HC, Haggarty, P, Whalley, LJ, McNeill, G, Goddard, ME, Espeseth, T, Lundervold, AJ, Reinvang, I, Pickles, A, Steen, VM, Ollier, W, Porteous, DJ, Horan, M, Starr, JM, Pendleton, N, Visscher, PM, and Deary, IJ
- Abstract
General intelligence is an important human quantitative trait that accounts for much of the variation in diverse cognitive abilities. Individual differences in intelligence are strongly associated with many important life outcomes, including educational and occupational attainments, income, health and lifespan. Data from twin and family studies are consistent with a high heritability of intelligence, but this inference has been controversial. We conducted a genome-wide analysis of 3511 unrelated adults with data on 549,692 single nucleotide polymorphisms (SNPs) and detailed phenotypes on cognitive traits. We estimate that 40% of the variation in crystallized-type intelligence and 51% of the variation in fluid-type intelligence between individuals is accounted for by linkage disequilibrium between genotyped common SNP markers and unknown causal variants. These estimates provide lower bounds for the narrow-sense heritability of the traits. We partitioned genetic variation on individual chromosomes and found that, on average, longer chromosomes explain more variation. Finally, using just SNP data we predicted ∼1% of the variance of crystallized and fluid cognitive phenotypes in an independent sample (P=0.009 and 0.028, respectively). Our results unequivocally confirm that a substantial proportion of individual differences in human intelligence is due to genetic variation, and are consistent with many genes of small effects underlying the additive genetic influences on intelligence.
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- 2011
14. Prospective evaluation of macular and parapapillary morphology and their association with cognition in childhood and old age
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LAUDE, A, primary, HENDERSON, RD, additional, GOW, AJ, additional, DHILLON, B, additional, STARR, JM, additional, and DEARY, IJ, additional
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- 2009
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15. Segmental Antigen Challenge Produces Alterations in Surfactant Protein D Expression and Multimeric Structure in Humans.
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Atochina-Vasserman, EN, primary, Winkler, C, additional, Abramova, H, additional, Beers, MF, additional, Schaumann, F, additional, Krug, N, additional, Gow, AJ, additional, and Hohlfeld, JM, additional
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- 2009
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16. Silica Exposure Alters Mouse Lung Mechanics through Inflammation and Type II Cell Hyperplasia.
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Joseph, LB, primary, Cervelli, J, additional, Elzind, DA, additional, Zeidler-Erdely, P, additional, Gow, AJ, additional, Laskin, JD, additional, Castranova, V, additional, and Laskin, D, additional
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- 2009
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17. Neuroprotective lifestyles and the aging brain: activity, atrophy, and white matter integrity.
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Gow AJ, Bastin ME, Muñoz Maniega S, Valdés Hernández MC, Morris Z, Murray C, Royle NA, Starr JM, Deary IJ, Wardlaw JM, Gow, Alan J, Bastin, Mark E, Muñoz Maniega, Susana, Valdés Hernández, Maria C, Morris, Zoe, Murray, Catherine, Royle, Natalie A, Starr, John M, Deary, Ian J, and Wardlaw, Joanna M
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- 2012
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18. Predicting mortality from human faces.
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Dykiert D, Bates TC, Gow AJ, Penke L, Starr JM, Deary IJ, Dykiert, Dominika, Bates, Timothy C, Gow, Alan J, Penke, Lars, Starr, John M, and Deary, Ian J
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- 2012
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19. Segmental allergen challenge alters multimeric structure and function of surfactant protein D in humans.
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Atochina-Vasserman EN, Winkler C, Abramova H, Schaumann F, Krug N, Gow AJ, Beers MF, Hohlfeld JM, Atochina-Vasserman, Elena N, Winkler, Carla, Abramova, Helen, Schaumann, Frank, Krug, Norbert, Gow, Andrew J, Beers, Michael F, and Hohlfeld, Jens M
- Abstract
Rationale: Surfactant protein D (SP-D), a 43-kD collectin, is synthesized and secreted by airway epithelia as a dodecamer formed by assembly of four trimeric subunits. We have previously shown that the quaternary structure of SP-D can be altered during inflammatory lung injury through its modification by S-nitrosylation, which in turn alters its functional behavior producing a proinflammatory response in effector cells.Objectives: We hypothesized that alterations in structure and function of SP-D may occur in humans with acute allergic inflammation.Methods: Bronchoalveolar lavage (BAL) fluid was collected from 15 nonsmoking patients with mild intermittent allergic asthma before and 24 hours after segmental provocation with saline, allergen, LPS, and mixtures of allergen and LPS. Structural modifications of SP-D were analyzed by native and sodium dodecyl sulfate gel electrophoresis.Measurements and Main Results: The multimeric structure of native SP-D was found to be disrupted after provocation with allergen or a mixture of allergen and LPS. Interestingly, under reducing conditions, sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated that 7 of 15 patients with asthma developed an abnormal cross-linked SP-D band after segmental challenge with either allergen or a mixture of allergen with LPS but not LPS alone. Importantly, patients with asthma with cross-linked SP-D demonstrated significantly higher levels of BAL eosinophils, nitrogen oxides, IL-4, IL-5, IL-13, and S-nitrosothiol-SP-D compared with patients without cross-linked SP-D.Conclusions: We conclude that segmental allergen challenge results in changes of SP-D multimeric structure and that these modifications are associated with an altered local inflammatory response in the distal airways. [ABSTRACT FROM AUTHOR]- Published
- 2011
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20. Caffeine consumption and cognitive function at age 70: the Lothian Birth Cohort 1936 study.
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Corley J, Jia X, Kyle JA, Gow AJ, Brett CE, Starr JM, McNeill G, Deary IJ, Corley, Janie, Jia, Xueli, Kyle, Janet A M, Gow, Alan J, Brett, Caroline E, Starr, John M, McNeill, Geraldine, and Deary, Ian J
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- 2010
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21. Reverse causation in the association between C-reactive protein and fibrinogen levels and cognitive abilities in an aging sample.
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Luciano M, Marioni RE, Gow AJ, Starr JM, Deary IJ, Luciano, Michelle, Marioni, Riccardo E, Gow, Alan J, Starr, John M, and Deary, Ian J
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- 2009
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22. Differences in the haematological profile of healthy 70 year old men and women: normal ranges with confirmatory factor analysis.
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McIlhagger R, Gow AJ, Brett CE, Corley J, Taylor M, Deary IJ, and Starr JM
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- 2010
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23. Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets from Blood and the Kidney
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Peter Vollenweider, Christophe Tzourio, Stefan Enroth, Cinzia Sala, Mark J. Caulfield, Murielle Bochud, Peter P. Pramstaller, Ozren Polasek, Paul Elliott, Dennis O. Mook-Kanamori, Daniel I. Chasman, Christian Gieger, Harriëtte Riese, Rodney J. Scott, Cristina Menni, Anubha Mahajan, Elizabeth G. Holliday, Ilja M. Nolte, Priyanka Nandakumar, Tatijana Zemunik, Dragana Vuckovic, Tõnu Esko, Franco Giulianini, Michael Boehnke, Antonietta Robino, Anne U. Jackson, Roby Joehanes, Alanna C. Morrison, Kay-Tee Khaw, Alison Pattie, Peter J. van der Most, Mika Kähönen, Rick Jansen, Andrew D. Johnson, John M. Starr, Marcus Dörr, Anders Hamsten, Kenneth Rice, Alice Stanton, James F. Wilson, Nabi Shah, Weihua Zhang, Andrew A. Hicks, Jeffrey Damman, Jing Hua Zhao, Aarno Palotie, Veronique Vitart, Alan J. Gow, Caroline Hayward, Alan James, Ben A. Oostra, Janina S. Ried, John Beilby, David P. Strachan, Martin D. Tobin, Eco J. C. de Geus, Vilmundur Gudnason, Bruce M. Psaty, Zoltán Kutalik, Neil Poulter, Paul M. Ridker, Johan Sundström, Cornelia M. van Duijn, Eleftheria Zeggini, Christopher Oldmeadow, Borbala Mifsud, Giorgia Girotto, Aravinda Chakravarti, Jonathan Marten, Alexander Teumer, Joanne Knight, Robert A. Scott, Vilmantas Giedraitis, Paul F. O'Reilly, Marco Brumat, Brenda W.J.H. Penninx, Peter J. Munson, Olli T. Raitakari, Leo-Pekka Lyytikäinen, He Gao, Massimo Mangino, Benjamin Lehne, J. Wouter Jukema, Paul Knekt, Catharina A. Hartman, Rona J. Strawbridge, Jouke-Jan Hottenga, Jaspal S. Kooner, Nilesh J. Samani, Kristin L. Ayers, A. Mesut Erzurumluoglu, Joshua C. Bis, Archie Campbell, Dan E. Arking, Germaine C. Verwoert, John Attia, Samuli Ripatti, Yuri Milaneschi, Caterina Barbieri, Fabiola M. Del Greco, C M Lindgren, Peter K. Joshi, Helen R. Warren, Nicholas J. Wareham, Simon Thom, Seppo Koskinen, Tamara B. Harris, Ilaria Gandin, Kent D. Taylor, Andrew D. Morris, Anna Morgan, Chiara Batini, Terho Lehtimäki, Walter Palmas, David Conen, Harold Snieder, Martin H. de Borst, Sarah E. Harris, Igor Rudan, Ruth J. F. Loos, Claudia Langenberg, Anuj Goel, Christopher P. Nelson, Peter S. Braund, Rossella Sorice, Yasaman Saba, Oscar H. Franco, Yongmei Liu, Mattias Frånberg, David S. Siscovick, Patricia B. Munroe, Rainer Rettig, Michela Traglia, Daniel Levy, Li Lin, Michael R. Barnes, Elin Org, Anne-Claire Vergnaud, Andres Metspalu, Stéphanie Debette, Yusuf Demirkale, John M. C. Connell, Jian'an Luan, Paolo Gasparini, Tim D. Spector, Marina Ciullo, Antti-Pekka Sarin, Ian J. Deary, Teemu J. Niiranen, Marty Larson, Heather J. Cordell, Jerome I. Rotter, Sekar Kathiresan, Teresa Nutile, Andrew P. Morris, Denis C. Shields, Alan F. Wright, Lorna M. Lopez, Aki S. Havulinna, Gonçalo R. Abecasis, Edith Hofer, Siim Sõber, Sébastien Thériault, Ahmad Vaez, Albert Hofman, Gonneke Willemsen, Lynda M. Rose, John C. Chambers, Peter S. Sever, Maryam Abedi, André G. Uitterlinden, François Mach, Massimiliano Cocca, Sarah H Wild, Reinhold Schmidt, Jaume Marrugat, Marc A. Seelen, Maris Laan, Aude Saint Pierre, David C. Liewald, Pim van der Harst, Sandosh Padmanabhan, Martin Farrall, Georg Ehret, Albert V. Smith, Quang Tri Nguyen, Ulf Gyllensten, Helena Schmidt, Ganesh Chauhan, Jennifer E. Huffman, Morris A. Swertz, Jaakko Tuomilehto, Louise V. Wain, Meixia Ren, Erwin P. Bottinger, Roberto Elosua, Ivana Kolcic, Veikko Salomaa, Stella Trompet, Bernard Keavney, Claudia P. Cabrera, Bram P. Prins, Jennie Hui, Uwe Völker, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Dorret I. Boomsma, Harry Campbell, Shih-Jen Hwang, Jie Yao, Francis S. Collins, Chrysovalanto Mamasoula, Kati Kristiansson, Markus Perola, Renée de Mutsert, Xiuqing Guo, Antti Jula, Daniela Toniolo, Ruifang Li-Gao, Åsa Johansson, Nick Shrine, Teresa Ferreira, Lars Lind, David J. Stott, Tineka Blake, Daniela Ruggiero, Mike A. Nalls, Erik Ingelsson, Colin N. A. Palmer, Christopher Newton-Cheh, Marjo-Riitta Järvelin, Guillaume Paré, Joris Deelen, Morris Brown, Gail Davies, Annette Peters, Ioanna Tzoulaki, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Hugh Watkins, Yingchang Lu, Wain, Lv, Vaez, A, Jansen, R, Joehanes, R, van der Most, Pj, Erzurumluoglu, Am, O'Reilly, Pf, Cabrera, Cp, Warren, Hr, Rose, Lm, Verwoert, Gc, Hottenga, Jj, Strawbridge, Rj, Esko, T, Arking, De, Hwang, Sj, Guo, X, Kutalik, Z, Trompet, S, Shrine, N, Teumer, A, Ried, J, Bis, Jc, Smith, Av, Amin, N, Nolte, Im, Lyytikäinen, Lp, Mahajan, A, Wareham, Nj, Hofer, E, Joshi, Pk, Kristiansson, K, Traglia, M, Havulinna, A, Goel, A, Nalls, Ma, Sõber, S, Vuckovic, Dragana, Luan, J, Del Greco, M. F, Ayers, Kl, Marrugat, J, Ruggiero, D, Lopez, Lm, Niiranen, T, Enroth, S, Jackson, Au, Nelson, Cp, Huffman, Je, Zhang, W, Marten, J, Gandin, I, Harris, Se, Zemunik, T, Lu, Y, Evangelou, E, Shah, N, de Borst, Mh, Mangino, M, Prins, Bp, Campbell, A, Li Gao, R, Chauhan, G, Oldmeadow, C, Abecasis, G, Abedi, M, Barbieri, Cm, Barnes, Mr, Batini, C, Beilby, J, Blake, T, Boehnke, M, Bottinger, Ep, Braund, P, Brown, M, Brumat, M, Campbell, H, Chambers, Jc, Cocca, M, Collins, F, Connell, J, Cordell, Hj, Damman, Jj, Davies, G, de Geus, Ej, de Mutsert, R, Deelen, J, Demirkale, Y, Doney, Asf, Dörr, M, Farrall, M, Ferreira, T, Frånberg, M, Gao, H, Giedraitis, V, Gieger, C, Giulianini, F, Gow, Aj, Hamsten, A, Harris, Tb, Hofman, A, Holliday, Eg, Hui, J, Jarvelin, Mr, Johansson, Å, Johnson, Ad, Jousilahti, P, Jula, A, Kähönen, M, Kathiresan, S, Khaw, Kt, Kolcic, I, Koskinen, S, Langenberg, C, Larson, M, Launer, Lj, Lehne, B, Liewald, Dcm, Lin, L, Lind, L, Mach, F, Mamasoula, C, Menni, C, Mifsud, B, Milaneschi, Y, Morgan, Anna, Morris, Ad, Morrison, Ac, Munson, Pj, Nandakumar, P, Nguyen, Qt, Nutile, T, Oldehinkel, Aj, Oostra, Ba, Org, E, Padmanabhan, S, Palotie, A, Paré, G, Pattie, A, Penninx, Bwjh, Poulter, N, Pramstaller, Pp, Raitakari, Ot, Ren, M, Rice, K, Ridker, Pm, Riese, H, Ripatti, S, Robino, A, Rotter, Ji, Rudan, I, Saba, Y, Saint Pierre, A, Sala, Cf, Sarin, Ap, Schmidt, R, Scott, R, Seelen, Ma, Shields, Dc, Siscovick, D, Sorice, R, Stanton, A, Stott, Dj, Sundström, J, Swertz, M, Taylor, Kd, Thom, S, Tzoulaki, I, Tzourio, C, Uitterlinden, Ag, Völker, U, Vollenweider, P, Wild, S, Willemsen, G, Wright, Af, Yao, J, Thériault, S, Conen, D, Attia, J, Sever, P, Debette, S, Mook Kanamori, Do, Zeggini, E, Spector, Td, van der Harst, P, Palmer, Cna, Vergnaud, Ac, Loos, Rjf, Polasek, O, Starr, Jm, Girotto, Giorgia, Hayward, C, Kooner, J, Lindgren, Cm, Vitart, V, Samani, Nj, Tuomilehto, J, Gyllensten, U, Knekt, P, Deary, Ij, Ciullo, M, Elosua, R, Keavney, Bd, Hicks, Aa, Scott, Ra, Gasparini, Paolo, Laan, M, Liu, Y, Watkins, H, Hartman, Ca, Salomaa, V, Toniolo, D, Perola, M, Wilson, Jf, Schmidt, H, Zhao, Jh, Lehtimäki, T, van Duijn, Cm, Gudnason, V, Psaty, Bm, Peters, A, Rettig, R, James, A, Jukema, Jw, Strachan, Dp, Palmas, W, Metspalu, A, Ingelsson, E, Boomsma, Di, Franco, Oh, Bochud, M, Newton Cheh, C, Munroe, Pb, Elliott, P, Chasman, Di, Chakravarti, A, Knight, J, Morris, Ap, Levy, D, Tobin, Md, Snieder, H, Caulfield, Mj, Ehret, G. b., Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Vascular Ageing Programme (VAP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Institute for Organ Transplantation (GIOT), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Epidemiology, Gastroenterology & Hepatology, Clinical Genetics, Internal Medicine, Erasmus MC other, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Epidemiology and Data Science, Division 6, APH - Mental Health, APH - Digital Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Methodology
- Subjects
0301 basic medicine ,cardiovascular risk ,Netherlands Twin Register (NTR) ,hypertension ,NETHERLANDS ,Sistema cardiovascular -- Malalties ,GWAS ,blood pressure ,complex traits ,eSNP ,Locus (genetics) ,Genome-wide association study ,Disease ,Biology ,PERIPHERAL-BLOOD ,1102 Cardiovascular Medicine And Haematology ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Genetic variation ,Internal Medicine ,Journal Article ,Cardiac and Cardiovascular Systems ,1000 Genomes Project ,Gene ,CENTRIC ARRAY ,METAANALYSIS ,Genetics ,ddc:616 ,Kardiologi ,PULSE PRESSURE ,COMMON VARIANTS ,1103 Clinical Sciences ,ta3121 ,3. Good health ,INDIVIDUALS ,030104 developmental biology ,Blood pressure ,TARGET ,Cardiovascular System & Hematology ,complex trait ,GWAS, blood pressure, cardiovascular risk, complex traits, eSNP, hypertension ,Hipertensió ,Imputation (genetics) ,TRAITS - Abstract
Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project–based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7 , TNXB , LRP12 , LOC283335 , SEPT9 , and AKT2 , and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA . Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
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- 2017
24. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations
- Author
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Jacqueline C.M. Witteman, Nicole Probst-Hensch, Gail Davies, Anna Köttgen, Qunyuan Zhang, Pio D'Adamo, Nicholas G. Martin, Silvia Tore, Stephan J. L. Bakker, Gian Andri Thun, Cinzia Sala, Peter P. Pramstaller, Tamara B. Harris, Aaron Isaacs, Sheila Ulivi, Rossella Sorice, Xuan Liu, Andrew A. Hicks, Henry Völzke, Daniela Ruggiero, Arnold von Eckardstein, Yukinori Okada, Andres Metspalu, Jeffrey Metter, Serena Sanna, Jennifer E. Huffman, Philipp S. Wild, Florian Ernst, Eva Albrecht, Mary F. Feitosa, Claudia Schurmann, Kathrin Budde, Veikko Salomaa, Darina Czamara, Elizabeth G. Holliday, Marcel Bruinenberg, Laura Portas, Maris Laan, Alan J. Gow, Caroline Hayward, Tim D. Spector, Ozren Polasek, Ilja M. Nolte, Rodney J. Scott, Massimo Mangino, David S. Siscovick, Nilesh J. Samani, Toomas Haller, Laura Frogheri, A. Jula, Mika Kähönen, Bruce H. R. Wolffenbuttel, Caroline S. Fox, David R. Jacobs, Julia Shi, Yusuke Nakamura, Daniel I. Chasman, Fabian J. Theis, Alan F. Wright, Ayse Demirkan, Francesco Cucca, Paolo Gasparini, Paul M. Ridker, Olli T. Raitakari, Daniela Toniolo, Maristella Steri, Mario Pirastu, Susan Campbell, Maksim Struchalin, So-Youn Shin, Mark J. Caulfield, H.-Erich Wichmann, Grant W. Montgomery, Åsa Johansson, Alexander Teumer, Ulf Gyllensten, Robert M. Plenge, Michel Burnier, Michael Schallert, Jan Krumsiek, Jing Hua Zhao, Andres Salumets, Poorva Mudgal, Anke Tönjes, James F. Meschia, Gauti Kjartan Gislason, Perttu Salo, Angela Döring, Afshin Parsa, Vilmundur Gudnason, Patrick F. McArdle, Rita P. S. Middelberg, W. H. Linda Kao, Aldi Kraja, Christopher Oldmeadow, Adrienne Tin, Loic Yengo, Murielle Bochud, Gerjan Navis, Christian Gieger, Toshiko Tanaka, Cornelia M. van Duijn, Samuli Ripatti, Terho Lehtimäki, Claudia Langenberg, Bernhard O. Boehm, Conall M. O'Seaghdha, Eric Boerwinkle, Nicole Soranzo, Tõnu Esko, Susan M. Farrington, Mike A. Nalls, John F. Peden, Hyon K. Choi, Anuj Goel, Andrew D. Johnson, Norman Klopp, Anne Grotevendt, Halit Ongen, Marcus E. Kleber, Myriam Fornage, Malcolm G. Dunlop, Igor Rudan, Federico Murgia, Beverley Balkau, Jorma Viikari, Christopher P. Nelson, Gérard Waeber, Lenore J. Launer, Ivana Persico, Inga Prokopenko, Guo Li, Tatijana Zemunik, Elisabetta Trabetti, Tanja Zeller, Hugh Watkins, Qiong Yang, James F. Wilson, Peter Vollenweider, Veronique Vitart, Markus Perola, Nicola Pirastu, Olivier Devuyst, Irene Mateo Leach, John Attia, Bruce M. Psaty, Nicholas J. Wareham, Susanne Lucae, Josef Coresh, Ingrid B. Borecki, Claudia Hundertmark, Weihua Zhang, Luigi Ferrucci, Jaspal S. Kooner, Stefan Kloiber, Lynda M. Rose, Naoyuki Kamatani, Zoltán Kutalik, Giovanni Malerba, Ian J. Deary, Albert V. Smith, Helena Schmidt, Eva Lattka, Philippe Froguel, Harry Campbell, Medea Imboden, Antonio Lupo, Angelo L. Gaffo, Vasiliki Lagou, Alan R. Shuldiner, John Whitfield, Abbas Dehghan, Winfried März, Elin Org, Albert Hofman, Margus Viigimaa, Konstantin Strauch, Toshihiro Tanaka, Andrew B. Singleton, Stefania Bandinelli, Christian Hengstenberg, Xinzhong Li, Wiek H. van Gilst, Pim van der Harst, Giorgio Pistis, Jerome I. Rotter, Maria Grazia Piras, Gary C. Curhan, Brenda W.J.H. Penninx, Ramaiah Nagaraja, Nabila Bouatia-Naji, Christian Müller, Ronald P. Stolk, Pau Navarro, Lorna M. Lopez, Ruth J. F. Loos, Albert Tenesa, Johannes H. Smit, Peter Kraft, Giovanni Gambaro, Sarah H. Wild, Patricia B. Munroe, André G. Uitterlinden, Ivana Kolcic, Bernhard R. Winkelmann, Pankaj Sharma, John C. Chambers, Nicholas D. Hastie, Matthias Nauck, Harold Snieder, Michael Stumvoll, Reinhold Schmidt, Hans L. Hillege, Kiang Liu, Fernando Rivadeneira, Owen M. Woodward, Morris J. Brown, Margus Putku, Sabine Schipf, Mirna Kirin, Kay-Tee Khaw, Melanie Waldenberger, Evropi Theodoratou, Marina Ciullo, Michiaki Kubo, Köttgen, A, Albrecht, E, Teumer, A, Vitart, V, Krumsiek, J, Hundertmark, C, Pistis, G, Ruggiero, D, O'Seaghdha, Cm, Haller, T, Yang, Q, Tanaka, T, Johnson, Ad, Kutalik, Z, Smith, Av, Shi, J, Struchalin, M, Middelberg, Rp, Brown, Mj, Gaffo, Al, Pirastu, Nicola, Li, G, Hayward, C, Zemunik, T, Huffman, J, Yengo, L, Zhao, Jh, Demirkan, A, Feitosa, Mf, Liu, X, Malerba, G, Lopez, Lm, van der Harst, P, Li, X, Kleber, Me, Hicks, Aa, Nolte, Im, Johansson, A, Murgia, F, Wild, Sh, Bakker, Sj, Peden, Jf, Dehghan, A, Steri, M, Tenesa, A, Lagou, V, Salo, P, Mangino, M, Rose, Lm, Lehtimäki, T, Woodward, Om, Okada, Y, Tin, A, Müller, C, Oldmeadow, C, Putku, M, Czamara, D, Kraft, P, Frogheri, L, Thun, Ga, Grotevendt, A, Gislason, Gk, Harris, Tb, Launer, Lj, Mcardle, P, Shuldiner, Ar, Boerwinkle, E, Coresh, J, Schmidt, H, Schallert, M, Martin, Ng, Montgomery, Gw, Kubo, M, Nakamura, Y, Munroe, Pb, Samani, Nj, Jacobs DR, Jr, Liu, K, D'Adamo, ADAMO PIO, Ulivi, S, Rotter, Ji, Psaty, Bm, Vollenweider, P, Waeber, G, Campbell, S, Devuyst, O, Navarro, P, Kolcic, I, Hastie, N, Balkau, B, Froguel, P, Esko, T, Salumets, A, Khaw, Kt, Langenberg, C, Wareham, Nj, Isaacs, A, Kraja, A, Zhang, Q, Wild, P, Scott, Rj, Holliday, Eg, Org, E, Viigimaa, M, Bandinelli, S, Metter, Je, Lupo, A, Trabetti, E, Sorice, R, Döring, A, Lattka, E, Strauch, K, Theis, F, Waldenberger, M, Wichmann, He, Davies, G, Gow, Aj, Bruinenberg, M, Stolk, Rp, Kooner, J, Zhang, W, Winkelmann, Br, Boehm, Bo, Lucae, S, Penninx, Bw, Smit, Jh, Curhan, G, Mudgal, P, Plenge, Rm, Portas, L, Persico, I, Kirin, M, Wilson, Jf, Leach, Im, van Gilst, Wh, Goel, A, Ongen, H, Hofman, A, Rivadeneira, F, Uitterlinden, Ag, Imboden, M, von Eckardstein, A, Cucca, F, Nagaraja, R, Piras, Mg, Nauck, M, Schurmann, C, Budde, K, Ernst, F, Farrington, Sm, Theodoratou, E, Prokopenko, I, Stumvoll, M, Jula, A, Perola, M, Salomaa, V, Shin, Sy, Spector, Td, Sala, C, Ridker, Pm, Kähönen, M, Viikari, J, Hengstenberg, C, Nelson, Cp, Meschia, Jf, Nalls, Ma, Sharma, P, Singleton, Ab, Kamatani, N, Zeller, T, Burnier, M, Attia, J, Laan, M, Klopp, N, Hillege, Hl, Kloiber, S, Choi, H, Pirastu, M, Tore, S, Probst Hensch, Nm, Völzke, H, Gudnason, V, Parsa, A, Schmidt, R, Whitfield, Jb, Fornage, M, Gasparini, Paolo, Siscovick, D, Polašek, O, Campbell, H, Rudan, I, Bouatia Naji, N, Metspalu, A, Loos, Rj, van Duijn, Cm, Borecki, Ib, Ferrucci, L, Gambaro, G, Deary, Ij, Wolffenbuttel, Bh, Chambers, Jc, März, W, Pramstaller, Pp, Snieder, H, Gyllensten, U, Wright, Af, Navis, G, Watkins, H, Witteman, Jc, Sanna, S, Schipf, S, Dunlop, Mg, Tönjes, A, Ripatti, S, Soranzo, N, Toniolo, D, Chasman, Di, Raitakari, O, Kao, Wh, Ciullo, M, Fox, C, Caulfield, M, Bochud, M, Gieger, C, LifeLines Cohort, Study, Cardiogram, Consortium, Diagram, Consortium, Icbp, Consortium, Magic, Consortium, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Center for Liver, Digestive and Metabolic Diseases (CLDM), Psychiatry, EMGO - Mental health, EMGO+ - Mental Health, LifeLines Cohort Study, CARDIoGRAM Consortium, DIAGRAM Consortium, ICBP Consortium, MAGIC Consortium, Epidemiology, Public Health, and Internal Medicine
- Subjects
Candidate gene ,Inhibins/genetics ,Genome-wide association study ,GENETIC-LOCI ,chemistry.chemical_compound ,0302 clinical medicine ,serum urate ,Gene Frequency ,Gout/blood ,association analysis, serum urate ,Glucose/metabolism ,Settore MED/14 - NEFROLOGIA ,Hyperuricemia ,serum ,urate ,gene ,POPULATION ,METABOLIC SYNDROME ,Genetics ,0303 health sciences ,education.field_of_study ,biology ,Polymorphism, Single Nucleotide/genetics ,3. Good health ,HYPERURICEMIA ,Genetic Loci/genetics ,SLC22A12 ,Single Nucleotide/genetics ,SNPs ,Signal Transduction ,MOLECULAR PHYSIOLOGY ,serum urate concentrations, gout, genome-wide meta-analysis ,European Continental Ancestry Group ,Population ,Polymorphism, Single Nucleotide ,White People ,Uric Acid/blood ,serum urate concentrations ,genome-wide meta-analysis ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,uric acid ,medicine ,Humans ,Inhibins ,Polymorphism ,education ,030304 developmental biology ,030203 arthritis & rheumatology ,Analysis of Variance ,GOUT ,IDENTIFICATION ,TRANSPORTER ,CARDIOVASCULAR-DISEASE RISK ,ta3121 ,medicine.disease ,association analysis ,Gout ,meta-analysis ,Glucose ,chemistry ,Genetic Loci ,genome-wide association studies ,biology.protein ,Signal Transduction/genetics ,Uric acid ,URIC-ACID LEVELS ,Genome-Wide Association Study ,SLC2A9 - Abstract
Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout. © 2013 Nature America, Inc. All rights reserved.
- Published
- 2013
25. Inhaled ethyl nitrite gas for persistent pulmonary hypertension in infants.
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Abman SH, Kinsella JP, Stamler JS, Moya MP, Gow AJ, Califf RM, and Goldberg RN
- Published
- 2002
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26. Protocol for detecting nitrative stress in biological lipid membranes in murine cells and tissues.
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Aggarwal T, Bellomo A, Stevenson ER, Herbert J, Laskin DL, Gow AJ, and Izgu EC
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- Animals, Mice, Membrane Lipids metabolism, Acute Lung Injury metabolism, Acute Lung Injury pathology, Lung metabolism, Lung pathology, Peroxynitrous Acid metabolism
- Abstract
Detection of nitrative stress is crucial to understanding redox signaling and pathophysiology. Dysregulated nitrative stress, which generates high levels of peroxynitrite, can damage lipid membranes and cause activation of proinflammatory pathways associated with pulmonary complications. Here, we present a protocol for implementing a peroxynitrite-sensing phospholipid to investigate nitrative stress in murine cells and lung tissue. We detail procedures for sensing ONOO
- in stimulated cells, both ex vivo and in vivo, using murine models of acute lung injury (ALI). For complete details on the use and execution of this protocol, please refer to Gutierrez and Aggarwal et al.1 ., Competing Interests: Declaration of interests E.C.I. is an inventor in a patent application filed by Rutgers University on the subject of this work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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27. Transcriptional profiling of lung macrophages following ozone exposure in mice identifies signaling pathways regulating immunometabolic activation.
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Smith LC, Abramova E, Vayas K, Rodriguez J, Gelfand-Titiyevksiy B, Roepke TA, Laskin JD, Gow AJ, and Laskin DL
- Subjects
- Animals, Mice, Male, Macrophage Activation drug effects, Gene Expression Profiling, Lung drug effects, Lung metabolism, Lung immunology, Transcriptome drug effects, Glycolysis drug effects, Cell Cycle drug effects, Oxidative Phosphorylation drug effects, Ozone toxicity, Signal Transduction drug effects, Macrophages, Alveolar drug effects, Macrophages, Alveolar metabolism, Mice, Inbred C57BL
- Abstract
Macrophages play a key role in ozone-induced lung injury by regulating both the initiation and resolution of inflammation. These distinct activities are mediated by pro-inflammatory and anti-inflammatory/proresolution macrophages which sequentially accumulate in injured tissues. Macrophage activation is dependent, in part, on intracellular metabolism. Herein, we used RNA-sequencing (seq) to identify signaling pathways regulating macrophage immunometabolic activity following exposure of mice to ozone (0.8 ppm, 3 h) or air control. Analysis of lung macrophages using an Agilent Seahorse showed that inhalation of ozone increased macrophage glycolytic activity and oxidative phosphorylation at 24 and 72 h post-exposure. An increase in the percentage of macrophages in S phase of the cell cycle was observed 24 h post ozone. RNA-seq revealed significant enrichment of pathways involved in innate immune signaling and cytokine production among differentially expressed genes at both 24 and 72 h after ozone, whereas pathways involved in cell cycle regulation were upregulated at 24 h and intracellular metabolism at 72 h. An interaction network analysis identified tumor suppressor 53 (TP53), E2F family of transcription factors (E2Fs), cyclin-dependent kinase inhibitor 1A (CDKN1a/p21), and cyclin D1 (CCND1) as upstream regulators of cell cycle pathways at 24 h and TP53, nuclear receptor subfamily 4 group a member 1 (NR4A1/Nur77), and estrogen receptor alpha (ESR1/ERα) as central upstream regulators of mitochondrial respiration pathways at 72 h. To assess whether ERα regulates metabolic activity, we used ERα-/- mice. In both air and ozone-exposed mice, loss of ERα resulted in increases in glycolytic capacity and glycolytic reserve in lung macrophages with no effect on mitochondrial oxidative phosphorylation. Taken together, these results highlight the complex interaction between cell cycle, intracellular metabolism, and macrophage activation which may be important in the initiation and resolution of inflammation following ozone exposure., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2024
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28. Effects of ozone exposure on lung injury, inflammation, and oxidative stress in a murine model of nonpneumonic endotoxemia.
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Radbel J, Meshanni JA, Vayas KN, Le-Hoang O, Abramova E, Zhou P, Joseph LB, Laskin JD, Gow AJ, and Laskin DL
- Subjects
- Animals, Male, Acute Lung Injury chemically induced, Acute Lung Injury metabolism, Acute Lung Injury pathology, Mice, Mice, Inbred C57BL, Lung drug effects, Lung pathology, Lung metabolism, Bronchoalveolar Lavage Fluid cytology, Bronchoalveolar Lavage Fluid chemistry, Inflammation chemically induced, Macrophages, Alveolar drug effects, Macrophages, Alveolar metabolism, Ozone toxicity, Oxidative Stress drug effects, Endotoxemia chemically induced, Endotoxemia metabolism, Disease Models, Animal, Lipopolysaccharides toxicity
- Abstract
Recent studies have identified exposure to environmental levels of ozone as a risk factor for the development of acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI) that can develop in humans with sepsis. The aim of this study was to develop a murine model of ALI to mechanistically explore the impact of ozone exposure on ARDS development. Mice were exposed to ozone (0.8 ppm, 3 h) or air control followed 24 h later by intravenous administration of 3 mg/kg lipopolysaccharide (LPS) or PBS. Exposure of mice to ozone + LPS caused alveolar hyperplasia; increased BAL levels of albumin, IgM, phospholipids, and proinflammatory mediators including surfactant protein D and soluble receptor for advanced glycation end products were also detected in BAL, along with markers of oxidative and nitrosative stress. Administration of ozone + LPS resulted in an increase in neutrophils and anti-inflammatory macrophages in the lung, with no effects on proinflammatory macrophages. Conversely, the numbers of resident alveolar macrophages decreased after ozone + LPS; however, expression of Nos2, Arg1, Cxcl1, Cxcl2, Ccl2 by these cells increased, indicating that they are activated. These findings demonstrate that ozone sensitizes the lung to respond to endotoxin, resulting in ALI, oxidative stress, and exacerbated pulmonary inflammation, and provide support for the epidemiologic association between ozone exposure and ARDS incidence., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2024
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29. Intermediate versus morning chronotype has lower vascular insulin sensitivity in adults with obesity.
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Malin SK, Remchak ME, Heiston EM, Battillo DJ, Gow AJ, Shah AM, and Liu Z
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- Adult, Humans, Female, Chronotype, Nitrates, Obesity, Brachial Artery physiology, Insulin, Endothelium, Vascular, Vasodilation, Arginine, Insulin Resistance, Cardiovascular Diseases
- Abstract
Aim: Chronotype reflects a circadian rhythmicity that regulates endothelial function. While the morning chronotype (MORN) usually has low cardiovascular disease risk, no study has examined insulin action on endothelial function between chronotypes. We hypothesized intermediate chronotypes (INT) would have lower vascular insulin sensitivity than morning chronotype (MORN)., Materials and Methods: Adults with obesity were classified per Morningness-Eveningness Questionnaire (MEQ) as either MORN (n = 27, 22 female, MEQ = 63.7 ± 4.7, 53.8 ± 6.7 years, 35.3 ± 4.9 kg/m
2 ) or INT (n = 29, 23 female, MEQ = 48.8 ± 6.7, 56.6 ± 9.0 years, 35.7 ± 6.1 kg/m2 ). A 120 min euglycaemic-hyperinsulinaemic clamp (40 mU/m2 /min, 90 mg/dl) was conducted to assess macrovascular insulin sensitivity via brachial artery flow-mediated dilation (%FMD; conduit artery), post-ischaemic flow velocity (resistance arteriole), as well as microvascular insulin sensitivity via contrast-enhanced ultrasound [e.g. microvascular blood volume (perfusion)]. Fasting plasma arginine and citrulline, as well as fasting and clamp-derived plasma endothelin-1 and nitrate/nitrite, were assessed as surrogates of vasoconstriction and nitric oxide-mediated vasodilation. Aerobic fitness (VO2 max) and body composition (dual-energy X-ray absorptiometry) were also collected., Results: MORN had a higher VO2 max compared with INT (p < .01), although there was no difference in fat mass. While fasting FMD was similar between groups, insulin lowered FMD corrected to shear stress and microvascular blood volume in INT compared with MORN after co-varying for VO2 max (both p ≤ .02). INT also had a lower fasting nitrate (p = .03) and arginine (p = .07). Higher MEQ correlated with elevated FMD (r = 0.33, p = .03) and lower post-ischaemic flow velocity (r = -0.33, p = .03) as well as shear rate (r = -0.36, p = .02) at 120 min., Conclusion: When measured during the morning, INT had a lower vascular insulin sensitivity than MORN. Additional work is needed to understand endothelial function differences among chronotypes to optimize cardiovascular disease risk reduction., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)- Published
- 2024
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30. Identification of early events in nitrogen mustard pulmonary toxicity that are independent of infiltrating inflammatory cells using precision cut lung slices.
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Bellomo A, Herbert J, Kudlak MJ, Laskin JD, Gow AJ, and Laskin DL
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- Animals, Mice, DNA Damage, Mice, Inbred C57BL, Dose-Response Relationship, Drug, Mitochondria drug effects, Mitochondria metabolism, Mitochondria pathology, Chemical Warfare Agents toxicity, Glycolysis drug effects, Male, Apoptosis drug effects, Oxidative Stress drug effects, Acute Lung Injury chemically induced, Acute Lung Injury pathology, Acute Lung Injury metabolism, Epithelial Cells drug effects, Epithelial Cells metabolism, Epithelial Cells pathology, Mechlorethamine toxicity, Lung drug effects, Lung pathology, Lung metabolism
- Abstract
Nitrogen mustard (NM; mechlorethamine) is a cytotoxic vesicant known to cause acute lung injury which can progress to chronic disease. Due to the complex nature of NM injury, it has been difficult to analyze early responses of resident lung cells that initiate inflammation and disease progression. To investigate this, we developed a model of acute NM toxicity using murine precision cut lung slices (PCLS), which contain all resident lung cell populations. PCLS were exposed to NM (1-100 μM) for 0.5-3 h and analyzed 1 and 3 d later. NM caused a dose-dependent increase in cytotoxicity and a reduction in metabolic activity, as measured by LDH release and WST-1 activity, respectively. Optimal responses were observed with 50 μM NM after 1 h incubation and these conditions were used in further experiments. Analysis of PCLS bioenergetics using an Agilent Seahorse showed that NM impaired both glycolytic activity and mitochondrial respiration. This was associated with injury to the bronchial epithelium and a reduction in methacholine-induced airway contraction. NM was also found to cause DNA damage in bronchial epithelial cells in PCLS, as measured by expression of γ-H2AX, and to induce oxidative stress, which was evident by a reduction in glutathione levels and upregulation of the antioxidant enzyme catalase. Cleaved caspase-3 was also upregulated in airway smooth muscle cells indicating apoptotic cell death. Characterizing early events in NM toxicity is key in identifying therapeutic targets for the development of efficacious countermeasures., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The author is an Associate Editor for Toxicology and Applied Pharmacology and was not involved in the editorial review or the decision to publish this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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31. Role of macrophage bioenergetics in N-acetylcysteine-mediated mitigation of lung injury and oxidative stress induced by nitrogen mustard.
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Malaviya R, Meshanni JA, Sunil VR, Venosa A, Guo C, Abramova EV, Vayas KN, Jiang C, Cervelli JA, Gow AJ, Laskin JD, and Laskin DL
- Subjects
- Animals, Male, Rats, Rats, Sprague-Dawley, Lung drug effects, Lung metabolism, Lung pathology, Macrophages drug effects, Macrophages metabolism, Acute Lung Injury chemically induced, Acute Lung Injury metabolism, Acute Lung Injury pathology, Macrophages, Alveolar drug effects, Macrophages, Alveolar metabolism, Chemical Warfare Agents toxicity, Oxidative Stress drug effects, Acetylcysteine pharmacology, Mechlorethamine toxicity, Energy Metabolism drug effects, Lung Injury chemically induced, Lung Injury metabolism, Lung Injury pathology
- Abstract
Nitrogen mustard (NM) is a toxic vesicant that causes acute injury to the respiratory tract. This is accompanied by an accumulation of activated macrophages in the lung and oxidative stress which have been implicated in tissue injury. In these studies, we analyzed the effects of N-acetylcysteine (NAC), an inhibitor of oxidative stress and inflammation on NM-induced lung injury, macrophage activation and bioenergetics. Treatment of rats with NAC (150 mg/kg, i.p., daily) beginning 30 min after administration of NM (0.125 mg/kg, i.t.) reduced histopathologic alterations in the lung including alveolar interstitial thickening, blood vessel hemorrhage, fibrin deposition, alveolar inflammation, and bronchiolization of alveolar walls within 3 d of exposure; damage to the alveolar-epithelial barrier, measured by bronchoalveolar lavage fluid protein and cells, was also reduced by NAC, along with oxidative stress as measured by heme oxygenase (HO)-1 and Ym-1 expression in the lung. Treatment of rats with NAC attenuated the accumulation of macrophages in the lung expressing proinflammatory genes including Ptgs2, Nos2, Il-6 and Il-12; macrophages expressing inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and tumor necrosis factor (TNF)α protein were also reduced in histologic sections. Conversely, NAC had no effect on macrophages expressing the anti-inflammatory proteins arginase-1 or mannose receptor, or on NM-induced increases in matrix metalloproteinase (MMP)-9 or proliferating cell nuclear antigen (PCNA), markers of tissue repair. Following NM exposure, lung macrophage basal and maximal glycolytic activity increased, while basal respiration decreased indicating greater reliance on glycolysis to generate ATP. NAC increased both glycolysis and oxidative phosphorylation. Additionally, in macrophages from both control and NM treated animals, NAC treatment resulted in increased S-nitrosylation of ATP synthase, protecting the enzyme from oxidative damage. Taken together, these data suggest that alterations in NM-induced macrophage activation and bioenergetics contribute to the efficacy of NAC in mitigating lung injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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32. Suppression of Lung Oxidative Stress, Inflammation, and Fibrosis following Nitrogen Mustard Exposure by the Selective Farnesoid X Receptor Agonist Obeticholic Acid.
- Author
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Meshanni JA, Lee JM, Vayas KN, Sun R, Jiang C, Guo GL, Gow AJ, Laskin JD, and Laskin DL
- Subjects
- Rats, Male, Animals, Irritants adverse effects, Rats, Wistar, Lung, Fibrosis, Inflammation chemically induced, Inflammation drug therapy, Inflammation pathology, Oxidative Stress, Lipids, Mechlorethamine toxicity, Lung Injury metabolism, Chenodeoxycholic Acid analogs & derivatives
- Abstract
Nitrogen mustard (NM) is a cytotoxic vesicant known to cause pulmonary injury that can progress to fibrosis. NM toxicity is associated with an influx of inflammatory macrophages in the lung. Farnesoid X receptor (FXR) is a nuclear receptor involved in bile acid and lipid homeostasis that has anti-inflammatory activity. In these studies, we analyzed the effects of FXR activation on lung injury, oxidative stress, and fibrosis induced by NM. Male Wistar rats were exposed to phosphate-buffered saline (vehicle control) or NM (0.125 mg/kg) by intratracheal Penncentury-MicroSprayer aerosolization; this was followed by treatment with the FXR synthetic agonist, obeticholic acid (OCA, 15 mg/kg), or vehicle control (0.13-0.18 g peanut butter) 2 hours later and then once per day, 5 days per week thereafter for 28 days. NM caused histopathological changes in the lung, including epithelial thickening, alveolar circularization, and pulmonary edema. Picrosirius red staining and lung hydroxyproline content were increased, indicative of fibrosis; foamy lipid-laden macrophages were also identified in the lung. This was associated with aberrations in pulmonary function, including increases in resistance and hysteresis. Following NM exposure, lung expression of HO-1 and iNOS, and the ratio of nitrates/nitrites in bronchoalveolar lavage fluid (BAL), markers of oxidative stress increased, along with BAL levels of inflammatory proteins, fibrinogen, and sRAGE. Administration of OCA attenuated NM-induced histopathology, oxidative stress, inflammation, and altered lung function. These findings demonstrate that FXR plays a role in limiting NM-induced lung injury and chronic disease, suggesting that activating FXR may represent an effective approach to limiting NM-induced toxicity. SIGNIFICANCE STATEMENT: In this study, the role of farnesoid-X-receptor (FXR) in mustard vesicant-induced pulmonary toxicity was analyzed using nitrogen mustard (NM) as a model. This study's findings that administration of obeticholic acid, an FXR agonist, to rats reduces NM-induced pulmonary injury, oxidative stress, and fibrosis provide novel mechanistic insights into vesicant toxicity, which may be useful in the development of efficacious therapeutics., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2024
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33. Longitudinal associations of volunteering, grandparenting, and family care with processing speed: A gender perspective on prosocial activity and cognitive aging in the second half of life.
- Author
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Henning G, Ehrlich U, Gow AJ, Kelle N, and Muniz-Terrera G
- Subjects
- Humans, Processing Speed, Longevity, Volunteers psychology, Longitudinal Studies, Aging psychology, Cognitive Aging psychology
- Abstract
An active lifestyle has been associated with better cognitive performance in many studies. However, most studies have focused on leisure activities or paid work, with less consideration of the kind of prosocial activities, many people engage in, including volunteering, grandparenting, and family care. In the present study, based on four waves of the German Ageing Survey ( N = 6,915, aged 40-85 at baseline), we used parallel growth curves to investigate the longitudinal association of level and change in volunteering, grandparenting, and family care with level and change in processing speed. Given the gendered nature of engagement in these activities over the life span, we tested for gender differences in the associations. Only volunteering was reliably associated with higher speed of processing at baseline, no consistent longitudinal associations were found. Our results show that although prosocial activities are of great societal importance, expectations of large rewards in terms of cognitive health may be exaggerated. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
- Published
- 2023
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34. Direct assessment of nitrative stress in lipid environments: Applications of a designer lipid-based biosensor for peroxynitrite.
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Gutierrez B, Aggarwal T, Erguven H, Stone MRL, Guo C, Bellomo A, Abramova E, Stevenson ER, Laskin DL, Gow AJ, and Izgu EC
- Abstract
Lipid membranes and lipid-rich organelles are targets of peroxynitrite (ONOO
- ), a highly reactive species generated under nitrative stress. We report a membrane-localized phospholipid ( DPPC-TC-ONOO- ) that allows the detection of ONOO- in diverse lipid environments: biomimetic vesicles, mammalian cell compartments, and within the lung lining. DPPC-TC-ONOO- and POPC self-assemble to membrane vesicles that fluorogenically and selectively respond to ONOO- . DPPC-TC-ONOO- , delivered through lipid nanoparticles, allowed for ONOO- detection in the endoplasmic reticulum upon cytokine-induced nitrative stress in live mammalian cells. It also responded to ONOO- within lung tissue murine models upon acute lung injury. We observed nitrative stress around bronchioles in precision cut lung slices exposed to nitrogen mustard and in pulmonary macrophages following intratracheal bleomycin challenge. Results showed that DPPC-TC-ONOO- functions specifically toward iNOS, a key enzyme modulating nitrative stress, and offers significant advantages over its hydrophilic analog in terms of localization and signal generation., Competing Interests: E.C.I., B.G., and H.E. are co-inventors of a provisional patent application filed by Rutgers University on the subject of this work., (© 2023 The Author(s).)- Published
- 2023
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35. Etiology of lipid-laden macrophages in the lung.
- Author
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Stevenson ER, Smith LC, Wilkinson ML, Lee SJ, and Gow AJ
- Subjects
- Foam Cells, Lung, Lipids, Macrophages, Macrophages, Alveolar
- Abstract
Uniquely positioned as sentinel cells constantly exposed to the environment, pulmonary macrophages are vital for the maintenance of the lung lining. These cells are responsible for the clearance of xenobiotics, pathogen detection and clearance, and homeostatic functions such as surfactant recycling. Among the spectrum of phenotypes that may be expressed by macrophages in the lung, the pulmonary lipid-laden phenotype is less commonly studied in comparison to its circulatory counterpart, the atherosclerotic lesion-associated foam cell, or the acutely activated inflammatory macrophage. Herein, we propose that lipid-laden macrophage formation in the lung is governed by lipid acquisition, storage, metabolism, and export processes. The cellular balance of these four processes is critical to the maintenance of homeostasis and the prevention of aberrant signaling that may contribute to lung pathologies. This review aims to examine mechanisms and signaling pathways that are involved in lipid-laden macrophage formation and the potential consequences of this phenotype in the lung., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)
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- 2023
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36. Exercise blood pressure and heart rate responses to graded exercise testing in intermediate versus morning chronotypes with obesity.
- Author
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Remchak ME, Dosik JK, Pappas G, Gow AJ, Shah AM, and Malin SK
- Subjects
- Adult, Female, Humans, Blood Pressure physiology, Leptin, Heart Rate physiology, Chronotype, Nitrates, Nitric Oxide, Obesity diagnosis, Exercise Test, Cardiovascular Diseases
- Abstract
Exaggerated exercise blood pressure (BP) is linked to cardiovascular disease (CVD). Although evening chronotypes have greater CVD risk than morning (Morn) types, it is unknown if exercise BP differs in intermediate (Int) types. Adults with obesity were classified as either Morn [ n = 23 (18 females), Morning-Eveningness Questionnaire (MEQ) = 63.96 ± 1.0, 54.74 ± 1.4 yr, 33.7 ± 0.6 kg/m
2 ] or Int [ n = 23 (19 females), MEQ = 51.36 ± 1.1, 55.96 ± 1.8 yr, 37.2 ± 1.2 kg/m2 ] chronotype per MEQ. A graded, incremental treadmill test to maximal aerobic capacity (V̇o2max ) was conducted. Systolic (SBP) and diastolic (DBP) blood pressure and mean arterial pressure (MAP), rate pressure product (RPP), heart rate (HR), and rate of perceived intensity (RPE) were determined at baseline, 4 min, 6 min, and maximal stages. HR recovery (HRR; maximum postexercise) was determined at 1 and 2 min postexercise. Preexercise fasted aortic waveforms (applanation tonometry), plasma leptin, nitrate/nitrite (nitric oxide bioavailability), and body composition (dual X-ray, DXA) were also collected. Int had lower V̇o2max and plasma nitrate (both P ≤ 0.02) than Morn. No difference in preexercise BP, aortic waveforms, or body composition were noted between groups, although higher plasma leptin was seen in Int compared with Morn ( P = 0.04). Although Int had higher brachial DBP and MAP across exercise stages (both P ≤ 0.05) and higher HR, RPE, and RPP at 6 min of exercise (all P ≤ 0.05), covarying for V̇o2max nullified the BP, but not HR or RPE, difference. HRR was greater in Morn independent of V̇o2max ( P = 0.046). Fasted leptin correlated with HR at exercise stage 4 ( r = 0.421, P = 0.041) and 6 min ( r = 0.593, P = 0.002). This observational study suggests that Int has exaggerated BP and HR responses to exercise compared with Morn, although fitness abolished BP differences. NEW & NOTEWORTHY This study compares blood pressure and heart rate responses with graded, incremental exercise between morning and intermediate chronotype adults with obesity. Herein, blood pressure responses to exercise were elevated in intermediate compared with morning chronotype, although V̇o2max abolished this observation. However, heart rate responses to exercise were higher in intermediate vs. morning chronotypes independent of fitness. Collectively, this exercise hemodynamic response among intermediate chronotype may be related to reduced aerobic fitness, altered nitric oxide metabolism, and/or elevated aortic waveforms.- Published
- 2023
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37. Older adults' experiences of taking up a new community-based leisure activity to promote brain health: A focus group study.
- Author
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Niechcial MA, Marr C, Potter LM, Dickson A, and Gow AJ
- Subjects
- Female, Humans, Aged, Male, Focus Groups, Learning, Leisure Activities, Brain, Pleasure
- Abstract
Introduction: An active and engaged lifestyle is supported as being beneficial for brain health. Activities comprising physical, mental and social demands, or combinations of those, are of particular interest, and have been the focus of specific interventions. Exploring how older people engage with such community-based activities, including facilitators and barriers to participation, may help improve the success of future translational activities. The purpose of this study was therefore to identify factors that enabled or hindered activity engagement by conducting focus groups with people who had been supported to take up a new activity as part of an intervention study., Materials and Methods: Twenty-seven older adults aged 65-86 (56% female) who had completed an activity-based intervention study participated in three focus groups. Discussions explored their experiences of taking up a new activity, including facilitators and barriers to their engagement, and their perceptions of any benefits., Results: Thematic analysis grouped participants' responses into five themes: positive aspects and facilitators of engagement in a new activity; challenges and barriers to engagement; ageing being a facilitator and a barrier to engagement; differential effects of activities on participants' health and wellbeing; and general project feedback (including opinions on study design)., Discussion and Conclusions: Participants' experiences and expectations included positive (e.g., enjoyment, socialisation) and negative factors (e.g., lack of confidence, other commitments, class costs and poor structure), consistent with previous research on social participation and engaging with new learning opportunities. Future studies should also consider those who do not readily participate in leisure activities to address earlier barriers. It is important that older adults have access to potentially beneficial activities and local authorities should prioritise increasing their provision., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Niechcial et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
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38. Role of PPARγ in dyslipidemia and altered pulmonary functioning in mice following ozone exposure.
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Smith LC, Gow AJ, Abramova E, Vayas K, Guo C, Noto J, Lyman J, Rodriquez J, Gelfand-Titiyevskiy B, Malcolm C, Laskin JD, and Laskin DL
- Subjects
- Mice, Animals, PPAR gamma metabolism, Lung metabolism, Macrophages, Alveolar metabolism, Phospholipids metabolism, Surface-Active Agents, Ozone toxicity, Dyslipidemias chemically induced, Dyslipidemias metabolism
- Abstract
Exposure to ozone causes decrements in pulmonary function, a response associated with alterations in lung lipids. Pulmonary lipid homeostasis is dependent on the activity of peroxisome proliferator activated receptor gamma (PPARγ), a nuclear receptor that regulates lipid uptake and catabolism by alveolar macrophages (AMs). Herein, we assessed the role of PPARγ in ozone-induced dyslipidemia and aberrant lung function in mice. Exposure of mice to ozone (0.8 ppm, 3 h) resulted in a significant reduction in lung hysteresivity at 72 h post exposure; this correlated with increases in levels of total phospholipids, specifically cholesteryl esters, ceramides, phosphatidylcholines, phosphorylethanolamines, sphingomyelins, and di- and triacylglycerols in lung lining fluid. This was accompanied by a reduction in relative surfactant protein-B (SP-B) content, consistent with surfactant dysfunction. Administration of the PPARγ agonist, rosiglitazone (5 mg/kg/day, i.p.) reduced total lung lipids, increased relative amounts of SP-B, and normalized pulmonary function in ozone-exposed mice. This was associated with increases in lung macrophage expression of CD36, a scavenger receptor important in lipid uptake and a transcriptional target of PPARγ. These findings highlight the role of alveolar lipids as regulators of surfactant activity and pulmonary function following ozone exposure and suggest that targeting lipid uptake by lung macrophages may be an efficacious approach for treating altered respiratory mechanics., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
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39. Menthol flavoring in e-cigarette condensate causes pulmonary dysfunction and cytotoxicity in precision cut lung slices.
- Author
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Herbert J, Kelty JS, Laskin JD, Laskin DL, and Gow AJ
- Subjects
- Animals, Mice, Menthol toxicity, Respiratory Aerosols and Droplets, Lung, Flavoring Agents toxicity, Nicotine toxicity, Electronic Nicotine Delivery Systems
- Abstract
E-cigarette consumption is under scrutiny by regulatory authorities due to concerns about product toxicity, lack of manufacturing standards, and increasing reports of e-cigarette- or vaping-associated acute lung injury. In vitro studies have demonstrated cytotoxicity, mitochondrial dysfunction, and oxidative stress induced by unflavored e-cigarette aerosols and flavoring additives. However, e-cigarette effects on the complex lung parenchyma remain unclear. Herein, the impact of e-cigarette condensates with or without menthol flavoring on functional, structural, and cellular responses was investigated using mouse precision cut lung slices (PCLS). PCLS were exposed to e-cigarette condensates prepared from aerosolized vehicle, nicotine, nicotine + menthol, and menthol e-fluids at doses from 50 to 500 mM. Doses were normalized to the glycerin content of vehicle. Video-microscopy of PCLS revealed impaired contractile responsiveness of airways to methacholine and dampened ciliary beating following exposure to menthol-containing condensates at concentrations greater than 300 mM. Following 500 mM menthol-containing condensate exposure, epithelial exfoliation in intrabronchial airways was identified in histological sections of PCLS. Measurement of lactate dehydrogenase release, mitochondrial water-soluble-tetrazolium salt-1 conversion, and glutathione content supported earlier findings of nicotine or nicotine + menthol e-cigarette-induced dose-dependent cytotoxicity and oxidative stress responses. Evaluation of PCLS metabolic activity revealed dose-related impairment of mitochondrial oxidative phosphorylation and glycolysis after exposure to menthol-containing condensates. Taken together, these data demonstrate prominent menthol-induced pulmonary toxicity and impairment of essential physiological functions in the lung, which warrants concerns about e-cigarette consumer safety and emphasizes the need for further investigations of molecular mechanisms of toxicity and menthol effects in an experimental model of disease.
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- 2023
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40. Lung injury and oxidative stress induced by inhaled chlorine in mice is associated with proinflammatory activation of macrophages and altered bioenergetics.
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Malaviya R, Gardner CR, Rancourt RC, Smith LC, Abramova EV, Vayas KN, Gow AJ, Laskin JD, and Laskin DL
- Subjects
- Mice, Male, Animals, Mice, Inbred C57BL, Lung, Macrophages, Bronchoalveolar Lavage Fluid, Oxidative Stress, Energy Metabolism, Chlorine toxicity, Lung Injury
- Abstract
Chlorine (Cl
2 ) gas is a highly toxic and oxidizing irritant that causes life-threatening lung injuries. Herein, we investigated the impact of Cl2 -induced injury and oxidative stress on lung macrophage phenotype and function. Spontaneously breathing male C57BL/6J mice were exposed to air or Cl2 (300 ppm, 25 min) in a whole-body exposure chamber. Bronchoalveolar lavage (BAL) fluid and cells, and lung tissue were collected 24 h later and analyzed for markers of injury, oxidative stress and macrophage activation. Exposure of mice to Cl2 resulted in increases in numbers of BAL cells and levels of IgM, total protein, and fibrinogen, indicating alveolar epithelial barrier dysfunction and inflammation. BAL levels of inflammatory proteins including surfactant protein (SP)-D, soluble receptor for glycation end product (sRAGE) and matrix metalloproteinase (MMP)-9 were also increased. Cl2 inhalation resulted in upregulation of phospho-histone H2A.X, a marker of double-strand DNA breaks in the bronchiolar epithelium and alveolar cells; oxidative stress proteins, heme oxygenase (HO)-1 and catalase were also upregulated. Flow cytometric analysis of BAL cells revealed increases in proinflammatory macrophages following Cl2 exposure, whereas numbers of resident and antiinflammatory macrophages were not altered. This was associated with increases in numbers of macrophages expressing cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS), markers of proinflammatory activation, with no effect on mannose receptor (MR) or Ym-1 expression, markers of antiinflammatory activation. Metabolic analysis of lung cells showed increases in glycolytic activity following Cl2 exposure in line with proinflammatory macrophage activation. Mechanistic understanding of Cl2 -induced injury will be useful in the identification of efficacious countermeasures for mitigating morbidity and mortality of this highly toxic gas., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Debra L Laskin reports financial support was provided by National Institutes of Health., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2023
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41. Novel method to assess resident alveolar macrophage efferocytosis of apoptotic neutrophils by flow cytometry.
- Author
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Radbel J, Meshanni JA, Gardner CR, Le-Hoang O, Cervelli J, Laskin JD, Gow AJ, and Laskin DL
- Subjects
- Mice, Animals, Flow Cytometry, Phagocytosis, Inflammation metabolism, Apoptosis, Neutrophils metabolism, Macrophages, Alveolar metabolism
- Abstract
Macrophage efferocytosis of apoptotic neutrophils (PMNs) plays a key role in the resolution of inflammation. In these studies, we describe a novel flow cytometric method to assess efferocytosis of apoptotic PMNs. Resident alveolar macrophages and PMNs were collected from lungs of mice exposed to inhaled ozone (0.8 ppm, 3 h) followed by lipopolysaccharide (3 mg/kg, i.v.) to induce acute lung injury. PMNs were labeled with PKH26 or DilC
18 (5)-DS (D12730) cell membrane dye and then incubated with resident alveolar macrophages at a ratio of 5:1. After 90 min, macrophage efferocytosis was analyzed by flow cytometry and confirmed by confocal microscopy. Whereas alveolar macrophages incubated with D12730-labeled PMNs could readily be identified as efferocytotic or non-efferocytotic, this was not possible with PKH26 labeled PMNs due to confounding macrophage autofluorescence. Using D12730 labeled PMNs, subsets of resident alveolar macrophages were identified with varying capacities to perform efferocytosis, which may be linked to the activation state of these cells. Future applications of this method will be useful in assessing the role of efferocytosis in the resolution of inflammation in response to toxicant exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2023
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42. Nitric oxide regulation of cellular metabolism: Adaptive tuning of cellular energy.
- Author
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Pappas G, Wilkinson ML, and Gow AJ
- Subjects
- Glycolysis physiology, Glucose metabolism, Fatty Acids, Nitric Oxide, Energy Metabolism physiology
- Abstract
Nitric oxide can interact with a wide range of proteins including many that are involved in metabolism. In this review we have summarized the effects of NO on glycolysis, fatty acid metabolism, the TCA cycle, and oxidative phosphorylation with reference to skeletal muscle. Low to moderate NO concentrations upregulate glucose and fatty acid oxidation, while higher NO concentrations shift cellular reliance toward a fully glycolytic phenotype. Moderate NO production directly inhibits pyruvate dehydrogenase activity, reducing glucose-derived carbon entry into the TCA cycle and subsequently increasing anaploretic reactions. NO directly inhibits aconitase activity, increasing reliance on glutamine for continued energy production. At higher or prolonged NO exposure, citrate accumulation can inhibit multiple ATP-producing pathways. Reduced TCA flux slows NADH/FADH entry into the ETC. NO can also inhibit the ETC directly, further limiting oxidative phosphorylation. Moderate NO production improves mitochondrial efficiency while improving O
2 utilization increasing whole-body energy production. Long-term bioenergetic capacity may be increased because of NO-derived ROS, which participate in adaptive cellular redox signaling through AMPK, PCG1-α, HIF-1, and NF-κB. However, prolonged exposure or high concentrations of NO can result in membrane depolarization and opening of the MPT. In this way NO may serve as a biochemical rheostat matching energy supply with demand for optimal respiratory function., Competing Interests: Declaration of competing interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2023
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43. A Decade Later on How to "Use It" So We Don't "Lose It": An Update on the Unanswered Questions about the Influence of Activity Participation on Cognitive Performance in Older Age.
- Author
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Bielak AAM and Gow AJ
- Subjects
- Humans, Aged, Aging, Brain, Cognition, Geriatrics
- Abstract
Activity engagement is a modifiable factor that has been widely-cited as being good for the aging brain and cognition and represents a valuable target for reducing dementia risk. However, specific issues about activity engagement (mental, social, and physical) and cognition in older adulthood remain, and Bielak [Gerontology 2010;56: 507-519] reviewed seven major methodological and theoretical questions about this relationship. We present an updated reflection on these key questions, focusing on research published in the last 10 years. For some questions, a significant amount of work has been done and conclusions have become clearer; for others, there have been few additions to the literature and our knowledge remains much the same as it was a decade ago. We review the issues identified in the 2010 paper including the directionality and temporal nature of the relationship; whether specific activity domains offer different benefits to cognition and what domain(s) of cognition are affected; variation in the relation by age, gender, or education; potential mechanisms involved; and how activity engagement is assessed. For each, we present the most up-to-date research, discuss remaining challenges and possible future directions. This formal unifying of the information in the field is intended as a guide to support continued progress by spurring on studies addressing specific questions while reminding researchers of critical issues. We conclude with recommendations that future studies investigating the link between activity engagement and cognitive performance in adulthood should consider., (© 2022 S. Karger AG, Basel.)
- Published
- 2023
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44. Regulation of macrophage activation by S-Nitrosothiols following ozone-induced lung injury.
- Author
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Taylor S, Murray A, Francis M, Abramova E, Guo C, Laskin DL, and Gow AJ
- Abstract
Acute exposure to ozone causes oxidative stress, characterized by increases in nitric oxide (NO) and other reactive nitrogen species in the lung. NO has been shown to modify thiols generating S-nitrosothiols (SNOs); this results in altered protein function. In macrophages this can lead to changes in inflammatory activity which impact the resolution of inflammation. As SNO formation is dependent on the redox state of both the NO donor and the recipient thiol, the local microenvironment plays a key role in its regulation. This dictates not only the chemical feasibility of SNO formation but also mechanisms by which they may form. In these studies, we compared the ability of the SNO donors, ethyl nitrite (ENO), which targets both hydrophobic and hydrophilic thiols, SNO-propanamide (SNOPPM) which targets hydrophobic thiols, and S-nitroso-N-acetylcysteine. (SNAC) which targets hydrophilic thiols. to modify macrophage activation following ozone exposure. Mice were treated with air or ozone (0.8 ppm, 3 h) followed 1 h later by intranasal administration of ENO, SNOPPM or SNAC (1-500 μM) or appropriate controls. Mice were euthanized 48 h later. Each of the SNO donors reduced ozone-induced inflammation and modified the phenotype of macrophages both within the lung lining fluid and the tissue. ENO and SNOPPM were more effective than SNAC. These findings suggest that the hydrophobic SNO thiol pool targeted by SNOPPM and ENO plays a major role in regulating macrophage phenotype following ozone induced injury., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Debra Laskin reports financial support was provided by National Institutes of Health. Andrew Gow reports financial support was provided by National Institutes of Health. Sheryse Taylor reports financial support was provided by National Institutes of Health. Alexa Murray reports financial support was provided by National Institutes of Health. Elena Abramova reports financial support was provided by National Institutes of Health. Changjiang Guo reports financial support was provided by National Institutes of Health. Dr. Laskin, a co-author of the paper, is a guest editor for the journal, (Copyright © 2022. Published by Elsevier Inc.)
- Published
- 2022
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45. Farnesoid X receptor regulates lung macrophage activation and injury following nitrogen mustard exposure.
- Author
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Murray A, Banota T, Guo GL, Smith LC, Meshanni JA, Lee J, Kong B, Abramova EV, Goedken M, Gow AJ, Laskin JD, and Laskin DL
- Subjects
- Animals, Cyclooxygenase 2 metabolism, Heme Oxygenase-1 genetics, Heme Oxygenase-1 metabolism, Irritants toxicity, Lipids, Lung, Macrophage Activation, Male, Mice, Acute Lung Injury pathology, Mechlorethamine toxicity
- Abstract
Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis; this is associated with a sequential accumulation of pro- and anti-inflammatory macrophages in the lung which have been implicated in NM toxicity. Farnesoid X receptor (FXR) is a nuclear receptor involved in regulating lipid homeostasis and inflammation. In these studies, we analyzed the role of FXR in inflammatory macrophage activation, lung injury and oxidative stress following NM exposure. Wild-type (WT) and FXR
-/- mice were treated intratracheally with PBS (control) or NM (0.08 mg/kg). Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 3, 14 and 28 d later. NM caused progressive histopathologic alterations in the lung including inflammatory cell infiltration and alveolar wall thickening and increases in protein and cells in BAL; oxidative stress was also noted, as reflected by upregulation of heme oxygenase-1. These changes were more prominent in male FXR-/- mice. Flow cytometric analysis revealed that loss of FXR resulted in increases in proinflammatory macrophages at 3 d post NM; this correlated with upregulation of COX-2 and ARL11, markers of macrophage activation. Markers of anti-inflammatory macrophage activation, CD163 and STAT6, were also upregulated after NM; this response was exacerbated in FXR-/- mice at 14 d post-NM. These findings demonstrate that FXR plays a role in limiting macrophage inflammatory responses important in lung injury and oxidative stress. Maintaining or enhancing FXR function may represent a useful strategy in the development of countermeasures to treat mustard lung toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)- Published
- 2022
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46. Intratracheal Administration of Acyl Coenzyme A Acyltransferase-1 Inhibitor K-604 Reduces Pulmonary Inflammation Following Bleomycin-Induced Lung Injury.
- Author
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Stevenson ER, Wilkinson ML, Abramova E, Guo C, and Gow AJ
- Subjects
- Acyl Coenzyme A, Acyltransferases, Animals, Benzimidazoles, Bleomycin, Cholesterol, Female, Male, Mice, Mice, Inbred C57BL, Sterol O-Acyltransferase genetics, Acute Lung Injury chemically induced, Acute Lung Injury drug therapy, Pneumonia
- Abstract
Acute lung injury (ALI) is characterized by epithelial damage, barrier dysfunction, and pulmonary edema. Macrophage activation and failure to resolve play a role in ALI; thus, macrophage phenotype modulation is a rational target for therapeutic intervention. Large, lipid-laden macrophages have been observed in various injury models, including intratracheal bleomycin (ITB), suggesting that lipid storage may play a role in ALI severity. The endoplasmic reticulum-associated enzyme acyl coenzyme A acyltransferase-1 (Acat-1 /Soat1 ) is highly expressed in macrophages, where it catalyzes the esterification of cholesterol, leading to intracellular lipid accumulation. We hypothesize that inhibition of Acat-1 will reduce macrophage activation and improve outcomes of lung injury in ITB. K-604, a selective inhibitor of Acat-1, was used to reduce cholesterol esterification and hence lipid accumulation in response to ITB. Male and female C57BL6/J mice ( n = 16-21/group) were administered control, control + K-604, ITB, or ITB + K-604 on d0, control or K-604 on d3, and were sacrificed on day 7. ITB caused significant body weight loss and an increase in cholesterol accumulation in bronchoalveolar lavage cells. These changes were mitigated by Acat-1 inhibition. K-604 also significantly reduced ITB-induced alveolar thickening. Surfactant composition was normalized as indicated by a significant decrease in phospholipid: SP-B ratio in ITB+K-604 compared with ITB. K-604 administration preserved mature alveolar macrophages, decreased activation in response to ITB, and decreased the percentage mature and pro-fibrotic interstitial macrophages. These results show that inhibition of Acat-1 in the lung is associated with reduced inflammatory response to ITB-mediated lung injury. SIGNIFICANCE STATEMENT: Acyl coenzyme A acyltransferase-1 (Acat-1) is critical to lipid droplet formation, and thus inhibition of Acat-1 presents as a pharmacological target. Intratracheal administration of K-604, an Acat-1 inhibitor, reduces intracellular cholesterol ester accumulation in lung macrophages, attenuates inflammation and macrophage activation, and normalizes mediators of surface-active function after intratracheal bleomycin administration in a rodent model. The data presented within suggest that inhibition of Acat-1 in the lung improves acute lung injury outcomes., (Copyright © 2022 by The Author(s).)
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- 2022
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47. Assessing Emotional Expressions During a Cycling-Based Initiative for Older Care Home Residents Using Video-Based Recordings.
- Author
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Gray R, Faraghat S, and Gow AJ
- Abstract
Objective: Through Cycling Without Age, trained volunteers use specially designed trishaws to provide rides for older adults living in care homes and other supported living environments. Qualitative and quantitative research suggests benefits in terms of improvements in mood and wellbeing. Those studies have predominantly been interviews with participants reflecting on previous rides, or as pre-/post-assessments. The current study assessed emotional experiences using video recordings acquired during participants' rides. Methods: Twelve older adults (50% female; 67-92 years old (M = 81.8, SD = 7.4)) living in care homes or supported living environments were recruited. During a Cycling Without Age ride, participants were filmed using an action camera mounted on the trishaw. Recordings were rated using the Facial Expression Coding System by two researchers to assess the frequency, duration and intensity of positive and negative emotions. Results: On average, 23.7 positive emotional expressions were observed per ride, significantly higher than negative emotions (0.4). As well as more frequent, positive emotions were observed over a longer duration in total (139.5 seconds vs. 1.3) and rated as more intense (1.9 out of 5 vs. 0.3). Conclusion: The study supported the value of directly assessing emotional responses during this cycling-based initiative, including minimising the input required from participants. The predominantly positive emotional expressions observed were consistent with both qualitative and quantitative assessments of Cycling Without Age, and suggests a potential pathway by which those benefits manifest. Future studies might adopt a triangulated approach, using in-activity monitoring, quantitative assessments and participant reflections., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)
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- 2022
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48. Genes Versus Lifestyles: Exploring Beliefs About the Determinants of Cognitive Ageing.
- Author
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Niechcial MA, Vaportzis E, and Gow AJ
- Abstract
Genetic and lifestyle factors contribute to cognitive ageing. However, the extent to which the public attribute changes in thinking skills to either genetic or lifestyle factors is largely unknown. This may be important if it impacts engagement in activities deemed beneficial to thinking skills. This study, therefore, explored people's beliefs about determinants of cognitive ageing and whether those beliefs were associated with engagement in potentially beneficial behaviours. Data were collected through a United Kingdom-wide survey of people aged 40 and over. Participants completed questions about their beliefs regarding cognitive ageing, and specifically the extent to which they believed lifestyle or genetic factors influence those changes, and their engagement in specific behaviours that may be cognitively beneficial. Responses from 3,130 individuals (94.0% of the survey sample) were analysed using chi-square tests of independence, principal component analysis and ANCOVAs to investigate whether their attribution of genetic or lifestyle determinants were associated with their beliefs about cognitive ageing and their participation in brain health-related behaviours. Most respondents (62.2%) believed genes and lifestyle contribute equally to age-related changes in cognitive skills. Respondents who believed genetic factors were more influential were less likely to expect cognitive skills might be improved or maintained with age, less sure what behaviours might be associated with brain health, and less likely to engage in behaviours comprising mental challenge/novelty supported as beneficial for brain health. From this United Kingdom-wide survey about beliefs regarding potential determinants of cognitive ageing, some of our respondents' views were not aligned with the findings from ageing research. It is important for the public to know how to keep their brains healthy. Our results indicate a need for clearer messaging highlighting the role of lifestyle factors for brain health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Niechcial, Vaportzis and Gow.)
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- 2022
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49. Human Mesenchymal Stem Cells as a Carrier for a Cell-Mediated Drug Delivery.
- Author
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Litvinova LS, Shupletsova VV, Khaziakhmatova OG, Daminova AG, Kudryavtseva VL, Yurova KA, Malashchenko VV, Todosenko NM, Popova V, Litvinov RI, Korotkova EI, Sukhorukov GB, Gow AJ, Weissman D, Atochina-Vasserman EN, and Khlusov IA
- Abstract
A number of preclinical and clinical studies have demonstrated the efficiency of mesenchymal stromal cells to serve as an excellent base for a cell-mediated drug delivery system. Cell-based targeted drug delivery has received much attention as a system to facilitate the uptake a nd transfer of active substances to specific organs and tissues with high efficiency. Human mesenchymal stem cells (MSCs) are attracting increased interest as a promising tool for cell-based therapy due to their high proliferative capacity, multi-potency, and anti-inflammatory and immunomodulatory properties. In particular, these cells are potentially suitable for use as encapsulated drug transporters to sites of inflammation. Here, we studied the in vitro effects of incorporating synthetic polymer microcapsules at various microcapsule-to-cell ratios on the morphology, ultrastructure, cytokine profile, and migration ability of human adipose-derived MSCs at various time points post-phagocytosis. The data show that under appropriate conditions, human MSCs can be efficiently loaded with synthesized microcapsules without damaging the cell's structural integrity with unexpressed cytokine secretion, retained motility, and ability to migrate through 8 μm pores. Thus, the strategy of using human MSCs as a delivery vehicle for transferring microcapsules, containing bioactive material, across the tissue-blood or tumor-blood barriers to facilitate the treatment of stroke, cancer, or inflammatory diseases may open a new therapeutic perspective., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Litvinova, Shupletsova, Khaziakhmatova, Daminova, Kudryavtseva, Yurova, Malashchenko, Todosenko, Popova, Litvinov, Korotkova, Sukhorukov, Gow, Weissman, Atochina-Vasserman and Khlusov.)
- Published
- 2022
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50. Apolipoprotein E Genotype Moderation of the Association Between Physical Activity and Brain Health. A Systematic Review and Meta-Analysis.
- Author
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Pearce AM, Marr C, Dewar M, and Gow AJ
- Abstract
Introduction: Possession of one or two e4 alleles of the apolipoprotein E ( APOE ) gene is associated with cognitive decline and dementia risk. Some evidence suggests that physical activity may benefit carriers of the e4 allele differently., Method: We conducted a systematic review and meta-analysis of studies which assessed APOE differences in the association between physical activity and: lipid profile, Alzheimer's disease pathology, brain structure and brain function in healthy adults. Searches were carried out in PubMed, SCOPUS, Web of Science and PsycInfo., Results: Thirty studies were included from 4,896 papers screened. Carriers of the e4 allele gained the same benefit from physical activity as non-carriers on most outcomes. For brain activation, e4 carriers appeared to gain a greater benefit from physical activity on task-related and resting-state activation and resting-state functional connectivity compared to non-carriers. Post-hoc analysis identified possible compensatory mechanisms allowing e4 carriers to maintain cognitive function., Discussion: Though there is evidence suggesting physical activity may benefit e4 carriers differently compared to non-carriers, this may vary by the specific brain health outcome, perhaps limited to brain activation. Further research is required to confirm these findings and elucidate the mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pearce, Marr, Dewar and Gow.)
- Published
- 2022
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