222 results on '"Pilling, Luke C."'
Search Results
2. Does physical activity moderate the association between shorter leukocyte telomere length and incident coronary heart disease? Data from 54,180 UK Biobank participants
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Xiang, Meiruo, Pilling, Luke C., Melzer, David, Kirk, Ben, Duque, Gustavo, Liu, Rui, Kuchel, George A., Wood, Andrew R., Metcalf, Brad, Diniz, Breno S., Hillsdon, Melvyn, and Kuo, Chia-Ling
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- 2024
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3. Polygenic scores for cardiovascular risk factors improve estimation of clinical outcomes in CCB treatment compared to pharmacogenetic variants alone
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Türkmen, Deniz, Bowden, Jack, Masoli, Jane A. H., Delgado, João, Kuo, Chia-Ling, Melzer, David, and Pilling, Luke C.
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- 2024
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4. MRI-derived brain iron, grey matter volume, and risk of dementia and Parkinson's disease: Observational and genetic analysis in the UK Biobank cohort
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Casanova, Francesco, Tian, Qu, Williamson, Daniel S., Qian, Yong, Zweibaum, David, Ding, Jun, Atkins, Janice L., Melzer, David, Ferrucci, Luigi, and Pilling, Luke C.
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- 2024
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5. Heavy-load exercise in older adults activates vasculogenesis and has a stronger impact on muscle gene expression than in young adults
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Gautvik, Kaare M., Olstad, Ole K., Raue, Ulrika, Gautvik, Vigdis T., Kvernevik, Karl J., Utheim, Tor P., Ravnum, Solveig, Kirkegaard, Camilla, Wiig, Håvard, Jones, Garan, Pilling, Luke C., Trappe, Scott, Raastad, Truls, and Reppe, Sjur
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- 2022
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6. Proteomic aging clock (PAC) predicts age‐related outcomes in middle‐aged and older adults.
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Kuo, Chia‐Ling, Chen, Zhiduo, Liu, Peiran, Pilling, Luke C., Atkins, Janice L., Fortinsky, Richard H., Kuchel, George A., and Diniz, Breno S.
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AGE ,OLDER people ,BLOOD proteins ,RANK correlation (Statistics) ,TELOMERES - Abstract
Beyond mere prognostication, optimal biomarkers of aging provide insights into qualitative and quantitative features of biological aging and might, therefore, offer useful information for the testing and, ultimately, clinical use of gerotherapeutics. We aimed to develop a proteomic aging clock (PAC) for all‐cause mortality risk as a proxy of biological age. Data were from the UK Biobank Pharma Proteomics Project, including 53,021 participants aged between 39 and 70 years and 2923 plasma proteins assessed using the Olink Explore 3072 assay®. 10.9% of the participants died during a mean follow‐up of 13.3 years, with the mean age at death of 70.1 years. The Spearman correlation between PAC proteomic age and chronological age was 0.77. PAC showed robust age‐adjusted associations and predictions for all‐cause mortality and the onset of various diseases in general and disease‐free participants. The proteins associated with PAC proteomic age deviation were enriched in several processes related to the hallmarks of biological aging. Our results expand previous findings by showing that biological age acceleration, based on PAC, strongly predicts all‐cause mortality and several incident disease outcomes. Particularly, it facilitates the evaluation of risk for multiple conditions in a disease‐free population, thereby, contributing to the prevention of initial diseases, which vary among individuals and may subsequently lead to additional comorbidities. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Is Mitochondrial DNA Copy Number from Human Blood Associated with Iron Deposits in the Brain?
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Tian, Qu, Zweibaum, David A., Pilling, Luke C., Casanova, Francesco, Qian, Yong, Atkins, Janice L., Melzer, David, Ding, Jun, and Ferrucci, Luigi
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- 2024
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8. Iron and risk of dementia: Mendelian randomisation analysis in UK Biobank.
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Casanova, Francesco, Qu Tian, Atkins, Janice L., Wood, Andrew R., Williamson, Daniel, Yong Qian, Zweibaum, David, Jun Ding, Melzer, David, Ferrucci, Luigi, and Pilling, Luke C.
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Background Brain iron deposition is common in dementia, but whether serum iron is a causal risk factor is unknown. We aimed to determine whether genetic predisposition to higher serum iron status biomarkers increased risk of dementia and atrophy of grey matter. Methods We analysed UK Biobank participants clustered into European (N=451284), African (N=7477) and South Asian (N=9570) groups by genetic similarity to the 1000 genomes project. Using Mendelian randomisation methods, we estimated the association between genetically predicted serum iron (transferrin saturation [TSAT] and ferritin), grey matter volume and genetic liability to clinically defined dementia (including Alzheimer's disease [AD], non-AD dementia, and vascular dementia) from hospital and primary care records. We also performed time-to-event (competing risks) analysis of the TSAT polygenic score on risk of clinically defined non-AD dementia. Results In Europeans, higher genetically predicted TSAT increased genetic liability to dementia (Odds Ratio [OR]: 1.15, 95% Confidence Intervals [CI] 1.04 to 1.26, p=0.0051), non-AD dementia (OR: 1.27, 95% CI 1.12 to 1.45, p=0.00018) and vascular dementia (OR: 1.37, 95% CI 1.12 to 1.69, p=0.0023), but not AD (OR: 1.00, 95% CI 0.86 to 1.15, p=0.97). Higher TSAT was also associated with increased risk of non-AD dementia in participants of African, but not South Asian groups. In survival analysis using a TSAT polygenic score, the effect was independent of apolipoprotein-E ε4 genotype (with adjustment subdistribution Hazard Ratio: 1.74, 95% CI 1.33 to 2.28, p=0.00006). Genetically predicted TSAT was associated with lower grey matter volume in caudate, putamen and thalamus, and not in other areas of interest. Discussion Genetic evidence supports a causal relationship between higher TSAT and risk of clinically defined non-AD and vascular dementia, in European and African groups. This association appears to be independent of apolipoprotein-E ε4. [ABSTRACT FROM AUTHOR]
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- 2024
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9. SLCO1B1 Exome Sequencing and Statin Treatment Response in 64,000 UK Biobank Patients.
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Türkmen, Deniz, Bowden, Jack, Masoli, Jane A. H., Melzer, David, and Pilling, Luke C.
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STATINS (Cardiovascular agents) ,ORGANIC anion transporters ,HAPLOTYPES ,GENETIC variation ,ATORVASTATIN - Abstract
The solute carrier organic anion transporter family member 1B1 (SLCO1B1) encodes the organic anion-transporting polypeptide 1B1 (OATP1B1 protein) that transports statins to liver cells. Common genetic variants in SLCO1B1, such as *5, cause altered systemic exposure to statins and therefore affect statin outcomes, with potential pharmacogenetic applications; yet, evidence is inconclusive. We studied common and rare SLCO1B1 variants in up to 64,000 patients from UK Biobank prescribed simvastatin or atorvastatin, combining whole-exome sequencing data with up to 25-year routine clinical records. We studied 51 predicted gain/loss-of-function variants affecting OATP1B1. Both SLCO1B1*5 alone and the SLCO1B1*15 haplotype increased LDL during treatment (beta*5 = 0.08 mmol/L, p = 6 × 10
−8 ; beta*15 = 0.03 mmol/L, p = 3 × 10−4 ), as did the likelihood of discontinuing statin prescriptions (hazard ratio*5 = 1.12, p = 0.04; HR*15 = 1.05, p = 0.04). SLCO1B1*15 and SLCO1B1*20 increased the risk of General Practice (GP)-diagnosed muscle symptoms (HR*15 = 1.22, p = 0.003; HR*20 = 1.25, p = 0.01). We estimated that genotype-guided prescribing could potentially prevent 18% and 10% of GP-diagnosed muscle symptoms experienced by statin patients, with *15 and *20, respectively. The remaining common variants were not individually significant. Rare variants in SLCO1B1 increased LDL in statin users by up to 1.05 mmol/L, but replication is needed. We conclude that genotype-guided treatment could reduce GP-diagnosed muscle symptoms in statin patients; incorporating further SLCO1B1 variants into clinical prediction scores could improve LDL control and decrease adverse events, including discontinuation. [ABSTRACT FROM AUTHOR]- Published
- 2024
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10. The relationship of parental longevity with the aging brain—results from UK Biobank
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Tian, Qu, Pilling, Luke C., Atkins, Janice L., Melzer, David, and Ferrucci, Luigi
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- 2020
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11. Human population studies of transcriptome-wide expression in age-related traits
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Pilling, Luke C., Melzer, David, Harries, Lorna W., and Studholme, David
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612.6 ,Epidemiology ,Genomic ,Ageing - Abstract
This thesis presents novel investigations of three common ageing phenotypes in human population studies, using microarray technology to assess ‘transcriptome-wide’ expression in whole blood to identify mechanisms and biomarkers. Muscle strength is related to frailty and is predictive of disability in older persons. I assessed the association between transcript abundance in the InCHIANTI peripheral blood samples (N=695) and muscle strength. One gene (CEBPB) passed the multiple testing criteria, and is involved in macrophage-mediated repair of damaged muscle. I extended this work with a meta-analysis of over 7,781 individuals in four collaborating cohorts; expression of over 222 genes were significantly associated with strength, less than half of which have previously been linked to muscle in the literature. CEBPB did not replicate in these younger cohorts. I then performed the first human analysis of gene expression and cognitive function (and separately with decline in cognitive ability over nine years) in the InCHIANTI cohort (N=681), and one gene was identified; CCR2, a chemokine receptor. Evidence in mice has implicated this gene in the accumulation of β-amyloid and cognitive impairment. Finally, in a collaborative project with the Framingham Heart Study I studied age-related inflammation – another hallmark of ageing - using a novel approach to ‘transcriptome-wide’ analysis; each transcript was assessed for the proportion of the association between age and interleukin-6 (IL6) that it statistically mediated. Very few of the genes associated with IL6 alone also mediated the relationship with age. Findings include; SLC4A10, the strongest mediator, not previously linked to inflammation, and interleukin-1 beta and perforin, a cytokine and cytotoxic protein, respectively. These novel analyses highlight key molecular pathways associated with age-related phenotypes in whole blood and provide links between mouse models and humans. They provide biological insight and directions for future research.
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- 2015
12. Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women
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Jones, Garan, Trajanoska, Katerina, Santanasto, Adam J., Stringa, Najada, Kuo, Chia-Ling, Atkins, Janice L., Lewis, Joshua R., Duong, ThuyVy, Hong, Shengjun, Biggs, Mary L., Luan, Jian’an, Sarnowski, Chloe, Lunetta, Kathryn L., Tanaka, Toshiko, Wojczynski, Mary K., Cvejkus, Ryan, Nethander, Maria, Ghasemi, Sahar, Yang, Jingyun, Zillikens, M. Carola, Walter, Stefan, Sicinski, Kamil, Kague, Erika, Ackert-Bicknell, Cheryl L., Arking, Dan E., Windham, B. Gwen, Boerwinkle, Eric, Grove, Megan L., Graff, Misa, Spira, Dominik, Demuth, Ilja, van der Velde, Nathalie, de Groot, Lisette C. P. G. M., Psaty, Bruce M., Odden, Michelle C., Fohner, Alison E., Langenberg, Claudia, Wareham, Nicholas J., Bandinelli, Stefania, van Schoor, Natasja M., Huisman, Martijn, Tan, Qihua, Zmuda, Joseph, Mellström, Dan, Karlsson, Magnus, Bennett, David A., Buchman, Aron S., De Jager, Philip L., Uitterlinden, Andre G., Völker, Uwe, Kocher, Thomas, Teumer, Alexander, Rodriguéz-Mañas, Leocadio, García, Francisco J., Carnicero, José A., Herd, Pamela, Bertram, Lars, Ohlsson, Claes, Murabito, Joanne M., Melzer, David, Kuchel, George A., Ferrucci, Luigi, Karasik, David, Rivadeneira, Fernando, Kiel, Douglas P., and Pilling, Luke C.
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- 2021
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13. The genetics of human ageing
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Melzer, David, Pilling, Luke C., and Ferrucci, Luigi
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- 2020
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14. circRNAs expressed in human peripheral blood are associated with human aging phenotypes, cellular senescence and mouse lifespan
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Haque, Shahnaz, Ames, Ryan M., Moore, Karen, Pilling, Luke C., Peters, Luanne L., Bandinelli, Stefania, Ferrucci, Luigi, and Harries, Lorna W.
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- 2020
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15. The transcript expression levels of HNRNPM, HNRNPA0 and AKAP17A splicing factors may be predictively associated with ageing phenotypes in human peripheral blood
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Lee, Benjamin P., Pilling, Luke C., Bandinelli, Stefania, Ferrucci, Luigi, Melzer, David, and Harries, Lorna W.
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- 2019
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16. Vitamin D levels and risk of delirium: A mendelian randomization study in the UK Biobank
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Bowman, Kirsty, Jones, Lindsay, Pilling, Luke C., Delgado, João, Kuchel, George A., Ferrucci, Luigi, Fortinsky, Richard H., and Melzer, David
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- 2019
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17. Clinical Outcomes of CADASIL-Associated NOTCH3 Mutations in 451,424 European Ancestry Community Volunteers
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Masoli, Jane A. H., Pilling, Luke C., Kuchel, George A., and Melzer, David
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- 2019
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18. Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease: A Longitudinal Study of 11 461 Participants From Population-Based Cohorts
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Agha, Golareh, Mendelson, Michael M., Ward-Caviness, Cavin K., Joehanes, Roby, Huan, TianXiao, Gondalia, Rahul, Salfati, Elias, Brody, Jennifer A., Fiorito, Giovanni, Bressler, Jan, Chen, Brian H., Ligthart, Symen, Guarrera, Simonetta, Colicino, Elena, Just, Allan C., Wahl, Simone, Gieger, Christian, Vandiver, Amy R., Tanaka, Toshiko, Hernandez, Dena G., Pilling, Luke C., Singleton, Andrew B., Sacerdote, Carlotta, Krogh, Vittorio, Panico, Salvatore, Tumino, Rosario, Li, Yun, Zhang, Guosheng, Stewart, James D., Floyd, James S., Wiggins, Kerri L., Rotter, Jerome I., Multhaup, Michael, Bakulski, Kelly, Horvath, Steven, Tsao, Philip S., Absher, Devin M., Vokonas, Pantel, Hirschhorn, Joel, Fallin, M. Daniele, Liu, Chunyu, Bandinelli, Stefania, Boerwinkle, Eric, Dehghan, Abbas, Schwartz, Joel D., Psaty, Bruce M., Feinberg, Andrew P., Hou, Lifang, Ferrucci, Luigi, Sotoodehnia, Nona, Matullo, Giuseppe, Peters, Annette, Fornage, Myriam, Assimes, Themistocles L., Whitsel, Eric A., Levy, Daniel, and Baccarelli, Andrea A.
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- 2019
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19. Mid‐life leukocyte telomere length and dementia risk: An observational and mendelian randomization study of 435,046 UK Biobank participants.
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Liu, Rui, Xiang, Meiruo, Pilling, Luke C., Melzer, David, Wang, Lihong, Manning, Kevin J., Steffens, David C., Bowden, Jack, Fortinsky, Richard H., Kuchel, George A., Rhee, Taeho G., Diniz, Breno S., and Kuo, Chia‐Ling
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TELOMERES ,DISEASE risk factors ,ALZHEIMER'S disease ,MIDDLE age ,CELLULAR aging ,LEUCOCYTES ,MAGNETIC resonance imaging - Abstract
Telomere attrition is one of biological aging hallmarks and may be intervened to target multiple aging‐related diseases, including Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). The objective of this study was to assess associations of leukocyte telomere length (TL) with AD/ADRD and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging (MRI) phenotypes. Data from European‐ancestry participants in the UK Biobank (n = 435,046) were used to evaluate whether mid‐life leukocyte TL is associated with incident AD/ADRD over a mean follow‐up of 12.2 years. In a subsample without AD/ADRD and with brain imaging data (n = 43,390), we associated TL with brain MRI phenotypes related to AD or vascular dementia pathology. Longer TL was associated with a lower risk of incident AD/ADRD (adjusted Hazard Ratio [aHR] per SD = 0.93, 95% CI 0.90–0.96, p = 3.37 × 10−7). Longer TL also was associated with better cognitive performance in specific cognitive domains, larger hippocampus volume, lower total volume of white matter hyperintensities, and higher fractional anisotropy and lower mean diffusivity in the fornix. In conclusion, longer TL is inversely associated with AD/ADRD, cognitive impairment, and brain structural lesions toward the development of AD/ADRD. However, the relationships between genetically determined TL and the outcomes above were not statistically significant based on the results from Mendelian randomization analysis results. Our findings add to the literature of prioritizing risk for AD/ADRD. The causality needs to be ascertained in mechanistic studies. [ABSTRACT FROM AUTHOR]
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- 2023
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20. Genome-wide Association Study of Parental Life Span
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Tanaka, Toshiko, Dutta, Ambarish, Pilling, Luke C, Xue, Luting, Lunetta, Kathryn L, Murabito, Joanne M, Bandinelli, Stefania, Wallace, Robert, Melzer, David, and Ferrucci, Luigi
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- 2017
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21. Association between Residential Exposure to Air Pollution and Incident Coronary Heart Disease Is Not Mediated by Leukocyte Telomere Length: A UK Biobank Study.
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Kuo, Chia-Ling, Liu, Rui, Godoy, Lucas da Cunha, Pilling, Luke C., Fortinsky, Richard H., and Brugge, Doug
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AIR pollution ,CORONARY disease ,AIR pollution measurement ,PROPORTIONAL hazards models ,TELOMERES ,LEUCOCYTES - Abstract
Higher air pollution exposure and shorter leukocyte telomere length (LTL) are both associated with increased risk of coronary heart disease (CHD), and share plausible mechanisms, including inflammation. LTL may serve as a biomarker of air pollution exposure and may be intervened with to reduce the risk of CHD. To the best of our knowledge, we are the first to test the mediation effect of LTL in the relationship between air pollution exposure and incident CHD. Using the UK Biobank (UKB) data (n = 317,601), we conducted a prospective study linking residential air pollution exposure (PM
2.5 , PM10 , NO2 , NOx ) and LTL to incident CHD during a mean follow-up of 12.6 years. Cox proportional hazards models and generalized additive models with penalized spline functions were used to model the associations of pollutant concentrations and LTL with incident CHD. We found non-linear associations of air pollution exposure with LTL and CHD. Pollutant concentrations in the lower range were decreasingly associated with longer LTL and reduced risk of CHD. The associations between lower pollutant concentrations and reduced risk of CHD, however, were minimally mediated by LTL (<3%). Our findings suggest that air pollution influences CHD through pathways that do not involve LTL. Replication is needed with improved measurements of air pollution that more accurately assesses personal exposure. [ABSTRACT FROM AUTHOR]- Published
- 2023
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22. Very Low and High Levels of Vitamin D Are Associated with Shorter Leukocyte Telomere Length in 148,321 UK Biobank Participants.
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Kuo, Chia-Ling, Kirk, Ben, Xiang, Meiruo, Pilling, Luke C., Kuchel, George A., Kremer, Richard, and Duque, Gustavo
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Background: Shorter leukocyte telomere length (LTL) is observed in multiple age-related diseases, which are also associated with vitamin D deficiency (i.e., osteosarcopenia, neurocognitive disorders, cancer, osteoarthritis, etc.), suggesting a close association between vitamin D and LTL. In this study, we examined the relationship between vitamin D levels and LTL in older participants of the UK Biobank. Methods: Data were collected from the UK Biobank. Participants aged 60 and older (n = 148,321) were included. Baseline LTL was measured using a multiplex qPCR technique and expressed as the ratio of the telomere amplification product (T) to that of a single-copy gene (S) (T/S ratio). Serum 25-hydroxyvitamin D (25OHD) was stratified by z score and linked to LTL in a linear regression model adjusting for covariates. Results: Compared to the medium level, a low (in the range of 16.6 nmol/L, 29.7 nmol/L) or extremely low (≤16.6 nmol/L) level of serum 25OHD was associated with shorter LTL: 0.018 SD (standardized β = −0.018, 95% CI −0.033 to −0.003, p = 0.022) and 0.048 SD (standardized β = −0.048, 95% CI −0.083 to −0.014, p = 0.006), respectively. Additionally, the high serum 25OHD groups (>95.9 nmol/L) had 0.038 SD (standardized β = −0.038, 95% CI −0.072 to −0.004, p = 0.030) shorter mean LTL than the group with medium 25OHD levels. The associations above were adjusted for multiple variables. Conclusions: In this population-based study, we identified an inverted U-shape relationship between LTL and vitamin D status. Our findings could be affected by unmeasured confounders. Whether high or low vitamin D-associated shorter LTL is mechanistically related to age-related conditions remains to be elucidated. [ABSTRACT FROM AUTHOR]
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- 2023
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23. Calcium‐channel blockers: Clinical outcome associations with reported pharmacogenetics variants in 32 000 patients.
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Türkmen, Deniz, Masoli, Jane A. H., Delgado, João, Kuo, Chia‐Ling, Bowden, Jack, Melzer, David, and Pilling, Luke C.
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PHARMACOGENOMICS ,TREATMENT effectiveness ,CORONARY disease ,GENETIC variation ,CARDIAC patients - Abstract
Aims: Pharmacogenetic variants impact dihydropyridine calcium‐channel blockers (dCCBs; e.g., amlodipine) treatment efficacy, yet evidence on clinical outcomes in routine primary care is limited. Reported associations in pharmacogenomics knowledge base PharmGKB have weak supporting evidence. We aimed to estimate associations between reported pharmacogenetic variants and incident adverse events in a community‐based cohort prescribed dCCB. Methods: We analysed up to 32 360 UK Biobank participants prescribed dCCB in primary care (from UK general practices, 1990–2017). We investigated 23 genetic variants. Outcomes were incident diagnosis of coronary heart disease, heart failure (HF), chronic kidney disease, oedema and switching antihypertensive medication. Results: Participants were aged 40–79 years at first dCCB prescription. Carriers of rs877087 T allele in RYR3 had increased risk of hazard ratio (HF 1.13: 95% confidence interval 1.02 to 1.25, P =.02). Although nonsignificant after multiple testing correction, the association is consistent with prior evidence. We estimated that if rs877087 T allele could experience the same treatment effect as noncarriers, the incidence of HF in patients prescribed dCCB would reduce by 9.2% (95% confidence interval 3.1 to 15.4). In patients with a history of heart disease prior to dCCB (n = 2296), rs877087 homozygotes had increased risk of new coronary heart disease or HF compared to CC variant. rs10898815 in NUMA1 and rs776746 in CYP3A5 increased likelihood of switching to an alternative antihypertensive. The remaining variants were not strongly or consistently associated with studied outcomes. Conclusion: Patients with common genetic variants in NUMA1, CYP3A5 and RYR3 had increased adverse clinical outcomes. Work is needed to establish whether outcomes of dCCB prescribing could be improved by prior knowledge of pharmacogenetics variants supported by clinical evidence of association with adverse events. [ABSTRACT FROM AUTHOR]
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- 2023
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24. Comparison of senescence-associated miRNAs in primary skin and lung fibroblasts
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Holly, Alice C., Grellscheid, Sushma, van de Walle, Pieter, Dolan, David, Pilling, Luke C., Daniels, Darren J., von Zglinicki, Thomas, Ferrucci, Luigi, Melzer, David, and Harries, Lorna W.
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- 2015
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25. Changes in CEBPB expression in circulating leukocytes following eccentric elbow-flexion exercise
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Blackwell, Jamie, Harries, Lorna W., Pilling, Luke C., Ferrucci, Luigi, Jones, Andrew, and Melzer, David
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- 2015
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26. Genomics and multimorbidity.
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Masoli, Jane A H, Pilling, Luke C, and Frayling, Timothy M
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PHARMACOGENOMICS , *INDIVIDUALIZED medicine , *GENETIC variation , *GENOMICS , *AGING , *COMORBIDITY - Abstract
Multimorbidity has increased in prevalence world-wide. It is anticipated to affect over 1 in 6 of the UK population by 2035 and is now recognised as a global priority for health research. Genomic medicine has rapidly advanced over the last 20 years from the first sequencing of the human genome to integration into clinical care for rarer conditions. Genetic studies help identify new disease mechanisms as they are less susceptible to the bias and confounding that affects epidemiological studies, as genetics are assigned from conception. There is also genetic variation in the efficacy of medications and the risk of side effects, pharmacogenetics. Genomic approaches offer the potential to improve our understanding of mechanisms underpinning multiple long-term conditions/multimorbidity and guide precision approaches to risk, diagnosis and optimisation of management. In this commentary as part of the Age and Ageing 50th anniversary commentary series, we summarise genomics and the potential utility of genomics in multimorbidity. [ABSTRACT FROM AUTHOR]
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- 2022
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27. Genetic modifiers of penetrance to liver endpoints in HFE hemochromatosis: Associations in a large community cohort.
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Pilling, Luke C., Atkins, Janice L., and Melzer, David
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- 2022
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28. Gene expression markers of age-related inflammation in two human cohorts
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Pilling, Luke C., Joehanes, Roby, Melzer, David, Harries, Lorna W., Henley, William, Dupuis, Josée, Lin, Honghuang, Mitchell, Marcus, Hernandez, Dena, Ying, Sai-Xia, Lunetta, Kathryn L., Benjamin, Emelia J., Singleton, Andrew, Levy, Daniel, Munson, Peter, Murabito, Joanne M., and Ferrucci, Luigi
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- 2015
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29. Sarcopenia and Variation in the Human Leukocyte Antigen Complex
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Jones, Garan, Pilling, Luke C, Kuo, Chia-Ling, Kuchel, George, Ferrucci, Luigi, and Melzer, David
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Inflammation ,Male ,UK Biobank ,Sarcopenia ,Genotype ,Hand Strength ,THE JOURNAL OF GERONTOLOGY: Medical Sciences ,Articles ,Middle Aged ,musculoskeletal system ,Polymorphism, Single Nucleotide ,United Kingdom ,Autoimmune Diseases ,body regions ,Phenotype ,HLA Antigens ,Surveys and Questionnaires ,Muscle ,Humans ,Female ,human activities ,Autoimmune ,Aged ,Genome-Wide Association Study - Abstract
Background Aging is characterized by chronic inflammation plus loss of muscle mass and strength, termed sarcopenia. Human leukocyte antigen (HLA) types are drivers of autoimmune disease, although with limited penetrance. We tested whether autoimmune diagnoses are associated with sarcopenia, and whether HLA types and related genetic variants are associated with sarcopenia in autoimmune disease-free older people. Methods Data were collected from 181,301 UK Biobank European descent volunteers aged 60–70 with measured hand grip strength and impedance. Logistic regression analysis estimated HLA type and sarcopenia associations, adjusted for confounders and multiple testing. Results Having any autoimmune diagnosis was associated with sarcopenia (odds ratio [OR] 1.83, 95% confidence interval (CI) 1.74–1.92, p = 4.0*10−125). After excluding autoimmune diagnoses, 6 of 100 HLA types (allele frequency >1%) were associated with sarcopenia (low grip strength and muscle mass). Having two HLA-DQA1*03:01 alleles increased odds of sarcopenia by 19.3% (OR 1.19, CI 1.09–1.29, p = 2.84*10–5), compared to no alleles. Having ≥6 of the 12 HLA alleles increased sarcopenia odds by 23% (OR 1.23, CI 1.12–1.35, p = 7.28*10–6). Of 658 HLA region non-coding genetic variants previously implicated in disease, 4 were associated with sarcopenia, including rs41268896 and rs29268645 (OR 1.08, CI 1.05–1.11, p = 1.06*10–8 and 1.07, CI 1.04–1.09, p = 1.5*10–6, respectively). Some HLA associations with sarcopenia were greater in female participants. Conclusion Autoimmune diagnoses are strongly associated with sarcopenia in 60- to 70-year olds. Variation in specific HLA types and non-coding single nucleotide polymorphisms is also associated with sarcopenia in older carriers free of diagnosed autoimmune diseases. Patients with sarcopenia might benefit from targeted treatment of autoimmune processes.
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- 2019
30. Hereditary Hemochromatosis Variant Associations with Incident Nonliver Malignancies: 11-Year Follow-up in UK Biobank.
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Atkins, Janice L., Pilling, Luke C., Torti, Suzy V., Torti, Frank M., Kuchel, George A., and Melzer, David
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Background: In European ancestry populations, iron overload disorder hereditary hemochromatosis is predominantly caused by HFE p.C282Y and p.H63D mutations. Male p.C282Y homozygotes have markedly increased hepatic malignancy incidence, but risks for other cancers in male and female homozygotes are unclear. Methods: 451,143 UK Biobank European ancestry participants (aged 40-70 years; 54.3% female) were followed (mean 11.6 years) via hospital admissions and national cancer registries. We estimated risks of any incident cancer (other than nonmelanoma and liver cancer) and common incident cancers [bladder, blood (with subanalyses of leukemia and lymphoma), bone, brain, breast, colorectal, kidney, lung, melanoma, esophageal, ovarian, pancreatic, prostate and stomach] in those with p.C282Y and p.H63D genotypes, compared with participants without HFE mutations. Results: Male p.C282Y homozygotes (n = 2,890, 12.1% with baseline diagnosed hereditary hemochromatosis) had increased incidence of prostate cancer [6.8% vs. 5.4% without mutations; HR = 1.32; 95% confidence interval (CI), 1.07-1.63; P = 0.01; Bonferroni adjusted P = 0.17] during follow-up. In life table estimates from ages 40 to 75 years, 14.4% of male p.C282Y homozygotes are projected to develop prostate cancer (versus 10.7% without mutations, excess 3.8%; 95% CI, 1.3-6.8). No increases in risks were found for other studied cancers in male or female p.C282Y homozygotes, or in any other p.C282Y/p.H63D genotype groups of either sex. Conclusions: In a large community sample of male p.C282Y homozygotes, there is suggestive evidence of increased prostate cancer incidence, with no evidence of excess of other studied (nonliver) cancers. [ABSTRACT FROM AUTHOR]
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- 2022
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31. Statin treatment effectiveness and the SLCO1B1*5 reduced function genotype: Long‐term outcomes in women and men.
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Türkmen, Deniz, Masoli, Jane A. H., Kuo, Chia‐Ling, Bowden, Jack, Melzer, David, and Pilling, Luke C.
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STATINS (Cardiovascular agents) ,TREATMENT effectiveness ,TERMINATION of treatment ,GENOTYPES ,MEDICAL prescriptions ,ATORVASTATIN - Abstract
Objective: To estimate the effect of rs4149056 (SLCO1B1*5) genotype (decreases statin transport) on cholesterol control and treatment duration in male and female primary care patients prescribed common statin medications. Methods and Analysis: This study comprised 69 185 European‐ancestry UK Biobank cohort participants prescribed simvastatin or atorvastatin (aged 40‐79 years at first prescription, treatment duration 1 month to 29 years, mean 5.7 years). Principal outcomes were clinically high total cholesterol (>5 mmol/L) at baseline, plus treatment discontinuation. Results: A total of 48.4% of 591 females homozygous for SLCO1B1*5 decreased function genotype had raised cholesterol vs 41.7% of those with functioning SLCO1B1 (odds ratio 1.31, 95% confidence interval [CI] 1.1‐1.55, P =.001). Fewer males had high cholesterol and the genotype effect was attenuated. In primary care prescribing, females homozygous for SLCO1B1*5 were more likely to stop receiving these statins (29.5%) than women with normal SLCO1B1 (25.7%) (hazard ratio [HR] 1.19, 95% CI 1.03‐1.37, P =.01), amounting to five discontinuations per 100 statin‐years in the SLCO1B1*5 group vs four in the normal SLCO1B1 function group. This remained significant after the first year of treatment (HR for discontinuing >1 year after first prescription 1.3, 95% CI 1.08‐1.56, P =.006). In men SLCO1B1*5 was only associated with treatment discontinuation in the first year. Conclusions: In this large community sample of patients on commonly prescribed statins, the SLCO1B1*5 decreased function variant had much larger effects on cholesterol control and treatment duration in women than in men. Efforts to improve the effectiveness of statin therapy in women may need to include SLCO1B1*5 genotype‐guided statin selection. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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32. Impact of Low Cardiovascular Risk Profiles on Geriatric Outcomes: Evidence From 421,000 Participants in Two Cohorts
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Atkins, Janice L, Delgado, João, Pilling, Luke C, Bowman, Kirsty, Masoli, Jane A H, Kuchel, George A, Ferrucci, Luigi, and Melzer, David
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Blood Glucose ,Male ,Incontinence ,Frailty ,Smoking ,Chronic pain ,Blood Pressure ,Articles ,Cholesterol, LDL ,Middle Aged ,Cardiovascular risk ,United Kingdom ,Body Mass Index ,Cohort Studies ,Healthy aging ,Logistic Models ,The Journal of Gerontology: Medical Sciences ,Cardiovascular Diseases ,Risk Factors ,Humans ,Female ,Exercise ,Geriatric Assessment ,Aged ,Proportional Hazards Models - Abstract
Background Individuals with low cardiovascular risk factor profiles experience lower rates of cardiovascular diseases, but associations with geriatric syndromes are unclear. We tested whether individuals with low cardiovascular disease risk, aged 60–69 years old at baseline in two large cohorts, were less likely to develop aging-related adverse health outcomes. Methods Data were from population representative medical records (Clinical Practice Research Datalink [CPRD] England, n = 239,591) and healthy volunteers (UK Biobank [UKB], n = 181,820), followed for ≤10 years. A cardiovascular disease risk score (CRS) summarized smoking status, LDL-cholesterol, blood pressure, body mass index, fasting glucose and physical activity, grouping individuals as low (ie, all factors near ideal), moderate, or high CRS. Logistic regression, Cox models, and Fine and Grey risk models tested the associations between the CRS and health outcomes. Results Low CRS individuals had less chronic pain (UKB: baseline odds ratio = 0.52, confidence interval [CI] = 0.50–0.54), lower incidence of incontinence (CPRD: subhazard ratio [sub-HR] = 0.75, 0.63–0.91), falls (sub-HR = 0.82, CI = 0.73–0.91), fragility fractures (sub-HR = 0.78, CI = 0.65–0.93), and dementia (vs. high risks; UKB: sub-HR = 0.67, CI = 0.50–0.89; CPRD: sub-HR = 0.79, CI = 0.56–1.12). Only 5.4% in CPRD with low CRS became frail (Rockwood index) versus 24.2% with high CRS. All-cause mortality was markedly lower in the low CRS group (vs. high CRS; HR = 0.40, 95% CI = 0.35–0.47). All associations showed dose–response relationships, and results were similar in both cohorts. Conclusions Persons aged 60–69 years with near-ideal cardiovascular risk factor profiles have substantially lower incidence of geriatric conditions and frailty. Optimizing cardiovascular disease risk factors may substantially reduce the burden of morbidity in later life.
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- 2018
33. Uric Acid Measurement Improves Prediction of Cardiovascular Mortality in Later Life
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Dutta, Ambarish, Henley, William, Pilling, Luke C., Wallace, Robert B., and Melzer, David
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- 2013
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34. CCAAT-enhancer-binding protein-beta expression in vivo is associated with muscle strength
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Harries, Lorna W., Pilling, Luke C., Hernandez, Dena L. G., Bradley-Smith, Rachel, Henley, William, Singleton, Andrew B., Guralnik, Jack M., Bandinelli, Stefania, Ferrucci, Luigi, and Melzer, David
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- 2012
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35. A genome‐wide association study of the frailty index highlights brain pathways in ageing.
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Atkins, Janice L., Jylhävä, Juulia, Pedersen, Nancy L., Magnusson, Patrik K., Lu, Yi, Wang, Yunzhang, Hägg, Sara, Melzer, David, Williams, Dylan M., and Pilling, Luke C.
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GENOME-wide association studies ,FRAILTY ,DISEASE risk factors ,CARDIOVASCULAR diseases ,FRONTAL lobe ,FRAIL elderly - Abstract
Frailty is a common geriatric syndrome and strongly associated with disability, mortality and hospitalization. Frailty is commonly measured using the frailty index (FI), based on the accumulation of a number of health deficits during the life course. The mechanisms underlying FI are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 30 and 45%. Understanding the genetic determinants and biological mechanisms underpinning FI may help to delay or even prevent frailty. We performed a genome‐wide association study (GWAS) meta‐analysis of a frailty index in European descent UK Biobank participants (n = 164,610, 60–70 years) and Swedish TwinGene participants (n = 10,616, 41–87 years). FI calculation was based on 49 or 44 self‐reported items on symptoms, disabilities and diagnosed diseases for UK Biobank and TwinGene, respectively. 14 loci were associated with the FI (p < 5*10−8). Many FI‐associated loci have established associations with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, one appears to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 11% (0.11, SE 0.005). In enrichment analysis, genes expressed in the frontal cortex and hippocampus were significantly downregulated (adjusted p < 0.05). We also used Mendelian randomization to identify modifiable traits and exposures that may affect frailty risk, with a higher educational attainment genetic risk score being associated with a lower degree of frailty. Risk of frailty is influenced by many genetic factors, including well‐known disease risk factors and mental health, with particular emphasis on pathways in the brain. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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36. Biological Aging Predicts Vulnerability to COVID-19 Severity in UK Biobank Participants.
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Kuo, Chia-Ling, Pilling, Luke C, Atkins, Janice L, Masoli, Jane A H, Delgado, João, Tignanelli, Christopher, Kuchel, George A, Melzer, David, Beckman, Kenneth B, and Levine, Morgan E
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COVID-19 , *COVID-19 pandemic , *DISEASE risk factors , *AGE , *DISEASE prevalence - Abstract
Background: Age and disease prevalence are the 2 biggest risk factors for Coronavirus disease 2019 (COVID-19) symptom severity and death. We therefore hypothesized that increased biological age, beyond chronological age, may be driving disease-related trends in COVID-19 severity.Methods: Using the UK Biobank England data, we tested whether a biological age estimate (PhenoAge) measured more than a decade prior to the COVID-19 pandemic was predictive of 2 COVID-19 severity outcomes (inpatient test positivity and COVID-19-related mortality with inpatient test-confirmed COVID-19). Logistic regression models were used with adjustment for age at the pandemic, sex, ethnicity, baseline assessment centers, and preexisting diseases/conditions.Results: Six hundred and thirteen participants tested positive at inpatient settings between March 16 and April 27, 2020, 154 of whom succumbed to COVID-19. PhenoAge was associated with increased risks of inpatient test positivity and COVID-19-related mortality (ORMortality = 1.63 per 5 years, 95% CI: 1.43-1.86, p = 4.7 × 10-13) adjusting for demographics including age at the pandemic. Further adjustment for preexisting diseases/conditions at baseline (ORM = 1.50, 95% CI: 1.30-1.73 per 5 years, p = 3.1 × 10-8) and at the early pandemic (ORM = 1.21, 95% CI: 1.04-1.40 per 5 years, p = .011) decreased the association.Conclusions: PhenoAge measured in 2006-2010 was associated with COVID-19 severity outcomes more than 10 years later. These associations were partly accounted for by prevalent chronic diseases proximate to COVID-19 infection. Overall, our results suggest that aging biomarkers, like PhenoAge may capture long-term vulnerability to diseases like COVID-19, even before the accumulation of age-related comorbid conditions. [ABSTRACT FROM AUTHOR]- Published
- 2021
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37. Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans
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Lee, Benjamin P., Pilling, Luke C., Emond, Florence, Flurkey, Kevin, Harrison, David E., Yuan, Rong, Peters, Luanne L., Kuchel, George A., Ferrucci, Luigi, Melzer, David, and Harries, Lorna W.
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Muscles ,Longevity ,isoforms ,Genetic Variation ,Original Articles ,mRNA splicing ,Mice, Inbred C57BL ,Alternative Splicing ,splicing factors ,Mice, Inbred NOD ,Animals ,Humans ,Protein Isoforms ,Original Article ,RNA Splicing Factors ,RNA, Messenger ,lifespan ,mouse ,Spleen - Abstract
Summary Dysregulation of splicing factor expression and altered alternative splicing are associated with aging in humans and other species, and also with replicative senescence in cultured cells. Here, we assess whether expression changes of key splicing regulator genes and consequent effects on alternative splicing are also associated with strain longevity in old and young mice, across 6 different mouse strains with varying lifespan (A/J, NOD.B10Sn‐H2b/J, PWD.Phj, 129S1/SvlmJ, C57BL/6J and WSB/EiJ). Splicing factor expression and changes to alternative splicing were associated with strain lifespan in spleen and to a lesser extent in muscle. These changes mainly involved hnRNP splicing inhibitor transcripts with most changes more marked in spleens of young animals from long‐lived strains. Changes in spleen isoform expression were suggestive of reduced cellular senescence and retained cellular proliferative capacity in long‐lived strains. Changes in muscle isoform expression were consistent with reduced pro‐inflammatory signalling in longer‐lived strains. Two splicing regulators, HNRNPA1 and HNRNPA2B1, were also associated with parental longevity in humans, in the InCHIANTI aging study. Splicing factors may represent a driver, mediator or early marker of lifespan in mouse, as expression differences were present in the young animals of long‐lived strains. Changes to alternative splicing patterns of key senescence genes in spleen and key remodelling genes in muscle suggest that correct regulation of alternative splicing may enhance lifespan in mice. Expression of some splicing factors in humans was also associated with parental longevity, suggesting that splicing regulation may also influence lifespan in humans.
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- 2016
38. Genetic associations for two biological age measures point to distinct aging phenotypes.
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Kuo, Chia‐Ling, Pilling, Luke C., Liu, Zuyun, Atkins, Janice L., and Levine, Morgan E.
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AGING , *PHENOTYPES , *GENOME-wide association studies , *AGE , *CLINICAL biochemistry - Abstract
Biological age measures outperform chronological age in predicting various aging outcomes, yet little is known regarding genetic predisposition. We performed genome‐wide association scans of two age‐adjusted biological age measures (PhenoAgeAcceleration and BioAgeAcceleration), estimated from clinical biochemistry markers (Levine et al., 2018; Levine, 2013) in European‐descent participants from UK Biobank. The strongest signals were found in the APOE gene, tagged by the two major protein‐coding SNPs, PhenoAgeAccel—rs429358 (APOE e4 determinant) (p = 1.50 × 10−72); BioAgeAccel—rs7412 (APOE e2 determinant) (p = 3.16 × 10−60). Interestingly, we observed inverse APOE e2 and e4 associations and unique pathway enrichments when comparing the two biological age measures. Genes associated with BioAgeAccel were enriched in lipid related pathways, while genes associated with PhenoAgeAccel showed enrichment for immune system, cell function, and carbohydrate homeostasis pathways, suggesting the two measures capture different aging domains. Our study reaffirms that aging patterns are heterogeneous across individuals, and the manner in which a person ages may be partly attributed to genetic predisposition. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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39. Hemochromatosis Mutations, Brain Iron Imaging, and Dementia in the UK Biobank Cohort.
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Atkins, Janice L, Pilling, Luke C, Heales, Christine J, Savage, Sharon, Kuo, Chia-Ling, Kuchel, George A, Steffens, David C, and Melzer, David
- Abstract
Background: Brain iron deposition occurs in dementia. In European ancestry populations, the HFE p.C282Y variant can cause iron overload and hemochromatosis, mostly in homozygous males.Objective: To estimate p.C282Y associations with brain MRI features plus incident dementia diagnoses during follow-up in a large community cohort.Methods: UK Biobank participants with follow-up hospitalization records (mean 10.5 years). MRI in 206 p.C282Y homozygotes versus 23,349 without variants, including T2* measures (lower values indicating more iron).Results: European ancestry participants included 2,890 p.C282Y homozygotes. Male p.C282Y homozygotes had lower T2* measures in areas including the putamen, thalamus, and hippocampus, compared to no HFE mutations. Incident dementia was more common in p.C282Y homozygous men (Hazard Ratio HR = 1.83; 95% CI 1.23 to 2.72, p = 0.003), as was delirium. There were no associations in homozygote women or in heterozygotes.Conclusion: Studies are needed of whether early iron reduction prevents or slows related brain pathologies in male HFE p.C282Y homozygotes. [ABSTRACT FROM AUTHOR]- Published
- 2021
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40. Low Vitamin D Levels and Risk of Incident Delirium in 351,000 Older UK Biobank Participants.
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Pilling, Luke C., Jones, Lindsay C., Masoli, Jane A. H., Delgado, João, Atkins, Janice L., Bowden, Jack, Fortinsky, Richard H., Kuchel, George A., and Melzer, David
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HEALTH of older people , *VITAMIN D deficiency , *BIOMARKERS , *OLD age ,RISK of delirium - Abstract
BACKGROUND/OBJECTIVES: Delirium is common in older adults, especially following hospitalization. Because low vitamin D levels may be associated with increased delirium risk, we aimed to determine the prognostic value of blood vitamin D levels, extending our previous genetic analyses of this relationship. DESIGN: Prospective cohort analysis. SETTING: Community‐based cohort study of adults from 22 cities across the United Kingdom (the UK Biobank). PARTICIPANTS: Adults aged 60 and older by the end of follow‐up in the linked hospital inpatient admissions data, up to 14 years after baseline (n = 351,320). MEASUREMENTS: At baseline, serum vitamin D (25‐OH‐D) levels were measured. We used time‐to‐event models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between vitamin D deficiency and incident hospital‐diagnosed delirium, adjusted for age, sex, assessment month, assessment center, and ethnicity. We performed Mendelian randomization genetic analysis in European participants to further investigate vitamin D and delirium risk. RESULTS: A total of 3,634 (1.03%) participants had at least one incident hospital‐diagnosed delirium episode. Vitamin D deficiency (<25 nmol/L) predicted a large incidence in delirium (HR = 2.49; 95% CI = 2.24–2.76; P = 3*10−68, compared with >50 nmol/L). Increased risk was not limited to the deficient group: insufficient levels (25–50 nmol/L) were also at increased risk (HR = 1.38; 95% CI = 1.28–1.49; P = 4*10−18). The association was independent of calcium levels, hospital‐diagnosed fractures, dementia, and other relevant cofactors. In genetic analysis, participants carrying more vitamin D–increasing variants had a reduced likelihood of incident delirium diagnosis (HR =.80 per standard deviation increase in genetically instrumented vitamin D:.73–.87; P = 2*10−7). CONCLUSION: Progressively lower vitamin D levels predicted increased risks of incident hospital‐diagnosed delirium, and genetic evidence supports a shared causal pathway. Because low vitamin D levels are simple to detect and inexpensive and safe to correct, an intervention trial to confirm these results is urgently needed. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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41. Association of Hemochromatosis HFE p.C282Y Homozygosity With Hepatic Malignancy.
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Atkins, Janice L., Pilling, Luke C., Masoli, Jane A. H., Kuo, Chia-Ling, Shearman, Jeremy D., Adams, Paul C., and Melzer, David
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- *
HEMOCHROMATOSIS , *HOMOZYGOSITY , *LIVER cancer , *CANCER-related mortality , *GENETIC disorder diagnosis - Abstract
Importance: Hereditary hemochromatosis is predominantly caused by the HFE p.C282Y homozygous pathogenic variant. Liver carcinoma and mortality risks are increased in individuals with clinically diagnosed hereditary hemochromatosis, but risks are unclear in mostly undiagnosed p.C282Y homozygotes identified in community genotyping.Objective: To estimate the incidence of primary hepatic carcinoma and death by HFE variant status.Design, Setting, and Participants: Cohort study of 451 186 UK Biobank participants of European ancestry (aged 40-70 years), followed up from baseline assessment (2006-2010) until January 2018.Exposures: Men and women with HFE p.C282Y and p.H63D genotypes compared with those with neither HFE variants.Main Outcomes and Measures: Two linked co-primary outcomes (incident primary liver carcinoma and death from any cause) were ascertained from follow-up via hospital inpatient records, national cancer registry, and death certificate records, and from primary care data among a subset of participants for whom data were available. Associations between genotype and outcomes were tested using Cox regression adjusted for age, assessment center, genotyping array, and population genetics substructure. Kaplan-Meier lifetable probabilities of incident diagnoses were estimated from age 40 to 75 years by HFE genotype and sex.Results: A total of 451 186 participants (mean [SD] age, 56.8 [8.0] years; 54.3% women) were followed up for a median (interquartile range) of 8.9 (8.3-9.5) years. Among the 1294 male p.C282Y homozygotes, there were 21 incident hepatic malignancies, 10 of which were in participants without a diagnosis of hemochromatosis at baseline. p.C282Y homozygous men had a higher risk of hepatic malignancies (hazard ratio [HR], 10.5 [95% CI, 6.6-16.7]; P < .001) and all-cause mortality (n = 88; HR, 1.2 [95% CI, 1.0-1.5]; P = .046) compared with men with neither HFE variant. In lifetables projections for male p.C282Y homozygotes to age 75 years, the risk of primary hepatic malignancy was 7.2% (95% CI, 3.9%-13.1%), compared with 0.6% (95% CI, 0.4%-0.7%) for men with neither variant, and the risk of death was 19.5% (95% CI, 15.8%-24.0%), compared with 15.1% (95% CI, 14.7%-15.5%) among men with neither variant. Among female p.C282Y homozygotes (n = 1596), there were 3 incident hepatic malignancies and 60 deaths, but the associations between homozygosity and hepatic malignancy (HR, 2.1 [95% CI, 0.7-6.5]; P = .22) and death (HR, 1.2 [95% CI, 0.9-1.5]; P = .20) were not statistically significant.Conclusions and Relevance: Among men with HFE p.C282Y homozygosity, there was a significantly increased risk of incident primary hepatic malignancy and death compared with men without p.C282Y or p.H63D variants; there was not a significant association for women. Further research is needed to understand the effects of early diagnosis and treatment. [ABSTRACT FROM AUTHOR]- Published
- 2020
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42. Preexisting Comorbidities Predicting COVID-19 and Mortality in the UK Biobank Community Cohort.
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Atkins, Janice L, Masoli, Jane A H, Delgado, Joao, Pilling, Luke C, Kuo, Chia-Ling, Kuchel, George A, and Melzer, David
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COVID-19 ,COMORBIDITY ,CORONARY disease ,OBSTRUCTIVE lung diseases ,TYPE 2 diabetes - Abstract
Background: Hospitalized COVID-19 patients tend to be older and frequently have hypertension, diabetes, or coronary heart disease, but whether these comorbidities are true risk factors (ie, more common than in the general older population) is unclear. We estimated associations between preexisting diagnoses and hospitalized COVID-19 alone or with mortality, in a large community cohort.Methods: UK Biobank (England) participants with baseline assessment 2006-2010, followed in hospital discharge records to 2017 and death records to 2020. Demographic and preexisting common diagnoses association tested with hospitalized laboratory-confirmed COVID-19 (March 16 to April 26, 2020), alone or with mortality, in logistic models.Results: Of 269 070 participants aged older than 65, 507 (0.2%) became COVID-19 hospital inpatients, of which 141 (27.8%) died. Common comorbidities in hospitalized inpatients were hypertension (59.6%), history of fall or fragility fractures (29.4%), coronary heart disease (21.5%), type 2 diabetes (type 2, 19. 9%), and asthma (17.6%). However, in models adjusted for comorbidities, age group, sex, ethnicity, and education, preexisting diagnoses of dementia, type 2 diabetes, chronic obstructive pulmonary disease, pneumonia, depression, atrial fibrillation, and hypertension emerged as independent risk factors for COVID-19 hospitalization, the first 5 remaining statistically significant for related mortality. Chronic kidney disease and asthma were risk factors for COVID-19 hospitalization in women but not men.Conclusions: There are specific high-risk preexisting comorbidities for COVID-19 hospitalization and related deaths in community-based older men and women. These results do not support simple age-based targeting of the older population to prevent severe COVID-19 infections. [ABSTRACT FROM AUTHOR]- Published
- 2020
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43. The Longevity-Associated SH2B3 (LNK) Genetic Variant: Selected Aging Phenotypes in 379,758 Subjects.
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Kuo, Chia-Ling, Joaquim, Micaella, Kuchel, George A, Ferrucci, Luigi, Harries, Lorna W, Pilling, Luke C, Melzer, David, and Harries, Lorna
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LEUKOCYTE count ,CORONARY disease ,CHILD death ,PARENTAL death ,CARDIOVASCULAR diseases ,ALLELES in plants ,DATABASES ,RESEARCH ,GENETICS ,RESEARCH methodology ,GENETIC polymorphisms ,ALLELES ,EVALUATION research ,MEDICAL cooperation ,COMPARATIVE studies ,RESEARCH funding ,LONGEVITY ,GENETIC techniques ,CARRIER proteins ,PARENTS - Abstract
Human SH2B3 is involved in growth factor and inflammation signaling. A SH2B3 missense variant (rs3184504) is associated with cardiovascular diseases plus breast, colorectal, and lung cancers, with highly correlated variants across the ATXN2/SH2B3/BRAP locus linked to parental age at death, suggesting a geroscience common mechanism of aging and disease. To better understand the SH2B3-related aging pathway and its potential as an intervention target, we undertook a phenotype-wide association study (PheWAS) of 52 aging traits. Data were obtained from 379,758 European-descent UK Biobank participants, aged 40-70 at baseline: 27% of participants were CC homozygotes and 23% TT at rs3184504. Parental extreme longevity (mothers aged ≥98 years, fathers aged ≥96 years) was more common in CC versus TT (odds ratio [OR] = 1.18, 95% confidence interval [CI]: 1.07 to 1.29) with an additive per allele effect. The C allele associated with better cognitive function and white blood cell counts were more likely to be normal. The C allele reduced risks of coronary heart disease (OR = 0.95, 95% CI: 0.93 to 0.96) but was also associated with a modestly higher cancer rate (OR = 1.03, 95% CI: 1.02 to 1.04), suggesting a trade-off across aging outcomes and limiting its potential as an anti-aging target. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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44. Sarcopenia and Variation in the Human Leukocyte Antigen Complex.
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Jones, Garan, Pilling, Luke C, Kuo, Chia-Ling, Kuchel, George, Ferrucci, Luigi, and Melzer, David
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HLA histocompatibility antigens , *SARCOPENIA , *SINGLE nucleotide polymorphisms , *LOGISTIC regression analysis , *MUSCLE mass - Abstract
Background: Aging is characterized by chronic inflammation plus loss of muscle mass and strength, termed sarcopenia. Human leukocyte antigen (HLA) types are drivers of autoimmune disease, although with limited penetrance. We tested whether autoimmune diagnoses are associated with sarcopenia, and whether HLA types and related genetic variants are associated with sarcopenia in autoimmune disease-free older people.Methods: Data were collected from 181,301 UK Biobank European descent volunteers aged 60-70 with measured hand grip strength and impedance. Logistic regression analysis estimated HLA type and sarcopenia associations, adjusted for confounders and multiple testing.Results: Having any autoimmune diagnosis was associated with sarcopenia (odds ratio [OR] 1.83, 95% confidence interval (CI) 1.74-1.92, p = 4.0*10-125). After excluding autoimmune diagnoses, 6 of 100 HLA types (allele frequency >1%) were associated with sarcopenia (low grip strength and muscle mass). Having two HLA-DQA1*03:01 alleles increased odds of sarcopenia by 19.3% (OR 1.19, CI 1.09-1.29, p = 2.84*10-5), compared to no alleles. Having ≥6 of the 12 HLA alleles increased sarcopenia odds by 23% (OR 1.23, CI 1.12-1.35, p = 7.28*10-6). Of 658 HLA region non-coding genetic variants previously implicated in disease, 4 were associated with sarcopenia, including rs41268896 and rs29268645 (OR 1.08, CI 1.05-1.11, p = 1.06*10-8 and 1.07, CI 1.04-1.09, p = 1.5*10-6, respectively). Some HLA associations with sarcopenia were greater in female participants.Conclusion: Autoimmune diagnoses are strongly associated with sarcopenia in 60- to 70-year olds. Variation in specific HLA types and non-coding single nucleotide polymorphisms is also associated with sarcopenia in older carriers free of diagnosed autoimmune diseases. Patients with sarcopenia might benefit from targeted treatment of autoimmune processes. [ABSTRACT FROM AUTHOR]- Published
- 2020
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45. Impact of Low Cardiovascular Risk Profiles on Geriatric Outcomes: Evidence From 421,000 Participants in Two Cohorts.
- Author
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Atkins, Janice L, Delgado, João, Pilling, Luke C, Bowman, Kirsty, Masoli, Jane A H, Kuchel, George A, Ferrucci, Luigi, and Melzer, David
- Abstract
Background: Individuals with low cardiovascular risk factor profiles experience lower rates of cardiovascular diseases, but associations with geriatric syndromes are unclear. We tested whether individuals with low cardiovascular disease risk, aged 60-69 years old at baseline in two large cohorts, were less likely to develop aging-related adverse health outcomes.Methods: Data were from population representative medical records (Clinical Practice Research Datalink [CPRD] England, n = 239,591) and healthy volunteers (UK Biobank [UKB], n = 181,820), followed for ≤10 years. A cardiovascular disease risk score (CRS) summarized smoking status, LDL-cholesterol, blood pressure, body mass index, fasting glucose and physical activity, grouping individuals as low (ie, all factors near ideal), moderate, or high CRS. Logistic regression, Cox models, and Fine and Grey risk models tested the associations between the CRS and health outcomes.Results: Low CRS individuals had less chronic pain (UKB: baseline odds ratio = 0.52, confidence interval [CI] = 0.50-0.54), lower incidence of incontinence (CPRD: subhazard ratio [sub-HR] = 0.75, 0.63-0.91), falls (sub-HR = 0.82, CI = 0.73-0.91), fragility fractures (sub-HR = 0.78, CI = 0.65-0.93), and dementia (vs. high risks; UKB: sub-HR = 0.67, CI = 0.50-0.89; CPRD: sub-HR = 0.79, CI = 0.56-1.12). Only 5.4% in CPRD with low CRS became frail (Rockwood index) versus 24.2% with high CRS. All-cause mortality was markedly lower in the low CRS group (vs. high CRS; HR = 0.40, 95% CI = 0.35-0.47). All associations showed dose-response relationships, and results were similar in both cohorts.Conclusions: Persons aged 60-69 years with near-ideal cardiovascular risk factor profiles have substantially lower incidence of geriatric conditions and frailty. Optimizing cardiovascular disease risk factors may substantially reduce the burden of morbidity in later life. [ABSTRACT FROM AUTHOR]- Published
- 2019
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46. Hereditary Hemochromatosis Associations with Frailty, Sarcopenia and Chronic Pain: Evidence from 200,975 Older UK Biobank Participants.
- Author
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Tamosauskaite, Jone, Atkins, Janice L, Pilling, Luke C, Kuo, Chia-Ling, Kuchel, George A, Ferrucci, Luigi, and Melzer, David
- Abstract
Background: Iron is essential for life but contributes to oxidative damage. In Northern-European ancestry populations, HFE gene C282Y mutations are relatively common (0.3%-0.6% rare homozygote prevalence) and associated with excessive iron absorption, fatigue, diabetes, arthritis, and liver disease, especially in men. Iron excess can be prevented or treated but diagnosis is often delayed or missed. Data on sarcopenia, pain, and frailty are scarce.Methods: Using 200,975 UK Biobank volunteers aged 60-70 years, we tested associations between C282Y homozygosity with Fried frailty, sarcopenia, and chronic pain using logistic regression adjusted for age and technical genetic covariates. As iron overload is progressive (with menstruation protective), we included specific analyses of older (65-70 years) females and males.Results: One thousand three hundred and twelve (0.65%) participants were C282Y homozygotes; 593 were men (0.62%) and 719 were women (0.68%). C282Y homozygote men had increased likelihoods of reporting chronic pain (odds ratio [OR] 1.23: 95% confidence interval [CI] 1.05-1.45, p = .01) and diagnoses of polymyalgia rheumatica, compared to common "wild-type" genotype. They were also more likely to have sarcopenia (OR 2.38: 1.80-3.13, p = 9.70 × 10-10) and frailty (OR 2.01: 1.45-2.80, p = 3.41 × 10-05). C282Y homozygote women (n = 312, 0.7%) aged 65-70 were more likely to be frail (OR 1.73: 1.05-2.84, p = .032) and have chronic knee, hip, and back pain. Overall, 1.50% of frail men and 1.51% of frail women in the 65-70 age group were C282Y homozygous.Conclusions: HFE C282Y homozygosity is associated with substantial excess sarcopenia, frailty, and chronic pain at older ages. Given the availability of treatment, hereditary hemochromatosis is a strong candidate for precision medicine approaches to improve outcomes in late life. [ABSTRACT FROM AUTHOR]- Published
- 2019
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47. Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank.
- Author
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Pilling, Luke C., Tamosauskaite, Jone, Jones, Garan, Wood, Andrew R., Jones, Lindsay, Chai- Ling Kuo, Kuchel, George A., Ferrucci, Luigi, and Melzer, David
- Published
- 2019
- Full Text
- View/download PDF
48. ApoE e4e4 Genotype and Mortality With COVID-19 in UK Biobank.
- Author
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Kuo, Chia-Ling, Pilling, Luke C, Atkins, Janice L, Masoli, Jane A H, Delgado, João, Kuchel, George A, and Melzer, David
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COVID-19 , *GENOTYPES , *MORTALITY - Published
- 2020
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49. Red cell distribution width and common disease onsets in 240,477 healthy volunteers followed for up to 9 years.
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Pilling, Luke C., Atkins, Janice L., Kuchel, George A., Ferrucci, Luigi, and Melzer, David
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ERYTHROCYTES , *PHYSIOLOGICAL effects of tobacco , *MORTALITY , *FOLLOW-up studies (Medicine) , *LONGITUDINAL method , *PHYSIOLOGY ,CARDIOVASCULAR disease related mortality - Abstract
Higher Red Blood Cell Distribution Width (RDW or anisocytosis) predicts incident coronary artery disease (CAD) plus all-cause and cardiovascular mortality, but its predictive value for other common diseases in healthy volunteers is less clear. We aimed to determine the shorter and longer term associations between RDW and incident common conditions in participants free of baseline disease, followed for 9 years. We undertook a prospective analysis of RDW% using 240,477 healthy UK Biobank study volunteers aged 40–70 years at baseline, with outcomes ascertained during follow-up (≤9 years). Participants were free of anemia, CAD, type-2 diabetes, stroke, hypertension, COPD, and any cancer (except non-melanoma skin cancer) at baseline. Survival models (with competing Hazards) tested associations with outcomes from hospital admission records and death certificates. High RDW (≥15% variation, n = 6,050) compared to low (<12.5% n = 20,844) was strongly associated with mortality (HR 3.10: 95% CI 2.57 to 3.74), adjusted for age, sex, smoking status, education level, mean cell volume and hemoglobin concentration. Higher RDW was also associated with incident CAD (sub-HR 1.67: 1.40 to 1.99), heart failure, peripheral vascular disease, atrial fibrillation, stroke, and cancer (sHR 1.37: 1.21 to 1.55; colorectal cancer sHR 1.92: 1.36 to 2.72), especially leukemia (sHR 2.85: 1.63 to 4.97). Associations showed dose-response relationships, and RDW had long-term predictive value (≥4.5 years after assessment) for the majority of outcomes, which were similar in younger and older persons. In conclusion, higher RDW predicted onsets of a wide range of common conditions as well as mortality in a large healthy volunteer cohort. RDW is not just a short term predictor, as high levels were predictive 4.5 to 9 years after baseline in healthy volunteers. The wide range of outcomes reflects known RDW genetic influences, including diverse disease risks. RDW may be a useful clinical marker for inclusion in wellness assessments. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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50. The VEGFA156b isoform is dysregulated in senescent endothelial cells and may be associated with prevalent and incident coronary heart disease.
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Latorre, Eva, Pilling, Luke C., Lee, Benjamin P., Bandinelli, Stefania, Melzer, David, Ferrucci, Luigi, and Harries, Lorna W.
- Subjects
- *
CORONARY disease , *VASCULAR endothelial growth factors , *CAUSES of death , *ENDOTHELIAL cells , *DISEASE prevalence , *DISEASE incidence , *AGE factors in disease - Abstract
Coronary heart disease (CHD) is a leading cause of morbidity in people over 65 years of age; >40% of all deaths are due to this condition. The association between increasing age and CHD is well documented; the accumulation of senescent cells in cardiac and vascular tissues may represent one factor underpinning this observation. We aimed to identify senescence-related expression changes in primary human senescent cardiomyocytes and endothelial cells and to relate transcript expression in peripheral blood leucocytes to prevalent and incident CHD in the InCHIANTI study of aging. We quantified splicing factor expression and splicing patterns of candidate transcripts in proliferative and senescent later passage endothelial cells and cardiomyocytes using qRTPCR. Senescence-associated isoforms also expressed in peripheral blood leucocytes were then examined for associations with CHD status in 134 pairs of age, sex and BMI-matched CHD cases and controls. Splicing factor expression was dysregulated in senescent cardiomyocytes, as previously reported for endothelial cells, as was the expression of alternatively expressed cardiac and vascular candidate genes in both cell types. We found nominal associations between the expression of VEGFA156b and FNI-EIIIIA isoforms in peripheral blood mRNA and CHD status. Dysregulated splicing factor expression is a key feature of senescent cardiomyocytes and endothelial cells. Altered splicing of key cardiac or endothelial genes may contribute to the risk of CHD in the human population. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
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