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101. Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies

Author

Nettleton, J.A., McKeown, N.M., Kanoni, S., Lemaitre, R.N., Hivert, M.F., Ngwa, J., van Rooij, F.J., Sonestedt, E., Wojczynski, M.K., Ye, Z., Tanaka, T., Garcia, M., Anderson, J.S., Follis, J.L., Djousse, L., Mukamal, K., Papoutsakis, C., Mozaffarian, D., Zillikens, M.C., Bandinelli, S., Bennett, A.J., Borecki, I.B., Feitosa, M.F., Ferrucci, L., Forouhi, N.G., Groves, C.J., Hallmans, G., Harris, T., Hofman, A., Houston, D.K., Hu, F.B., Johansson, I., Kritchevsky, S.B., Langenberg, C., Launer, L., Liu, Y., Loos, R.J., Nalls, M., Orho-Melander, M., Renstrom, F., Rice, K., Riserus, U., Rolandsson, O., Rotter, J.I., Saylor, G., Sijbrands, E.J., Sjogren, P., Smith, A., Steingrímsdóttir, L., Uitterlinden, A.G., Wareham, N.J., Prokopenko, I., Pankow, J.S., van Duijn, C.M., Florez, J.C., Witteman, J.C., Dupuis, J., Dedoussis, G.V., Ordovas, J.M., Ingelsson, E., Cupples, L., Siscovick, D.S., Franks, P.W., Meigs, J.B., MAGIC Investigators, Dupuis, J., Claudia, L., Prokopenko, I., Saxena, R., Soranzo, N., Jackson, A.U., Wheeler, E., Glazer, N.L., Bouatia-Naji, N., Lindgren, C.M., Mägi, R., Morris, A.P., Randal, J., Rybin, D., Johnson, T., Henneman, P., Gieger, C., Thorleifsson, G., Steinthorsdottir, V., Dehghan, A., Hottenga, J.J., Franklin, C.S., Navarro, P., Song, K., Goe, A., Perry, J.R., Lajunen, T., Grallert, H., Li, M., Stringham, H.M., Kumari, M., Timpson, N.J., Shrader, P., Ingelsson, E., Zabena, C., O'Connell, J., Cavalcanti-Proença, C., Luan, J., Elliott, A., McCarroll, S.A., Payne, F., Roccasecca, R.M., Sethupathy, P., Andrew, T., Ariyurek, Y., Balkau, B., Barter, P., Bennett, A.J., Ben-Shlomo, Y., Bergmann, S., Bochud, M., Boerwinkle, E., Bonnefond, A., Bonnycastle, L.L., Böttcher, Y., Brunner, E., Bumpstead, S.J., Chen, Y.D., Chines, P., Clarke, R., Coin, L.J., Crawford, G.J., Crisponi, L., Day, I.N., Geus, Ed, Dina, C., Doney, A., Egan, J.M., Elliott, P., Erdos, M.R., Fischer-Rosinsky, A., Forouhi, N.G., Fox, C.S., Frants, R., Franzosi, M.G., Galan, P., Goodarzi, M.O., Graessler, J., Groves, C.J., Grundy, S., Gwilliam, R., Hallmans, G., Hammond, N., Han, X., Hartikainen, A.L., Hayward, C., Heath, S.C., Hercberg, S., Herder, C., Hicks, A.A., Hingorani, A.D., Hofman, A., Isomaa, B., Jula, A., Kaakinen, M., Kanoni, S., Kesaniemi, Y.A., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Lathrop, G.M., Lawlor, D.A., Li, Y., Lyssenko, V., Mahley, R., Mangino, M., Manning, A.K., Martínez-Larrad, M.T., McAteer, J.B., McPherson, R., Meisinger, C., Melzer, D., Meyre, D., Mitchell, B.D., Morken, M.A., Naitza, S., Narisu, N., Neville, M.J., Oostra, B.A., Orrù, M., Pakyz, R., Palmer, C.N., Paolisso, G., Pattaro, C., Pearson, D., Peden, J.F., Perola, M., Pfeiffer, A.F., Pichler, I., Polasek, O., Posthuma, D., Potter, S.C., Pouta, A., Psaty, B.M., Rathmann, W., Rayner, N.W., Rice, K., Ripatti, S., Rivadeneira, F., Rolandsson, O., Sandhu, M., Sanna, S., Sayer, A.A., Scheet, P., Scott, L.J., Seedorf, U., Sharp, S.J., Shields, B., Sijbrands, E.J., Silveira, A., Singleton, A., Smith, N.L., Sovio, U., Swift, A., Syddall, H., Syvänen, A.C., Tanaka, T., Tönjes, A., Tuomi, T., Uitterlinden, A.G., van Dijk, K.W., Varma, D., Visvikis-Siest, S., Vitart, V., Vogelzangs, N., Waeber, G., Wagner, P.J., Watkins, H., Weedon, M.N., Wild, S.H., Willemsen, G., Witteman, J.C., Yarnell, J.W., Zelenika, D., Zethelius, B., Zhai, G., Zhao, J.H., Zillikens, M.C., GIANT Consortium, X., Global BPgen Consortium, X., Loos, R.J., Meneton, P., Nathan, D.M., Williams, G.H., Hattersley, A.T., Silander, K., Salomaa, V., Smith, G.D., Bornstein, S.R., Schwarz, P., Spranger, J., Karpe, F., Shuldiner, A.R., Cooper, C., Dedoussis, G.V., Serrano-Ríos, M., Morris, A.D., Lind, L., Franks, P.W., Ebrahim, S., Marmot, M., Kuusisto, J., Laakso, M., Kao, W.H., Pankow, J.S., Pramstaller, P.P., Wichmann, H.E., Illig, T., Rudan, I., Wright, A., Stumvoll, M., Campbell, H., Wilson, J.F., Hamsten, A., Bergman, R.N., Buchanan, T.A., Collins, F.S., Mohlke, K.L., Tuomilehto, J., Valle, T.T., Altshuler, D., Rotter, J.I., Siscovick, D.S., Penninx, B.W., Boomsma, D., Deloukas, P., Spector, T.D., Frayling, T.M., Ferrucci, L., Kong, A., Thorsteinsdottir, U., Stefansson, K., van Duijn, C.M., Aulchenko, Y.S., Cao, A., Scuteri, A., Schlessinger, D., Uda, M., Ruokonen, A., Jarvelin, M.R., Waterworth, D.M., Vollenweider, P., Peltonen, L., Mooser, V., Abecasis, G.R., Wareham, N.J., Sladek, R., Froguel, P., Watanabe, R.M., Meigs, J.B., Groop, L., Boehnke, M., McCarthy, M.I., Florez, J.C., and Barroso, I.

Subjects
Adult, Blood Glucose, Male, Genotype, Reviews/Commentaries/ADA Statements, Fasting, Middle Aged, Polymorphism, Single Nucleotide, White People, Genetic Loci, Humans, Insulin, Female, Aged, Blood Glucose/genetics, Blood Glucose/metabolism, Edible Grain, European Continental Ancestry Group, Fasting/blood, Genetic Loci/genetics, Genome-Wide Association Study, Insulin/blood, Insulin/genetics, Polymorphism, Single Nucleotide/genetics, Meta-Analysis
Abstract

OBJECTIVE Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin. RESEARCH DESIGN AND METHODS Via meta-analysis of data from 14 cohorts comprising ∼48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value

Published
2010

103. PP.28.17

Author

Tagetti, A., primary, Ericson, U., additional, Orho-Melander, M., additional, Minuz, P., additional, Fava, C., additional, and Melander, O., additional

Published
2015
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104. 1C.07

Author

Fawad, A., primary, Schultz, C., additional, Nilsson, P.M., additional, Orho-Melander, M., additional, and Melander, O., additional

Published
2015
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105. Using genetics to test the causal relationship of total adiposity and periodontitis: Mendelian randomization analyses in the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium

Author

Shungin, D., primary, Cornelis, M. C., additional, Divaris, K., additional, Holtfreter, B., additional, Shaffer, J. R., additional, Yu, Y.-H., additional, Barros, S. P., additional, Beck, J. D., additional, Biffar, R., additional, Boerwinkle, E. A., additional, Crout, R. J., additional, Ganna, A., additional, Hallmans, G., additional, Hindy, G., additional, Hu, F. B., additional, Kraft, P., additional, McNeil, D. W., additional, Melander, O., additional, Moss, K. L., additional, North, K. E., additional, Orho-Melander, M., additional, Pedersen, N. L., additional, Ridker, P. M., additional, Rimm, E. B., additional, Rose, L. M., additional, Rukh, G., additional, Teumer, A., additional, Weyant, R. J., additional, Chasman, D. I., additional, Joshipura, K., additional, Kocher, T., additional, Magnusson, P. K., additional, Marazita, M. L., additional, Nilsson, P., additional, Offenbacher, S., additional, Davey Smith, G., additional, Lundberg, P., additional, Palmer, T. M., additional, Timpson, N. J., additional, Johansson, I., additional, and Franks, P. W., additional

Published
2015
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108. Genome-wide association study identifies eight loci associated with blood pressure

Author

Newton-Cheh, C, Johnson, T, Gateva, V, Tobin, MD, Bochud, M, Coin, L, Najjar, SS, Zhao, JH, Heath, SC, Eyheramendy, S, Papadakis, K, Voight, BF, Scott, LJ, Zhang, F, Farrall, M, Tanaka, T, Wallace, C, Chambers, JC, Khaw, KT, Nilsson, P, van der Harst, P, Polidoro, S, Grobbee, DE, Onland-Moret, NC, Bots, ML, Wain, LV, Elliott, KS, Teumer, A, Luan, J, Lucas, G, Kuusisto, J, Burton, PR, Hadley, D, McArdle, WL, Wellcome Trust Case Control Consortium, Brown, M, Dominiczak, A, Newhouse, SJ, Samani, NJ, Webster, J, Zeggini, E, Beckmann, JS, Bergmann, S, Lim, N, Song, K, Vollenweider, P, Waeber, G, Waterworth, DM, Yuan, X, Groop, L, Orho-Melander, M, Allione, A, Di Gregorio, A, Guarrera, S, Panico, S, Ricceri, F, Romanazzi, V, Sacerdote, C, Vineis, P, Barroso, I, Sandhu, MS, Luben, RN, Crawford, GJ, Jousilahti, P, Perola, M, Boehnke, M, Bonnycastle, LL, Collins, FS, Jackson, AU, Mohlke, KL, Stringham, HM, Valle, TT, Willer, CJ, Bergman, RN, Morken, MA, Döring, A, Gieger, C, Illig, T, Meitinger, T, Org, E, Pfeufer, A, Wichmann, HE, Kathiresan, S, Marrugat, J, O'Donnell, CJ, Schwartz, SM, Siscovick, DS, Subirana, I, Freimer, NB, Hartikainen, AL, McCarthy, MI, O'Reilly, PF, Peltonen, L, Pouta, A, de Jong, PE, Snieder, H, van Gilst, WH, Clarke, R, Goel, A, Hamsten, A, Peden, JF, Seedorf, U, Syvänen, AC, Tognoni, G, Lakatta, EG, Sanna, S, Scheet, P, Schlessinger, D, Scuteri, A, Dörr, M, Ernst, F, Felix, SB, Homuth, G, Lorbeer, R, Reffelmann, T, Rettig, R, Völker, U, Galan, P, Gut, IG, Hercberg, S, Lathrop, GM, Zelenika, D, Deloukas, P, Soranzo, N, Williams, FM, Zhai, G, Salomaa, V, Laakso, M, Elosua, R, Forouhi, NG, Völzke, H, Uiterwaal, CS, van der Schouw, YT, Numans, ME, Matullo, G, Navis, G, Berglund, G, Bingham, SA, Kooner, JS, Connell, JM, Bandinelli, S, Ferrucci, L, Watkins, H, Spector, TD, Tuomilehto, J, Altshuler, D, Strachan, DP, Laan, M, Meneton, P, Wareham, NJ, Uda, M, Jarvelin, MR, Mooser, V, Melander, O, Loos, RJ, Elliott, P, Abecasis, GR, Caulfield, M, and Munroe, PB

Published
2009

109. Genetic Loci for Retinal Arteriolar Microcirculation

Author

Xueling, Sim, Jensen, Richard A., Kamran Ikram, M., Mary Frances Cotch, Xiaohui, Li, Stuart, Macgregor, Jing, Xie, Albert Vernon Smith, Eric, Boerwinkle, Paul, Mitchell, Ronald, Klein, Klein, Barbara E. K., Glazer, Nicole L., Thomas, Lumley, Barbara, Mcknight, Psaty, Bruce M., de Jong, Paulus T. V. M., Albert, Hofman, Fernando, Rivadeneira, Uitterlinden, Andre G., van Duijn, Cornelia M., Thor, Aspelund, Gudny, Eiriksdottir, Harris, Tamara B., Fridbert, Jonasson, Launer, Lenore J., John, Attia, Baird, Paul N., Stephen, Harrap, Holliday, Elizabeth G., Michael, Inouye, Elena, Rochtchina, Scott, Rodney J., Ananth, Viswanathan, Guo, Li, Smith, Nicholas L., Wiggins, Kerri L., Kuo, Jane Z., Taylor, Kent D., Hewitt, Alex W., Martin, Nicholas G., Montgomery, Grant W., Cong, Sun, Young, Terri L., Mackey, David A., van Zuydam, Natalie R., Doney, Alex S. F., Palmer, Colin N. A., Morris, Andrew D., Rotter, Jerome I., Shyong Tai, E., Vilmundur, Gudnason, Vingerling, Johannes R., Siscovick, David S., Jie Jin Wang, Wong, Tien Y., Donnelly, P, Barroso, I, Blackwell, Jm, Bramon, E, Brown, Ma, Casas, Jp, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, Hs, Mathew, Cg, Palmer, Cn, Plomin, R, Rautanen, A, Sawcer, Sj, Trembath, Rc, Viswanathan, Ac, Wood, Nw, Spencer, Cc, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, Se, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, Sj, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, Mccann, Ot, Liddle, J, Potter, Sc, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Mathew, C, Mccarthy, Mi, Newton Cheh, C, Johnson, T, Gateva, V, Tobin, Md, Bochud, M, Coin, L, Najjar, Ss, Zhao, Jh, Heath, Sc, Eyheramendy, S, Papadakis, K, Voight, Bf, Scott, Lj, Zhang, F, Farrall, M, Tanaka, T, Wallace, C, Chambers, Jc, Khaw, Kt, Nilsson, P, van der Harst, P, Polidoro, Silvia, Grobbee, De, Onland Moret NC, Bots, Ml, Wain, Lv, Elliott, Ks, Teumer, A, Luan, J, Lucas, G, Kuusisto, J, Burton, Pr, Hadley, D, Mcardle, Wl, Brown, M, Dominiczak, A, Newhouse, Sj, Samani, Nj, Webster, J, Zeggini, E, Beckmann, Js, Bergmann, S, Lim, N, Song, K, Vollenweider, P, Waeber, G, Waterworth, Dm, Yuan, X, Groop, L, Orho Melander, M, Allione, A, Di Gregorio, A, Guarrera, Simonetta, Panico, S, Ricceri, Fulvio, Romanazzi, V, Sacerdote, Carlotta, Vineis, Paolo, Sandhu, Ms, Luben, Rn, Crawford, Gj, Jousilahti, P, Perola, M, Boehnke, M, Bonnycastle, Ll, Collins, Fs, Jackson, Au, Mohlke, Kl, Stringham, Hm, Valle, Tt, Willer, Cj, Bergman, Rn, Morken, Ma, Döring, A, Gieger, C, Illig, T, Meitinger, T, Org, E, Pfeufer, A, Wichmann, He, Kathiresan, S, Marrugat, J, O'Donnell, Cj, Schwartz, Sm, Siscovick, Ds, Subirana, I, Freimer, Nb, Hartikainen, Al, O'Reilly, Pf, Peltonen, L, Pouta, A, de Jong PE, Snieder, H, van Gilst WH, Clarke, R, Goel, A, Hamsten, A, Peden, Jf, Seedorf, U, Syvänen, Ac, Tognoni, G, Lakatta, Eg, Sanna, S, Scheet, P, Schlessinger, D, Scuteri, A, Dörr, M, Ernst, F, Felix, Sb, Homuth, G, Lorbeer, R, Reffelmann, T, Rettig, R, Völker, U, Galan, P, Gut, Ig, Hercberg, S, Lathrop, Gm, Zeleneka, D, Soranzo, N, Williams, Fm, Zhai, G, Salomaa, V, Laakso, M, Elosua, R, Forouhi, Ng, Völzke, H, Uiterwaal, Cs, van der Schouw YT, Numans, Me, Matullo, Giuseppe, Navis, G, Berglund, G, Bingham, Sa, Kooner, Js, Connell, Jm, Bandinelli, S, Ferrucci, L, Watkins, H, Spector, Td, Tuomilehto, J, Altshuler, D, Strachan, Dp, Laan, M, Meneton, P, Wareham, Nj, Uda, M, Jarvelin, Mr, Mooser, V, Melander, O, Loos, Rj, Elliott, P, Abecasis, Gr, Caulfield, M, Munroe, P. B., Inouye, Michael [0000-0001-9413-6520], Apollo - University of Cambridge Repository, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Wellcome Trust Case Control Consortium 2, Global BPGen Consortium, Donnelly, P., Barroso, I., Blackwell, J.M., Bramon, E., Brown, M.A., Casas, J.P., Corvin, A., Deloukas, P., Duncanson, A., Jankowski, J., Markus, H.S., Mathew, C.G., Palmer, C.N., Plomin, R., Rautanen, A., Sawcer, S.J., Trembath, R.C., Viswanathan, A.C., Wood, N.W., Spencer, C.C., Band, G., Bellenguez, C., Freeman, C., Hellenthal, G., Giannoulatou, E., Pirinen, M., Pearson, R., Strange, A., Su, Z., Vukcevic, D., Langford, C., Hunt, S.E., Edkins, S., Gwilliam, R., Blackburn, H., Bumpstead, S.J., Dronov, S., Gillman, M., Gray, E., Hammond, N., Jayakumar, A., McCann, O.T., Liddle, J., Potter, S.C., Ravindrarajah, R., Ricketts, M., Waller, M., Weston, P., Widaa, S., Whittaker, P., Mathew, C., McCarthy, M.I., Newton-Cheh, C., Johnson, T., Gateva, V., Tobin, M.D., Bochud, M., Coin, L., Najjar, S.S., Zhao, J.H., Heath, S.C., Eyheramendy, S., Papadakis, K., Voight, B.F., Scott, L.J., Zhang, F., Farrall, M., Tanaka, T., Wallace, C., Chambers, J.C., Khaw, K.T., Nilsson, P., van der Harst, P., Polidoro, S., Grobbee, D.E., Onland-Moret, N.C., Bots, M.L., Wain, L.V., Elliott, K.S., Teumer, A., Luan, J.J., Lucas, G., Kuusisto, J., Burton, P.R., Hadley, D., McArdle, W.L., Brown, M., Dominiczak, A., Newhouse, S.J., Samani, N.J., Webster, J., Zeggini, E., Beckmann, J.S., Bergmann, S., Lim, N., Song, K., Vollenweider, P., Waeber, G., Waterworth, D.M., Yuan, X., Groop, L., Orho-Melander, M., Allione, A., Di Gregorio, A., Guarrera, S., Panico, S., Ricceri, F., Romanazzi, V., Sacerdote, C., Vineis, P., Sandhu, M.S., Luben, R.N., Crawford, G.J., Jousilahti, P., Perola, M., Boehnke, M., Bonnycastle, L.L., Collins, F.S., Jackson, A.U., Mohlke, K.L., Stringham, H.M., Valle, T.T., Willer, C.J., Bergman, R.N., Morken, M.A., Döring, A., Gieger, C., Illig, T., Meitinger, T., Org, E., Pfeufer, A., Wichmann, H.E., Kathiresan, S., Marrugat, J., O'Donnell, C.J., Schwartz, S.M., Siscovick, D.S., Subirana, I., Freimer, N.B., Hartikainen, A.L., O'Reilly, P.F., Peltonen, L., Pouta, A., de Jong, P.E., Snieder, H., van Gilst, W.H., Clarke, R., Goel, A., Hamsten, A., Peden, J.F., Seedorf, U., Syvänen, A.C., Tognoni, G., Lakatta, E.G., Sanna, S., Scheet, P., Schlessinger, D., Scuteri, A., Dörr, M., Ernst, F., Felix, S.B., Homuth, G., Lorbeer, R., Reffelmann, T., Rettig, R., Völker, U., Galan, P., Gut, I.G., Hercberg, S., Lathrop, G.M., Zeleneka, D., Soranzo, N., Williams, F.M., Zhai, G., Salomaa, V., Laakso, M., Elosua, R., Forouhi, N.G., Völzke, H., Uiterwaal, C.S., van der Schouw, Y.T., Numans, M.E., Matullo, G., Navis, G., Berglund, G., Bingham, S.A., Kooner, J.S., Connell, J.M., Bandinelli, S., Ferrucci, L., Watkins, H., Spector, T.D., Tuomilehto, J., Altshuler, D., Strachan, D.P., Laan, M., Meneton, P., Wareham, N.J., Uda, M., Jarvelin, M.R., Mooser, V., Melander, O., Loos, R.J., Elliott, P., Abecasis, G.R., Caulfield, M., Munroe, P.B., Ophthalmology, Epidemiology, Internal Medicine, Erasmus School of Social and Behavioural Sciences, and Obstetrics & Gynecology

Subjects
Male, Pathology, BLUE MOUNTAINS EYE, VESSEL DIAMETERS, lcsh:Medicine, MICROVASCULAR ABNORMALITIES, Genome-wide association study, Cardiovascular, Coronary artery disease, chemistry.chemical_compound, 0302 clinical medicine, genome-wide association, Microcirculation, Retinal Arteriolar Microcirculation, Myocardial infarction, lcsh:Science, Aged, 80 and over, Medicine(all), 0303 health sciences, Multidisciplinary, Agricultural and Biological Sciences(all), MEF2 Transcription Factors, Genomics, Middle Aged, 3. Good health, Arterioles, medicine.anatomical_structure, Medicine, Chromosomes, Human, Pair 5, Female, INCIDENT SEVERE HYPERTENSION, Research Article, medicine.medical_specialty, Genotype, Clinical Research Design, ANTIHYPERTENSIVE DRUG THERAPIES, Single-nucleotide polymorphism, White People, 03 medical and health sciences, Genome Analysis Tools, Vascular Biology, BEAVER DAM EYE, Genetics, Genome-Wide Association Studies, medicine, Humans, CORONARY-HEART-DISEASE, GENOME-WIDE ASSOCIATION, Biology, Aged, 030304 developmental biology, Retina, Models, Genetic, Biochemistry, Genetics and Molecular Biology(all), Vascular disease, business.industry, lcsh:R, Computational Biology, Retinal Vessels, Human Genetics, Retinal, medicine.disease, Ophthalmology, chemistry, Genetic Loci, VASCULAR CALIBER, 030221 ophthalmology & optometry, lcsh:Q, Meta-Analyses, GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK, business, Genome-Wide Association Study
Abstract

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value -8. This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10-12 in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

Published
2013
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111. Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks

Author

Peloso, G.M. (Gina), Auer, P. (Paul), Bis, J.C. (Joshua), Voorman, J.M. (Jeanine), Morrison, A.C. (Alanna), Stitziel, N.O. (Nathan), Brody, J.A. (Jennifer A.), Khetarpal, S.A. (Sumeet), Crosby, S., Fornage, M. (Myriam), Isaacs, A.J. (Aaron), Jakobsdottir, M. (Margret), Feitosa, M.F. (Mary Furlan), Davies, G. (Gail), Huffman, J.E. (Jennifer), Manichaikul, A. (Ani), Davis, B. (Brian), Lohman, K. (Kurt), Joon, A.Y. (Aron), Smith, A.V. (Davey), Grove, M.L. (Megan), Zanoni, P. (Paolo), Redon, V. (Valeska), Demissie, S. (Serkalem), Lawson, K. (Kim), Peters, U. (Ulrike), Carlson, C.S. (Christopher), Jackson, R.D. (Rebecca), Ryckman, K.K. (Kelli), MacKey, R.H. (Rachel), Robinson, J.G. (Jennifer), Siscovick, D.S. (David), Schreiner, P.J. (Pamela), Mychaleckyj, J.C. (Josyf), Pankow, J.S. (James), Hofman, A. (Albert), Uitterlinden, A.G. (André), Harris, T.B. (Tamara), Taylor, K.D. (Kent), Stafford, M., Reynolds, L.M. (Lindsay), Marioni, R.E. (Riccardo), Dehghan, A. (Abbas), Franco, O.H. (Oscar), Patel, A.P. (Aniruddh), Lu, Y. (Yingchang), Hindy, G. (George), Gottesman, R.F. (Rebecca), Bottinger, E.P. (Erwin), Melander, O. (Olle), Orho-Melander, M. (Marju), Loos, R.J.F. (Ruth), Duga, S. (Stefano), Merlini, P.A. (Piera), Farrall, M. (Martin), Goel, A. (Anuj), Asselta, R. (Rosanna), Girelli, D. (Domenico), Martinelli, N. (Nicola), Shah, S.H. (Svati), Kraus, T. (Thomas), Rader, D.J. (Daniel), Reilly, M.P. (Muredach), McPherson, R. (Ruth), Watkins, H. (Hugh), Ardissino, D. (Diego), Zhang, Q. (Qunyuan), Wang, J. (Judy), Tsai, M.Y. (Michael), Taylor, H.A. (Herman), Correa, D.D., Griswold, M.D. (Michael), Lange, L.A. (Leslie), Starr, J.M. (John), Rudan, I. (Igor), Eiriksdottir, G. (Gudny), Launer, L.J. (Lenore), Ordovas, J.M. (Jose), Levy, D. (Daniel), Chen, Y.-D.I. (Y.-D. Ida), Reiner, A. (Alexander), Hayward, C. (Caroline), Polasek, O. (Ozren), Deary, I.J. (Ian), Borecki, I.B. (Ingrid), Liu, Y. (YongMei), Gudnason, V. (Vilmundur), Wilson, J.G. (James), Duijn, C.M. (Cornelia) van, Kooperberg, C. (Charles), Rich, S.S. (Stephen), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome), O'Donnell, C.J. (Christopher), Rice, K.M. (Kenneth), Boerwinkle, E.A. (Eric), Kathiresan, S. (Sekar), Cupples, L.A. (Adrienne), Li, M. (Mingyao), Peloso, G.M. (Gina), Auer, P. (Paul), Bis, J.C. (Joshua), Voorman, J.M. (Jeanine), Morrison, A.C. (Alanna), Stitziel, N.O. (Nathan), Brody, J.A. (Jennifer A.), Khetarpal, S.A. (Sumeet), Crosby, S., Fornage, M. (Myriam), Isaacs, A.J. (Aaron), Jakobsdottir, M. (Margret), Feitosa, M.F. (Mary Furlan), Davies, G. (Gail), Huffman, J.E. (Jennifer), Manichaikul, A. (Ani), Davis, B. (Brian), Lohman, K. (Kurt), Joon, A.Y. (Aron), Smith, A.V. (Davey), Grove, M.L. (Megan), Zanoni, P. (Paolo), Redon, V. (Valeska), Demissie, S. (Serkalem), Lawson, K. (Kim), Peters, U. (Ulrike), Carlson, C.S. (Christopher), Jackson, R.D. (Rebecca), Ryckman, K.K. (Kelli), MacKey, R.H. (Rachel), Robinson, J.G. (Jennifer), Siscovick, D.S. (David), Schreiner, P.J. (Pamela), Mychaleckyj, J.C. (Josyf), Pankow, J.S. (James), Hofman, A. (Albert), Uitterlinden, A.G. (André), Harris, T.B. (Tamara), Taylor, K.D. (Kent), Stafford, M., Reynolds, L.M. (Lindsay), Marioni, R.E. (Riccardo), Dehghan, A. (Abbas), Franco, O.H. (Oscar), Patel, A.P. (Aniruddh), Lu, Y. (Yingchang), Hindy, G. (George), Gottesman, R.F. (Rebecca), Bottinger, E.P. (Erwin), Melander, O. (Olle), Orho-Melander, M. (Marju), Loos, R.J.F. (Ruth), Duga, S. (Stefano), Merlini, P.A. (Piera), Farrall, M. (Martin), Goel, A. (Anuj), Asselta, R. (Rosanna), Girelli, D. (Domenico), Martinelli, N. (Nicola), Shah, S.H. (Svati), Kraus, T. (Thomas), Rader, D.J. (Daniel), Reilly, M.P. (Muredach), McPherson, R. (Ruth), Watkins, H. (Hugh), Ardissino, D. (Diego), Zhang, Q. (Qunyuan), Wang, J. (Judy), Tsai, M.Y. (Michael), Taylor, H.A. (Herman), Correa, D.D., Griswold, M.D. (Michael), Lange, L.A. (Leslie), Starr, J.M. (John), Rudan, I. (Igor), Eiriksdottir, G. (Gudny), Launer, L.J. (Lenore), Ordovas, J.M. (Jose), Levy, D. (Daniel), Chen, Y.-D.I. (Y.-D. Ida), Reiner, A. (Alexander), Hayward, C. (Caroline), Polasek, O. (Ozren), Deary, I.J. (Ian), Borecki, I.B. (Ingrid), Liu, Y. (YongMei), Gudnason, V. (Vilmundur), Wilson, J.G. (James), Duijn, C.M. (Cornelia) van, Kooperberg, C. (Charles), Rich, S.S. (Stephen), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome), O'Donnell, C.J. (Christopher), Rice, K.M. (Kenneth), Boerwinkle, E.A. (Eric), Kathiresan, S. (Sekar), Cupples, L.A. (Adrienne), and Li, M. (Mingyao)

Abstract

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121-], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

Published
2014
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112. GENETICALLY ELEVATED LOW-DENSITY LIPOPROTEIN CHOLESTEROL IS ASSOCIATED WITH AORTIC VALVE CALCIFICATION AND INCIDENT AORTIC STENOSIS: A MENDELIAN RANDOMIZATION STUDY

Author

Thanassoulis, G., primary, Luk, K., additional, Schulz, C., additional, Engert, J., additional, Do, R., additional, Hindy, G., additional, Rukh, G., additional, Dufresne, L., additional, Almgren, P., additional, Owens, D., additional, Harris, T., additional, Peloso, G.M., additional, Kerr, K., additional, Wong, Q., additional, Smith, A.V., additional, Budoff, M.J., additional, Rotter, J.I., additional, Cupples, L., additional, Rich, S.S., additional, Kathiresan, S., additional, Orho-Melander, M., additional, Gudnason, V., additional, O'Donnell, C.J., additional, Post, W., additional, and Smith, J., additional

Published
2014
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115. The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

Author

Fall, M. (Magnus), Hägg, S. (Sara), Mägi, R. (Reedik), Ploner, A. (Alexander), Fischer, K. (Krista), Horikoshi, M. (Momoko), Sarin, A.-P., Thorleifsson, G. (Gudmar), Ladenvall, C. (Claes), Kals, M. (Mart), Kuningas, M. (Maris), Draisma, G. (Gerrit), Ried, J.S. (Janina), Zuydam, N.R. (Natalie) van, Huikari, V. (Ville), Mangino, M. (Massimo), Sonestedt, E. (Emily), Benyamin, B. (Beben), Nelson, C.P. (Christopher P.), Rivera, N.V. (Natalia), Kristiansson, K. (Kati), Shen, H.-y. (Huei-yi), Havulinna, A.S. (Aki), Dehghan, A. (Abbas), Donnelly, L.A. (Louise), Kaakinen, M. (Marika), Nuotio, M.-L. (Marja-Liisa), Robertson, N. (Neil), Bruijn, R.F.A.G. (Renée) de, Ikram, M.A. (Arfan), Amin, N. (Najaf), Balmforth, A.J. (Anthony), Braund, P.S. (Peter), Doney, A.S.F. (Alex), Döring, A. (Angela), Elliott, P. (Paul), Esko, T. (Tõnu), Franco, O.H. (Oscar), Gretarsdottir, S. (Solveig), Hartikainen, A.L., Heikkilä, K. (Kauko), Herzig, K.H., Holm, H. (Hilma), Hottenga, J.J. (Jouke Jan), Hyppönen, E. (Elina), Illig, T. (Thomas), Isaacs, A.J. (Aaron), Isomaa, B. (Bo), Karssen, L.C. (Lennart), Kettunen, J. (Johannes), Koenig, W. (Wolfgang), Kuulasmaa, K. (Kari), Laatikainen, T. (Tiina), Laitinen, J. (Jaana), Lindgren, C. (Cecilia), Lyssenko, V. (Valeriya), Läärä, E. (Esa), Rayner, N.W. (Nigel William), Männistö, S. (Satu), Pouta, A. (Anneli), Rathmann, W. (Wolfgang), Rivadeneira Ramirez, F. (Fernando), Ruokonen, A. (Aimo), Savolainen, M.J. (Markku), Sijbrands, E.J.G. (Eric), Small, K.S. (Kerrin), Smit, J.H. (Jan), Steinthorsdottir, V. (Valgerdur), Syvanen, A.C., Taanila, A. (Anja), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Willems, S.M. (Sara), Willemsen, G.A.H.M. (Gonneke), Witteman, J.C.M. (Jacqueline), Perola, M. (Markus), Evans, A. (Andrew), Ferrières, J. (Jean), Virtamo, J. (Jarmo), Kee, F. (F.), Tregouet, D.-A. (David-Alexandre), Arveiler, D. (Dominique), Amouyel, P. (Philippe), Ferrario, F. (Franco), Brambilla, P. (Paolo), Hall, A. (Anne), Heath, A.C. (Andrew), Madden, P.A.F. (Pamela), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant), Whitfield, J. (John), Jula, A. (Antti), Knekt, P., Oostra, B.A. (Ben), Duijn, C.M. (Cornelia) van, Penninx, B.W.J.H. (Brenda), Davey-Smith, G. (George), Kaprio, J. (Jaakko), Samani, N.J. (Nilesh), Gieger, C. (Christian), Peters, A. (Annette), Wichmann, H.E. (Heinz Erich), Boomsma, D.I. (Dorret), Geus, E.J.C. (Eco) de, Tuomi, T. (Tiinamaija), Power, C. (Christopher), Hammond, C.J. (Christopher), Spector, T.D. (Timothy), Lind, L. (Lars), Orho-Melander, M. (Marju), Palmer, C.N.A. (Colin), Morris, A.D. (Andrew), Groop, L. (Leif), Jarvelin, M.-R. (Marjo-Riitta), Salomaa, V. (Veikko), Vartiainen, E. (Erkki), Hofman, A. (Albert), Ripatti, S. (Samuli), Metspalu, A. (Andres), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Pedersen, N.L. (Nancy), McCarthy, M.I. (Mark), Ingelsson, E. (Erik), Prokopenko, I. (Inga), Fall, M. (Magnus), Hägg, S. (Sara), Mägi, R. (Reedik), Ploner, A. (Alexander), Fischer, K. (Krista), Horikoshi, M. (Momoko), Sarin, A.-P., Thorleifsson, G. (Gudmar), Ladenvall, C. (Claes), Kals, M. (Mart), Kuningas, M. (Maris), Draisma, G. (Gerrit), Ried, J.S. (Janina), Zuydam, N.R. (Natalie) van, Huikari, V. (Ville), Mangino, M. (Massimo), Sonestedt, E. (Emily), Benyamin, B. (Beben), Nelson, C.P. (Christopher P.), Rivera, N.V. (Natalia), Kristiansson, K. (Kati), Shen, H.-y. (Huei-yi), Havulinna, A.S. (Aki), Dehghan, A. (Abbas), Donnelly, L.A. (Louise), Kaakinen, M. (Marika), Nuotio, M.-L. (Marja-Liisa), Robertson, N. (Neil), Bruijn, R.F.A.G. (Renée) de, Ikram, M.A. (Arfan), Amin, N. (Najaf), Balmforth, A.J. (Anthony), Braund, P.S. (Peter), Doney, A.S.F. (Alex), Döring, A. (Angela), Elliott, P. (Paul), Esko, T. (Tõnu), Franco, O.H. (Oscar), Gretarsdottir, S. (Solveig), Hartikainen, A.L., Heikkilä, K. (Kauko), Herzig, K.H., Holm, H. (Hilma), Hottenga, J.J. (Jouke Jan), Hyppönen, E. (Elina), Illig, T. (Thomas), Isaacs, A.J. (Aaron), Isomaa, B. (Bo), Karssen, L.C. (Lennart), Kettunen, J. (Johannes), Koenig, W. (Wolfgang), Kuulasmaa, K. (Kari), Laatikainen, T. (Tiina), Laitinen, J. (Jaana), Lindgren, C. (Cecilia), Lyssenko, V. (Valeriya), Läärä, E. (Esa), Rayner, N.W. (Nigel William), Männistö, S. (Satu), Pouta, A. (Anneli), Rathmann, W. (Wolfgang), Rivadeneira Ramirez, F. (Fernando), Ruokonen, A. (Aimo), Savolainen, M.J. (Markku), Sijbrands, E.J.G. (Eric), Small, K.S. (Kerrin), Smit, J.H. (Jan), Steinthorsdottir, V. (Valgerdur), Syvanen, A.C., Taanila, A. (Anja), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Willems, S.M. (Sara), Willemsen, G.A.H.M. (Gonneke), Witteman, J.C.M. (Jacqueline), Perola, M. (Markus), Evans, A. (Andrew), Ferrières, J. (Jean), Virtamo, J. (Jarmo), Kee, F. (F.), Tregouet, D.-A. (David-Alexandre), Arveiler, D. (Dominique), Amouyel, P. (Philippe), Ferrario, F. (Franco), Brambilla, P. (Paolo), Hall, A. (Anne), Heath, A.C. (Andrew), Madden, P.A.F. (Pamela), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant), Whitfield, J. (John), Jula, A. (Antti), Knekt, P., Oostra, B.A. (Ben), Duijn, C.M. (Cornelia) van, Penninx, B.W.J.H. (Brenda), Davey-Smith, G. (George), Kaprio, J. (Jaakko), Samani, N.J. (Nilesh), Gieger, C. (Christian), Peters, A. (Annette), Wichmann, H.E. (Heinz Erich), Boomsma, D.I. (Dorret), Geus, E.J.C. (Eco) de, Tuomi, T. (Tiinamaija), Power, C. (Christopher), Hammond, C.J. (Christopher), Spector, T.D. (Timothy), Lind, L. (Lars), Orho-Melander, M. (Marju), Palmer, C.N.A. (Colin), Morris, A.D. (Andrew), Groop, L. (Leif), Jarvelin, M.-R. (Marjo-Riitta), Salomaa, V. (Veikko), Vartiainen, E. (Erkki), Hofman, A. (Albert), Ripatti, S. (Samuli), Metspalu, A. (Andres), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Pedersen, N.L. (Nancy), McCarthy, M.I. (Mark), Ingelsson, E. (Erik), and Prokopenko, I. (Inga)

Abstract

Background:The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.Methods and Findings:We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses.Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05).

Published
2013
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116. The role of adiposity in cardiometabolic traits: a mendelian randomization analysis

Author

Fall, T, Hägg, S, Mägi, R, Ploner, A, Fischer, K, Horikoshi, M, Sarin, A, Thorleifsson, G, Ladenvall, C, Kals, M, Kuningas, M, Draisma, H, Ried, J, Van, Z, Nr, Huikari, V, Mangino, M, Sonestedt, E, Benyamin, B, Nelson, C, Rivera, N, Kristiansson, K, Shen, H, Havulinna, A, Dehghan, A, Donnelly, L, Kaakinen, M, Nuotio, M, Robertson, N, de Bruijn, R, Ikram, M, Amin, N, Balmforth, A, Braund, P, Doney, A, Döring, A, Elliott, P, Esko, T, Franco, O, Gretarsdottir, S, Hartikainen, A, Heikkilä, K, Herzig, K, Holm, H, Hottenga, J, Hyppönen, E, Illig, T, Isaacs, A, Isomaa, B, Karssen, L, Kettunen, J, Koenig, W, Kuulasmaa, K, Laatikainen, T, Laitinen, J, Lindgren, C, Lyssenko, V, Läärä, E, Rayner, N, Männistö, S, Pouta, A, Rathmann, W, Rivadeneira, F, Ruokonen, A, Savolainen, M, Sijbrands, E, Small, K, Smit, J, Steinthorsdottir, V, Syvänen, A, Taanila, A, Tobin, M, Uitterlinden, A, Willems, S, Willemsen, G, Witteman, J, Perola, M, Evans, A, Ferrières, J, Virtamo, J, Kee, F, Tregouet, D, Arveiler, D, Amouyel, P, Ferrario, M, Brambilla, P, Hall, A, Heath, A, Madden, P, Martin, N, Montgomery, G, Whitfield, J, Jula, A, Knekt, P, Oostra, B, van Duijn, C, Penninx, B, Davey Smith, G, Kaprio, J, Samani, N, Gieger, C, Peters, A, Wichmann, H, Boomsma, D, de Geus, E, Tuomi, T, Power, C, Hammond, C, Spector, T, Lind, L, Orho Melander, M, Palmer, C, Morris, A, Groop, L, Järvelin, M, Salomaa, V, Vartiainen, E, Hofman, A, Ripatti, S, Metspalu, A, Thorsteinsdottir, U, Stefansson, K, Pedersen, N, Mccarthy, M, Ingelsson, E, Prokopenko, I, Sarin, AP, Draisma, HH, Ried, JS, van, Zuydam, NR, Nelson, CP, Rivera, NV, Shen, HY, Havulinna, AS, Donnelly, LA, Nuotio, ML, de Bruijn, RF, Ikram, MA, Balmforth, AJ, Braund, PS, Doney, AS, Franco, OH, Hartikainen, AL, Herzig, KH, Hottenga, JJ, Karssen, LC, Rayner, NW, Savolainen, MJ, Sijbrands, EJ, Small, KS, Smit, JH, Syvänen, AC, Tobin, MD, Uitterlinden, AG, Willems, SM, Tregouet, DA, Ferrario, MM, BRAMBILLA, PAOLO, Hall, AS, Heath, AC, Madden, PA, Martin, NG, Montgomery, GW, Whitfield, JB, van Duijn, CM, Penninx, BW, Samani, NJ, Wichmann, HE, Boomsma, DI, de Geus, EJ, Hammond, CJ, Spector, TD, Palmer, CN, Morris, AD, Järvelin, MR, Pedersen, NL, McCarthy, MI, Prokopenko, I., Fall, T, Hägg, S, Mägi, R, Ploner, A, Fischer, K, Horikoshi, M, Sarin, A, Thorleifsson, G, Ladenvall, C, Kals, M, Kuningas, M, Draisma, H, Ried, J, Van, Z, Nr, Huikari, V, Mangino, M, Sonestedt, E, Benyamin, B, Nelson, C, Rivera, N, Kristiansson, K, Shen, H, Havulinna, A, Dehghan, A, Donnelly, L, Kaakinen, M, Nuotio, M, Robertson, N, de Bruijn, R, Ikram, M, Amin, N, Balmforth, A, Braund, P, Doney, A, Döring, A, Elliott, P, Esko, T, Franco, O, Gretarsdottir, S, Hartikainen, A, Heikkilä, K, Herzig, K, Holm, H, Hottenga, J, Hyppönen, E, Illig, T, Isaacs, A, Isomaa, B, Karssen, L, Kettunen, J, Koenig, W, Kuulasmaa, K, Laatikainen, T, Laitinen, J, Lindgren, C, Lyssenko, V, Läärä, E, Rayner, N, Männistö, S, Pouta, A, Rathmann, W, Rivadeneira, F, Ruokonen, A, Savolainen, M, Sijbrands, E, Small, K, Smit, J, Steinthorsdottir, V, Syvänen, A, Taanila, A, Tobin, M, Uitterlinden, A, Willems, S, Willemsen, G, Witteman, J, Perola, M, Evans, A, Ferrières, J, Virtamo, J, Kee, F, Tregouet, D, Arveiler, D, Amouyel, P, Ferrario, M, Brambilla, P, Hall, A, Heath, A, Madden, P, Martin, N, Montgomery, G, Whitfield, J, Jula, A, Knekt, P, Oostra, B, van Duijn, C, Penninx, B, Davey Smith, G, Kaprio, J, Samani, N, Gieger, C, Peters, A, Wichmann, H, Boomsma, D, de Geus, E, Tuomi, T, Power, C, Hammond, C, Spector, T, Lind, L, Orho Melander, M, Palmer, C, Morris, A, Groop, L, Järvelin, M, Salomaa, V, Vartiainen, E, Hofman, A, Ripatti, S, Metspalu, A, Thorsteinsdottir, U, Stefansson, K, Pedersen, N, Mccarthy, M, Ingelsson, E, Prokopenko, I, Sarin, AP, Draisma, HH, Ried, JS, van, Zuydam, NR, Nelson, CP, Rivera, NV, Shen, HY, Havulinna, AS, Donnelly, LA, Nuotio, ML, de Bruijn, RF, Ikram, MA, Balmforth, AJ, Braund, PS, Doney, AS, Franco, OH, Hartikainen, AL, Herzig, KH, Hottenga, JJ, Karssen, LC, Rayner, NW, Savolainen, MJ, Sijbrands, EJ, Small, KS, Smit, JH, Syvänen, AC, Tobin, MD, Uitterlinden, AG, Willems, SM, Tregouet, DA, Ferrario, MM, BRAMBILLA, PAOLO, Hall, AS, Heath, AC, Madden, PA, Martin, NG, Montgomery, GW, Whitfield, JB, van Duijn, CM, Penninx, BW, Samani, NJ, Wichmann, HE, Boomsma, DI, de Geus, EJ, Hammond, CJ, Spector, TD, Palmer, CN, Morris, AD, Järvelin, MR, Pedersen, NL, McCarthy, MI, and Prokopenko, I.

Abstract

Background:The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.Methods and Findings:We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses.Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (

Published
2013

117. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Author

DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Procardis Consortium, MAGIC investigators, GLGC Consortium, Olson, J., Kronmal, R., Robbins, J., Chaves, PH., Burke, G., Kuller, LH., Tracy, R., Gottdiener, J., Prineas, R., Becker, JT., Enright, P., Klein, R., O'Leary, DH., Dastani, Z., Hivert, M.F., Timpson, N., Perry, J.R., Yuan, X., Scott, R.A., Henneman, P., Heid, I.M., Kizer, J.R., Lyytikäinen, L.P., Fuchsberger, C., Tanaka, T., Morris, A.P., Small, K., Isaacs, A., Beekman, M., Coassin, S., Lohman, K., Qi, L., Kanoni, S., Pankow, J.S., Uh, H.W., Wu, Y., Bidulescu, A., Rasmussen-Torvik, L.J., Greenwood, C.M., Ladouceur, M., Grimsby, J., Manning, A.K., Liu, C.T., Kooner, J., Mooser, V.E., Vollenweider, P., Kapur, K.A., Chambers, J., Wareham, N.J., Langenberg, C., Frants, R., Willems-Vandijk, K., Oostra, B.A., Willems, S.M., Lamina, C., Winkler, T.W., Psaty, B.M., Tracy, R.P., Brody, J., Chen, I., Viikari, J., Kähönen, M., Pramstaller, P.P., Evans, D.M., St Pourcain, B., Sattar, N., Wood, A.R., Bandinelli, S., Carlson, O.D., Egan, J.M., Böhringer, S., van Heemst, D., Kedenko, L., Kristiansson, K., Nuotio, M.L., Loo, B.M., Harris, T., Garcia, M., Kanaya, A., Haun, M., Klopp, N., Wichmann, H.E., Deloukas, P., Katsareli, E., Couper, D.J., Duncan, B.B., Kloppenburg, M., Adair, L.S., Borja, J.B., Wilson, J.G., Musani, S., Guo, X., Johnson, T., Semple, R., Teslovich, T.M., Allison, M.A., Redline, S., Buxbaum, S.G., Mohlke, K.L., Meulenbelt, I., Ballantyne, C.M., Dedoussis, G.V., Hu, F.B., Liu, Y., Paulweber, B., Spector, T.D., Slagboom, P.E., Ferrucci, L., Jula, A., Perola, M., Raitakari, O., Florez, J.C., Salomaa, V., Eriksson, J.G., Frayling, T.M., Hicks, A.A., Lehtimäki, T., Smith, G.D., Siscovick, D.S., Kronenberg, F., van Duijn, C., Loos, R.J., Waterworth, D.M., Meigs, J.B., Dupuis, J., Richards, J.B., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Hofmann, O.M., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Hassanali, N., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lindgren, C.M., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Morris, A.D., Palmer, C.N., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Pedersen, O., Barroso, I., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., McCarthy, M.I., Soranzo, N., Wheeler, E., Glazer, N.L., Bouatia-Naji, N., Mägi, R., Randall, J., Elliott, P., Rybin, D., Dehghan, A., Hottenga, J.J., Song, K., Goel, A., Lajunen, T., Doney, A., Cavalcanti-Proença, C., Kumari, M., Timpson, N.J., Zabena, C., Ingelsson, E., An, P., O'Connell, J., Luan, J., Elliott, A., Roccasecca, R.M., Pattou, F., Sethupathy, P., Ariyurek, Y., Barter, P., Beilby, J.P., Ben-Shlomo, Y., Bergmann, S., Bochud, M., Bonnefond, A., Borch-Johnsen, K., Böttcher, Y., Brunner, E., Bumpstead, S.J., Chen, Y.D., Chines, P., Clarke, R., Coin, L.J., Cooper, M.N., Crisponi, L., Day, I.N., de Geus, E.J., Delplanque, J., Fedson, A.C., Fischer-Rosinsky, A., Forouhi, N.G., Franzosi, M.G., Galan, P., Goodarzi, M.O., Graessler, J., Grundy, S., Gwilliam, R., Hallmans, G., Hammond, N., Han, X., Hartikainen, A.L., Hayward, C., Heath, S.C., Hercberg, S., Hillman, D.R., Hingorani, A.D., Hui, J., Hung, J., Kaakinen, M., Kaprio, J., Kesaniemi, Y.A., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Kyvik, K.O., Lathrop, G.M., Lawlor, D.A., Le Bacquer, O., Lecoeur, C., Li, Y., Mahley, R., Mangino, M., Martínez-Larrad, M.T., McAteer, J.B., McPherson, R., Meisinger, C., Melzer, D., Meyre, D., Mitchell, B.D., Mukherjee, S., Naitza, S., Neville, M.J., Orrù, M., Pakyz, R., Paolisso, G., Pattaro, C., Pearson, D., Peden, J.F., Pedersen, N.L., Pfeiffer, A.F., Pichler, I., Polasek, O., Posthuma, D., Potter, S.C., Pouta, A., Province, M.A., Rice, K., Ripatti, S., Rivadeneira, F., Rolandsson, O., Sandbaek, A., Sandhu, M., Sanna, S., Sayer, A.A., Scheet, P., Seedorf, U., Sharp, S.J., Shields, B., Sigurðsson, G., Sijbrands, E.J., Silveira, A., Simpson, L., Singleton, A., Smith, N.L., Sovio, U., Swift, A., Syddall, H., Syvänen, A.C., Tönjes, A., Uitterlinden, A.G., van Dijk, K.W., Varma, D., Visvikis-Siest, S., Vitart, V., Vogelzangs, N., Waeber, G., Wagner, P.J., Walley, A., Ward, K.L., Watkins, H., Wild, S.H., Willemsen, G., Witteman, J.C., Yarnell, J.W., Zelenika, D., Zethelius, B., Zhai, G., Zhao, J.H., Zillikens, M.C., Borecki, I.B., Meneton, P., Magnusson, P.K., Nathan, D.M., Williams, G.H., Silander, K., Bornstein, S.R., Schwarz, P., Spranger, J., Karpe, F., Shuldiner, A.R., Cooper, C., Serrano-Ríos, M., Lind, L., Palmer, L.J., Franks, P.W., Ebrahim, S., Marmot, M., Wright, A.F., Stumvoll, M., Hamsten, A., Buchanan, T.A., Valle, T.T., Rotter, J.I., Penninx, B.W., Boomsma, D.I., Cao, A., Scuteri, A., Schlessinger, D., Uda, M., Ruokonen, A., Jarvelin, M.R., Peltonen, L., Mooser, V., Musunuru, K., Smith, A.V., Edmondson, A.C., Stylianou, I.M., Koseki, M., Pirruccello, J.P., Chasman, D.I., Johansen, C.T., Fouchier, S.W., Peloso, G.M., Barbalic, M., Ricketts, S.L., Bis, J.C., Feitosa, M.F., Orho-Melander, M., Melander, O., Li, X., Cho, Y.S., Go, M.J., Kim, Y.J., Lee, J.Y., Park, T., Kim, K., Sim, X., Ong, R.T., Croteau-Chonka, D.C., Lange, L.A., Smith, J.D., Ziegler, A., Zhang, W., Zee, R.Y., Whitfield, J.B., Thompson, J.R., Surakka, I., Smit, J.H., Sinisalo, J., Scott, J., Saharinen, J., Sabatti, C., Rose, L.M., Roberts, R., Rieder, M., Parker, A.N., Pare, G., O'Donnell, C.J., Nieminen, M.S., Nickerson, D.A., Montgomery, G.W., McArdle, W., Masson, D., Martin, N.G., Marroni, F., Lucas, G., Luben, R., Lokki, M.L., Lettre, G., Launer, L.J., Lakatta, E.G., Laaksonen, R., König, I.R., Khaw, K.T., Kaplan, L.M., Johansson, Å., Janssens, A.C., Igl, W., Hovingh, G.K., Hengstenberg, C., Havulinna, A.S., Hastie, N.D., Harris, T.B., Haritunians, T., Hall, A.S., Groop, L.C., Gonzalez, E., Freimer, N.B., Erdmann, J., Ejebe, K.G., Döring, A., Dominiczak, A.F., Demissie, S., de Faire, U., Caulfield, M.J., Boekholdt, S.M., Assimes, T.L., Quertermous, T., Seielstad, M., Wong, T.Y., Tai, E.S., Feranil, A.B., Kuzawa, C.W., Taylor, H.A., Gabriel, S.B., Holm, H., Gudnason, V., Krauss, R.M., Ordovas, J.M., Munroe, P.B., Kooner, J.S., Tall, A.R., Hegele, R.A., Kastelein, J.J., Schadt, E.E., Strachan, D.P., Reilly, M.P., Samani, N.J., Schunkert, H., Cupples, L.A., Sandhu, M.S., Ridker, P.M., Rader, D.J., Kathiresan, S., DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Procardis Consortium, MAGIC investigators, GLGC Consortium, Olson, J., Kronmal, R., Robbins, J., Chaves, PH., Burke, G., Kuller, LH., Tracy, R., Gottdiener, J., Prineas, R., Becker, JT., Enright, P., Klein, R., O'Leary, DH., Dastani, Z., Hivert, M.F., Timpson, N., Perry, J.R., Yuan, X., Scott, R.A., Henneman, P., Heid, I.M., Kizer, J.R., Lyytikäinen, L.P., Fuchsberger, C., Tanaka, T., Morris, A.P., Small, K., Isaacs, A., Beekman, M., Coassin, S., Lohman, K., Qi, L., Kanoni, S., Pankow, J.S., Uh, H.W., Wu, Y., Bidulescu, A., Rasmussen-Torvik, L.J., Greenwood, C.M., Ladouceur, M., Grimsby, J., Manning, A.K., Liu, C.T., Kooner, J., Mooser, V.E., Vollenweider, P., Kapur, K.A., Chambers, J., Wareham, N.J., Langenberg, C., Frants, R., Willems-Vandijk, K., Oostra, B.A., Willems, S.M., Lamina, C., Winkler, T.W., Psaty, B.M., Tracy, R.P., Brody, J., Chen, I., Viikari, J., Kähönen, M., Pramstaller, P.P., Evans, D.M., St Pourcain, B., Sattar, N., Wood, A.R., Bandinelli, S., Carlson, O.D., Egan, J.M., Böhringer, S., van Heemst, D., Kedenko, L., Kristiansson, K., Nuotio, M.L., Loo, B.M., Harris, T., Garcia, M., Kanaya, A., Haun, M., Klopp, N., Wichmann, H.E., Deloukas, P., Katsareli, E., Couper, D.J., Duncan, B.B., Kloppenburg, M., Adair, L.S., Borja, J.B., Wilson, J.G., Musani, S., Guo, X., Johnson, T., Semple, R., Teslovich, T.M., Allison, M.A., Redline, S., Buxbaum, S.G., Mohlke, K.L., Meulenbelt, I., Ballantyne, C.M., Dedoussis, G.V., Hu, F.B., Liu, Y., Paulweber, B., Spector, T.D., Slagboom, P.E., Ferrucci, L., Jula, A., Perola, M., Raitakari, O., Florez, J.C., Salomaa, V., Eriksson, J.G., Frayling, T.M., Hicks, A.A., Lehtimäki, T., Smith, G.D., Siscovick, D.S., Kronenberg, F., van Duijn, C., Loos, R.J., Waterworth, D.M., Meigs, J.B., Dupuis, J., Richards, J.B., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Hofmann, O.M., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Hassanali, N., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lindgren, C.M., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Morris, A.D., Palmer, C.N., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Pedersen, O., Barroso, I., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., McCarthy, M.I., Soranzo, N., Wheeler, E., Glazer, N.L., Bouatia-Naji, N., Mägi, R., Randall, J., Elliott, P., Rybin, D., Dehghan, A., Hottenga, J.J., Song, K., Goel, A., Lajunen, T., Doney, A., Cavalcanti-Proença, C., Kumari, M., Timpson, N.J., Zabena, C., Ingelsson, E., An, P., O'Connell, J., Luan, J., Elliott, A., Roccasecca, R.M., Pattou, F., Sethupathy, P., Ariyurek, Y., Barter, P., Beilby, J.P., Ben-Shlomo, Y., Bergmann, S., Bochud, M., Bonnefond, A., Borch-Johnsen, K., Böttcher, Y., Brunner, E., Bumpstead, S.J., Chen, Y.D., Chines, P., Clarke, R., Coin, L.J., Cooper, M.N., Crisponi, L., Day, I.N., de Geus, E.J., Delplanque, J., Fedson, A.C., Fischer-Rosinsky, A., Forouhi, N.G., Franzosi, M.G., Galan, P., Goodarzi, M.O., Graessler, J., Grundy, S., Gwilliam, R., Hallmans, G., Hammond, N., Han, X., Hartikainen, A.L., Hayward, C., Heath, S.C., Hercberg, S., Hillman, D.R., Hingorani, A.D., Hui, J., Hung, J., Kaakinen, M., Kaprio, J., Kesaniemi, Y.A., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Kyvik, K.O., Lathrop, G.M., Lawlor, D.A., Le Bacquer, O., Lecoeur, C., Li, Y., Mahley, R., Mangino, M., Martínez-Larrad, M.T., McAteer, J.B., McPherson, R., Meisinger, C., Melzer, D., Meyre, D., Mitchell, B.D., Mukherjee, S., Naitza, S., Neville, M.J., Orrù, M., Pakyz, R., Paolisso, G., Pattaro, C., Pearson, D., Peden, J.F., Pedersen, N.L., Pfeiffer, A.F., Pichler, I., Polasek, O., Posthuma, D., Potter, S.C., Pouta, A., Province, M.A., Rice, K., Ripatti, S., Rivadeneira, F., Rolandsson, O., Sandbaek, A., Sandhu, M., Sanna, S., Sayer, A.A., Scheet, P., Seedorf, U., Sharp, S.J., Shields, B., Sigurðsson, G., Sijbrands, E.J., Silveira, A., Simpson, L., Singleton, A., Smith, N.L., Sovio, U., Swift, A., Syddall, H., Syvänen, A.C., Tönjes, A., Uitterlinden, A.G., van Dijk, K.W., Varma, D., Visvikis-Siest, S., Vitart, V., Vogelzangs, N., Waeber, G., Wagner, P.J., Walley, A., Ward, K.L., Watkins, H., Wild, S.H., Willemsen, G., Witteman, J.C., Yarnell, J.W., Zelenika, D., Zethelius, B., Zhai, G., Zhao, J.H., Zillikens, M.C., Borecki, I.B., Meneton, P., Magnusson, P.K., Nathan, D.M., Williams, G.H., Silander, K., Bornstein, S.R., Schwarz, P., Spranger, J., Karpe, F., Shuldiner, A.R., Cooper, C., Serrano-Ríos, M., Lind, L., Palmer, L.J., Franks, P.W., Ebrahim, S., Marmot, M., Wright, A.F., Stumvoll, M., Hamsten, A., Buchanan, T.A., Valle, T.T., Rotter, J.I., Penninx, B.W., Boomsma, D.I., Cao, A., Scuteri, A., Schlessinger, D., Uda, M., Ruokonen, A., Jarvelin, M.R., Peltonen, L., Mooser, V., Musunuru, K., Smith, A.V., Edmondson, A.C., Stylianou, I.M., Koseki, M., Pirruccello, J.P., Chasman, D.I., Johansen, C.T., Fouchier, S.W., Peloso, G.M., Barbalic, M., Ricketts, S.L., Bis, J.C., Feitosa, M.F., Orho-Melander, M., Melander, O., Li, X., Cho, Y.S., Go, M.J., Kim, Y.J., Lee, J.Y., Park, T., Kim, K., Sim, X., Ong, R.T., Croteau-Chonka, D.C., Lange, L.A., Smith, J.D., Ziegler, A., Zhang, W., Zee, R.Y., Whitfield, J.B., Thompson, J.R., Surakka, I., Smit, J.H., Sinisalo, J., Scott, J., Saharinen, J., Sabatti, C., Rose, L.M., Roberts, R., Rieder, M., Parker, A.N., Pare, G., O'Donnell, C.J., Nieminen, M.S., Nickerson, D.A., Montgomery, G.W., McArdle, W., Masson, D., Martin, N.G., Marroni, F., Lucas, G., Luben, R., Lokki, M.L., Lettre, G., Launer, L.J., Lakatta, E.G., Laaksonen, R., König, I.R., Khaw, K.T., Kaplan, L.M., Johansson, Å., Janssens, A.C., Igl, W., Hovingh, G.K., Hengstenberg, C., Havulinna, A.S., Hastie, N.D., Harris, T.B., Haritunians, T., Hall, A.S., Groop, L.C., Gonzalez, E., Freimer, N.B., Erdmann, J., Ejebe, K.G., Döring, A., Dominiczak, A.F., Demissie, S., de Faire, U., Caulfield, M.J., Boekholdt, S.M., Assimes, T.L., Quertermous, T., Seielstad, M., Wong, T.Y., Tai, E.S., Feranil, A.B., Kuzawa, C.W., Taylor, H.A., Gabriel, S.B., Holm, H., Gudnason, V., Krauss, R.M., Ordovas, J.M., Munroe, P.B., Kooner, J.S., Tall, A.R., Hegele, R.A., Kastelein, J.J., Schadt, E.E., Strachan, D.P., Reilly, M.P., Samani, N.J., Schunkert, H., Cupples, L.A., Sandhu, M.S., Ridker, P.M., Rader, D.J., and Kathiresan, S.

Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

Published
2012

118. Physical activity attenuates the influence of FTO variants on obesity risk: A meta-analysis of 218,166 adults and 19,268 children

Author

Kilpeläinen, T.O. (Tuomas), Qi, L. (Lu), Brage, S. (Soren), Sharp, S.J. (Stephen), Sonestedt, E. (Emily), Demerath, E.W. (Ellen), Ahmad, T. (Tariq), Mora, S. (Samia), Kaakinen, M. (Marika), Sandholt, C. (Camilla), Holzapfel, C. (Christina), Autenrieth, C.S. (Christine), Hyppönen, E. (Elina), Cauchi, S. (Stephane), He, M. (Meian), Kutalik, Z. (Zoltán), Kumari, M. (Meena), Stancáková, A. (Alena), Meidtner, K. (Karina), Balkau, B. (Beverley), Tan, J.T. (Jonathan), Mangino, M. (Massimo), Timpson, N.J. (Nicholas), Song, Y. (Yiqing), Zillikens, M.C. (Carola), Jablonski, K.A. (Kathleen), Garcia, M. (Melissa), Johansson, S. (Stefan), Bragg-Gresham, J.L. (Jennifer L.), Wu, Y. (Ying), Vliet-Ostaptchouk, J.V. (Jana) van, Onland-Moret, N.C. (Charlotte), Zimmermann, E. (Esther), Rivera, N.V. (Natalia), Tanaka, T. (Toshiko), Stringham, H.M. (Heather), Silbernagel, G. (Günther), Kanoni, S. (Stavroula), Feitosa, M.F. (Mary Furlan), Snitker, S. (Soren), Ruiz, J.R. (Jonatan), Metter, J. (Jeffery), Larrad, M.T.M., Atalay, M. (Mustafa), Hakanen, M. (Maarit), Amin, N. (Najaf), Cavalcanti-Proença, C. (Christine), Grøntved, A. (Anders), Hallmans, G. (Göran), Jansson, J.O., Kuusisto, J. (Johanna), Kähönen, M. (Mika), Lutsey, P.L. (Pamela), Nolan, J.J. (John), Palla, L. (Luigi), Pedersen, O. (Oluf), Pérusse, L. (Louis), Renström, F. (Frida), Scott, R.A. (Robert), Shungin, D. (Dmitry), Sovio, U. (Ulla), Tammelin, T.H. (Tuija), Rönnemaa, T. (Tapani), Lakka, T.A. (Timo), Uusitupa, M. (Matti), Rios, M.S., Ferrucci, L. (Luigi), Bouchard, C. (Claude), Meirhaeghe, A. (Aline), Fu, M. (Mao), Walker, M. (Mark), Borecki, I.B. (Ingrid), Dedoussis, G.V. (George), Fritsche, A. (Andreas), Ohlsson, C. (Claes), Boehnke, M. (Michael), Bandinelli, S. (Stefania), Tikka-Kleemola, P. (Päivi), Lawlor, D.A. (Debbie), Gudnason, V. (Vilmundur), Harris, T.B. (Tamara), Sørensen, T.I.A. (Thorkild), Mohlke, K.L. (Karen), Hofman, A. (Albert), Uitterlinden, A.G. (André), Tuomilehto, J. (Jaakko), Lehtimäki, T. (Terho), Raitakari, O. (Olli), Isomaa, B. (Bo), Njolstad, P. (Pal), Florez, J.C. (Jose), Liu, S. (Simin), Ness, A.R. (Andrew), Spector, T.D. (Timothy), Tai, E.S. (Shyong), Froguel, P. (Philippe), Boeing, H. (Heiner), Laakso, M. (Markku), Marmot, M. (Michael), Bergmann, S.M. (Sven), Power, C. (Chris), Khaw, K.-T., Chasman, D.I. (Daniel), Ridker, P.M. (Paul), Hansen, T. (Torben), Monda, K.L. (Keri), Illig, T. (Thomas), Järvelin, M.R., Wareham, N.J. (Nick), Ebrahim, S. (Shanil), Hu, F.B. (Frank), Groop, L. (Leif), Orho-Melander, M. (Marju), Ekelund, U. (Ulf), Franks, P.W. (Paul), Loos, R.J.F. (Ruth), Kilpeläinen, T.O. (Tuomas), Qi, L. (Lu), Brage, S. (Soren), Sharp, S.J. (Stephen), Sonestedt, E. (Emily), Demerath, E.W. (Ellen), Ahmad, T. (Tariq), Mora, S. (Samia), Kaakinen, M. (Marika), Sandholt, C. (Camilla), Holzapfel, C. (Christina), Autenrieth, C.S. (Christine), Hyppönen, E. (Elina), Cauchi, S. (Stephane), He, M. (Meian), Kutalik, Z. (Zoltán), Kumari, M. (Meena), Stancáková, A. (Alena), Meidtner, K. (Karina), Balkau, B. (Beverley), Tan, J.T. (Jonathan), Mangino, M. (Massimo), Timpson, N.J. (Nicholas), Song, Y. (Yiqing), Zillikens, M.C. (Carola), Jablonski, K.A. (Kathleen), Garcia, M. (Melissa), Johansson, S. (Stefan), Bragg-Gresham, J.L. (Jennifer L.), Wu, Y. (Ying), Vliet-Ostaptchouk, J.V. (Jana) van, Onland-Moret, N.C. (Charlotte), Zimmermann, E. (Esther), Rivera, N.V. (Natalia), Tanaka, T. (Toshiko), Stringham, H.M. (Heather), Silbernagel, G. (Günther), Kanoni, S. (Stavroula), Feitosa, M.F. (Mary Furlan), Snitker, S. (Soren), Ruiz, J.R. (Jonatan), Metter, J. (Jeffery), Larrad, M.T.M., Atalay, M. (Mustafa), Hakanen, M. (Maarit), Amin, N. (Najaf), Cavalcanti-Proença, C. (Christine), Grøntved, A. (Anders), Hallmans, G. (Göran), Jansson, J.O., Kuusisto, J. (Johanna), Kähönen, M. (Mika), Lutsey, P.L. (Pamela), Nolan, J.J. (John), Palla, L. (Luigi), Pedersen, O. (Oluf), Pérusse, L. (Louis), Renström, F. (Frida), Scott, R.A. (Robert), Shungin, D. (Dmitry), Sovio, U. (Ulla), Tammelin, T.H. (Tuija), Rönnemaa, T. (Tapani), Lakka, T.A. (Timo), Uusitupa, M. (Matti), Rios, M.S., Ferrucci, L. (Luigi), Bouchard, C. (Claude), Meirhaeghe, A. (Aline), Fu, M. (Mao), Walker, M. (Mark), Borecki, I.B. (Ingrid), Dedoussis, G.V. (George), Fritsche, A. (Andreas), Ohlsson, C. (Claes), Boehnke, M. (Michael), Bandinelli, S. (Stefania), Tikka-Kleemola, P. (Päivi), Lawlor, D.A. (Debbie), Gudnason, V. (Vilmundur), Harris, T.B. (Tamara), Sørensen, T.I.A. (Thorkild), Mohlke, K.L. (Karen), Hofman, A. (Albert), Uitterlinden, A.G. (André), Tuomilehto, J. (Jaakko), Lehtimäki, T. (Terho), Raitakari, O. (Olli), Isomaa, B. (Bo), Njolstad, P. (Pal), Florez, J.C. (Jose), Liu, S. (Simin), Ness, A.R. (Andrew), Spector, T.D. (Timothy), Tai, E.S. (Shyong), Froguel, P. (Philippe), Boeing, H. (Heiner), Laakso, M. (Markku), Marmot, M. (Michael), Bergmann, S.M. (Sven), Power, C. (Chris), Khaw, K.-T., Chasman, D.I. (Daniel), Ridker, P.M. (Paul), Hansen, T. (Torben), Monda, K.L. (Keri), Illig, T. (Thomas), Järvelin, M.R., Wareham, N.J. (Nick), Ebrahim, S. (Shanil), Hu, F.B. (Frank), Groop, L. (Leif), Orho-Melander, M. (Marju), Ekelund, U. (Ulf), Franks, P.W. (Paul), and Loos, R.J.F. (Ruth)

Abstract

Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). Methods and Findings: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (pinteraction= 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. Conclu

Published
2011
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119. Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk: A Meta-Analysis of 218,166 Adults and 19,268 Children

Author

Kilpelainen, TO, Qi, L, Brage, S, Sharp, SJ, Sonestedt, E, Demerath, E, Ahmad, T, Mora, S, Kaakinen, M, Sandholt, CH, Holzapfel, C, Autenrieth, CS, Hypponen, E, Cauchi, S, He, MA, Kutalik, Z, Kumari, M, Stancakova, A, Meidtner, K, Balkau, B, Tan, JT, Mangino, M, Timpson, NJ, Song, YQ, Zillikens, M.C., Jablonski, KA, Garcia, ME, Johansson, S, Bragg-Gresham, JL, Wu, Fenny, van Vliet-Ostaptchouk, JV, Onland-Moret, NC, Zimmermann, E, Rivera, NV, Tanaka, T, Stringham, HM, Silbernagel, G, Kanoni, S, Feitosa, MF, Snitker, S, Ruiz, JR, Metter, J, Larrad, MTM, Atalay, M, Hakanen, M, Amin, Najaf, Cavalcanti-Proenca, C, Grontved, A, Hallmans, G, Jansson, JO, Kuusisto, J, Kahonen, M, Lutsey, PL, Nolan, JJ, Palla, L, Pedersen, O, Perusse, L, Renstrom, F, Scott, RA, Shungin, D, Sovio, U, Tammelin, TH, Ronnemaa, T, Lakka, TA, Uusitupa, M, Rios, MS, Ferrucci, L, Bouchard, C, Meirhaeghe, A, Fu, M, Walker, M, Borecki, IB, Dedoussis, GV, Fritsche, A, Ohlsson, C, Boehnke, M, Bandinelli, S, Duijn, Cornelia, Ebrahim, S, Lawlor, DA, Gudnason, V, Harris, TB, Sorensen, TIA, Mohlke, KL, Hofman, Bert, Uitterlinden, André, Tuomilehto, J, Lehtimaki, T, Raitakari, O, Isomaa, B, Njolstad, PR, Florez, JC, Liu, SM (Simin), Ness, A, Spector, TD, Tai, ES, Froguel, P, Boeing, H, Laakso, M, Marmot, M, Bergmann, S, Power, C, Khaw, KT, Chasman, D, Ridker, P, Hansen, T, Monda, KL, Illig, T, Jarvelin, MR, Wareham, NJ, Hu, FB, Groop, LC, Orho-Melander, M, Ekelund, U, Franks, PW, Loos, RJF, Kilpelainen, TO, Qi, L, Brage, S, Sharp, SJ, Sonestedt, E, Demerath, E, Ahmad, T, Mora, S, Kaakinen, M, Sandholt, CH, Holzapfel, C, Autenrieth, CS, Hypponen, E, Cauchi, S, He, MA, Kutalik, Z, Kumari, M, Stancakova, A, Meidtner, K, Balkau, B, Tan, JT, Mangino, M, Timpson, NJ, Song, YQ, Zillikens, M.C., Jablonski, KA, Garcia, ME, Johansson, S, Bragg-Gresham, JL, Wu, Fenny, van Vliet-Ostaptchouk, JV, Onland-Moret, NC, Zimmermann, E, Rivera, NV, Tanaka, T, Stringham, HM, Silbernagel, G, Kanoni, S, Feitosa, MF, Snitker, S, Ruiz, JR, Metter, J, Larrad, MTM, Atalay, M, Hakanen, M, Amin, Najaf, Cavalcanti-Proenca, C, Grontved, A, Hallmans, G, Jansson, JO, Kuusisto, J, Kahonen, M, Lutsey, PL, Nolan, JJ, Palla, L, Pedersen, O, Perusse, L, Renstrom, F, Scott, RA, Shungin, D, Sovio, U, Tammelin, TH, Ronnemaa, T, Lakka, TA, Uusitupa, M, Rios, MS, Ferrucci, L, Bouchard, C, Meirhaeghe, A, Fu, M, Walker, M, Borecki, IB, Dedoussis, GV, Fritsche, A, Ohlsson, C, Boehnke, M, Bandinelli, S, Duijn, Cornelia, Ebrahim, S, Lawlor, DA, Gudnason, V, Harris, TB, Sorensen, TIA, Mohlke, KL, Hofman, Bert, Uitterlinden, André, Tuomilehto, J, Lehtimaki, T, Raitakari, O, Isomaa, B, Njolstad, PR, Florez, JC, Liu, SM (Simin), Ness, A, Spector, TD, Tai, ES, Froguel, P, Boeing, H, Laakso, M, Marmot, M, Bergmann, S, Power, C, Khaw, KT, Chasman, D, Ridker, P, Hansen, T, Monda, KL, Illig, T, Jarvelin, MR, Wareham, NJ, Hu, FB, Groop, LC, Orho-Melander, M, Ekelund, U, Franks, PW, and Loos, RJF

Abstract

Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n=218,166) and nine studies of children and adolescents (n=19,268). Methods and Findings: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTOxPA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction) = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. Conclusions: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.

Published
2011

120. Biological, clinical and population relevance of 95 loci for blood lipids

Author

Teslovich, T.M. (Tanya), Musunuru, K. (Kiran), Smith, A.V. (Albert Vernon), Edmondson, A.C. (Andrew), Stylianou, I.M. (Ioannis), Koseki, M. (Masahiro), Pirruccello, J.P. (James), Ripatti, S. (Samuli), Chasman, D.I. (Daniel), Willer, C.J. (Cristen), Johansen, C.T. (Christopher), Fouchier, S.W. (Sigrid), Isaacs, A.J. (Aaron), Peloso, G.M. (Gina), Barbalic, M. (maja), Ricketts, S.L. (Sally), Bis, J.C. (Joshua), Aulchenko, Y.S. (Yurii), Thorleifsson, G. (Gudmar), Feitosa, M.F. (Mary Furlan), Chambers, J. (John), Orho-Melander, M. (Marju), Melander, O. (Olle), Johnson, T. (Toby), Li, X. (Xiaohui), Guo, X. (Xiuqing), Shin Cho, Y. (Yoon), Jin Go, M. (Min), Jin Kim, Y. (Young), Lee, J.Y. (Jong Young), Park, T. (Taesung), Kim, Y-J. (Yong-Jin), Sim, X. (Xueling), Twee-Hee Ong, R. (Rick), Croteau-Chonka, D.C. (Damien), Lange, L.A. (Leslie), Song, K. (Kijoung), Zhao, J.H. (Jing Hua), Yuan, X. (Xin), Luan, J., Lamina, C. (Claudia), Ziegler, A. (Andreas), Zhang, W. (Weibo), Zee, R.Y.L. (Robert), Wright, A.F. (Alan), Witteman, J.C.M. (Jacqueline), Wilson, J.F. (James), Willemsen, G.A.H.M. (Gonneke), Wichmann, H.E. (Heinz Erich), Whitfield, J. (John), Waterworth, D. (Dawn), Wareham, N.J. (Nick), Waeber, G. (Gérard), Vollenweider, P. (Peter), Voight, B.F. (Benjamin), Vitart, V. (Veronique), Uitterlinden, A.G. (André), Uda, M. (Manuela), Tuomilehto, J. (Jaakko), Thompson, J.R. (John), Tanaka, T. (Toshiko), Surakka, I. (Ida), Stringham, H.M. (Heather), Spector, T.D. (Timothy), Soranzo, N. (Nicole), Smit, J.H. (Johannes), Sinisalo, J. (Juha), Silander, K. (Kaisa), Sijbrands, E.J.G. (Eric), Scuteri, A. (Angelo), Scott, J. (James), Schlessinger, D. (David), Sanna, S. (Serena), Salomaa, V. (Veikko), Saharinen, J. (Juha), Sabatti, C. (Chiara), Ruokonen, A. (Aimo), Rudan, I. (Igor), Rose, L.M. (Lynda), Roberts, R. (Robert), Rieder, M. (Mark), Psaty, B.M. (Bruce), Pramstaller, P.P. (Peter Paul), Pichler, I. (Irene), Perola, M. (Markus), Penninx, B.W.J.H. (Brenda), Pedersen, N.L. (Nancy), Pattaro, C. (Cristian), Parker, A.N. (Alex), Pare, G. (Guillaume), Oostra, B.A. (Ben), Nieminen, M.S. (Markku), Nickerson, D.A. (Deborah), Montgomery, G.W. (Grant), Meitinger, T. (Thomas), McPherson, R. (Ruth), McCarthy, M.I. (Mark), McArdle, W.L. (Wendy), Masson, D. (David), Martin, N.G. (Nicholas), Marroni, F. (Fabio), Mangino, M. (Massimo), Magnusson, P.K. (Patrik), Lucas, G. (Gavin), Luben, R.N. (Robert), Loos, R.J.F. (Ruth), Lokki, M.L., Lettre, G. (Guillaume), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lakatta, E. (Edward), Laaksonen, R. (Reijo), Kyvik, K.O. (Kirsten Ohm), Kronenberg, F. (Florian), König, I.R. (Inke), Khaw, K-T. (Kay-Tee), Kaprio, J. (Jaakko), Kaplan, R.C. (Robert), Johansson, A. (Åsa), Jarvelin, M.-R. (Marjo-Riitta), Cecile, A. (A.), Ingelsson, E. (Erik), Igl, W. (Wilmar), Hovingh, G.K. (Kees), Hottenga, J.J. (Jouke Jan), Hofman, A. (Albert), Hicks, A.A. (Andrew), Hengstenberg, C. (Christian), Heid, I.M. (Iris), Hayward, C. (Caroline), Havulinna, A.S. (Aki), Hastie, N. (Nick), Harris, T.B. (Tamara), Haritunians, T. (Talin), Hall, A.S. (Alistair), Gyllensten, U. (Ulf), Guiducci, C. (Candace), Groop, L. (Leif), Gonzalez, E. (Elena), Gieger, C. (Christian), Freimer, N.B. (Nelson), Ferrucci, L. (Luigi), Erdmann, J. (Jeanette), Elliott, P. (Paul), Ejebe, K.G. (Kenechi), Döring, A. (Angela), Dominiczak, A. (Anna), Demissie, S. (Serkalem), Deloukas, P. (Panagiotis), Geus, E.J.C. (Eco) de, Faire, U. (Ulf) de, Crawford, G. (Gabe), Collins, F.S. (Francis), Chen, C. (Chao), Caulfield, M. (Mark), Campbell, H. (Harry), Burtt, N.P. (Noël), Bonnycastle, L.L. (Lori), Boomsma, D.I. (Dorret), Boekholdt, S.M. (Matthijs), Bergman, R.N. (Richard), Barroso, I.E. (Inês), Bandinelli, S. (Stefania), Ballantyne, C. (Christie), Assimes, T.L. (Themistocles), Quertermous, T. (Thomas), Altshuler, D. (David), Seielstad, M. (Mark), Wong, T.Y. (Tien Yin), Tai, E.S. (Shyong), Feranil, A.B. (Alan), Kuzawa, C.W. (Christopher), Adair, L.S. (Linda), Taylor, H.A. (Herman), Borecki, I.B. (Ingrid), Gabriel, S.B. (Stacey), Holm, H. (Hilma), Thorsteinsdottir, U. (Unnur), Gudnason, V. (Vilmundur), Krauss, R.M. (Ronald), Mohlke, K.L. (Karen), Ordovas, J.M. (Jose), Munroe, P. (Patricia), Kooner, J.S. (Jaspal), Tall, A.R. (Alan), Hegele, R.A. (Robert), Kastelein, J.J.P. (John), Schadt, E.E. (Eric), Rotter, J.I. (Jerome), Boerwinkle, E.A. (Eric), Strachan, D.P. (David), Mooser, V. (Vincent), Zwart, J-A. (John-Anker), Reilly, M.P. (Muredach), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Cupples, L.A. (Adrienne), Sandhu, M.S. (Manjinder), Ridker, P.M. (Paul), Rader, D.J. (Daniel), Tikka-Kleemola, P. (Päivi), Peltonen, L. (Leena Johanna), Abecasis, G.R. (Gonçalo), Boehnke, M. (Michael), Kathiresan, S. (Sekar), O'Donnell, C.J. (Christopher), Teslovich, T.M. (Tanya), Musunuru, K. (Kiran), Smith, A.V. (Albert Vernon), Edmondson, A.C. (Andrew), Stylianou, I.M. (Ioannis), Koseki, M. (Masahiro), Pirruccello, J.P. (James), Ripatti, S. (Samuli), Chasman, D.I. (Daniel), Willer, C.J. (Cristen), Johansen, C.T. (Christopher), Fouchier, S.W. (Sigrid), Isaacs, A.J. (Aaron), Peloso, G.M. (Gina), Barbalic, M. (maja), Ricketts, S.L. (Sally), Bis, J.C. (Joshua), Aulchenko, Y.S. (Yurii), Thorleifsson, G. (Gudmar), Feitosa, M.F. (Mary Furlan), Chambers, J. (John), Orho-Melander, M. (Marju), Melander, O. (Olle), Johnson, T. (Toby), Li, X. (Xiaohui), Guo, X. (Xiuqing), Shin Cho, Y. (Yoon), Jin Go, M. (Min), Jin Kim, Y. (Young), Lee, J.Y. (Jong Young), Park, T. (Taesung), Kim, Y-J. (Yong-Jin), Sim, X. (Xueling), Twee-Hee Ong, R. (Rick), Croteau-Chonka, D.C. (Damien), Lange, L.A. (Leslie), Song, K. (Kijoung), Zhao, J.H. (Jing Hua), Yuan, X. (Xin), Luan, J., Lamina, C. (Claudia), Ziegler, A. (Andreas), Zhang, W. (Weibo), Zee, R.Y.L. (Robert), Wright, A.F. (Alan), Witteman, J.C.M. (Jacqueline), Wilson, J.F. (James), Willemsen, G.A.H.M. (Gonneke), Wichmann, H.E. (Heinz Erich), Whitfield, J. (John), Waterworth, D. (Dawn), Wareham, N.J. (Nick), Waeber, G. (Gérard), Vollenweider, P. (Peter), Voight, B.F. (Benjamin), Vitart, V. (Veronique), Uitterlinden, A.G. (André), Uda, M. (Manuela), Tuomilehto, J. (Jaakko), Thompson, J.R. (John), Tanaka, T. (Toshiko), Surakka, I. (Ida), Stringham, H.M. (Heather), Spector, T.D. (Timothy), Soranzo, N. (Nicole), Smit, J.H. (Johannes), Sinisalo, J. (Juha), Silander, K. (Kaisa), Sijbrands, E.J.G. (Eric), Scuteri, A. (Angelo), Scott, J. (James), Schlessinger, D. (David), Sanna, S. (Serena), Salomaa, V. (Veikko), Saharinen, J. (Juha), Sabatti, C. (Chiara), Ruokonen, A. (Aimo), Rudan, I. (Igor), Rose, L.M. (Lynda), Roberts, R. (Robert), Rieder, M. (Mark), Psaty, B.M. (Bruce), Pramstaller, P.P. (Peter Paul), Pichler, I. (Irene), Perola, M. (Markus), Penninx, B.W.J.H. (Brenda), Pedersen, N.L. (Nancy), Pattaro, C. (Cristian), Parker, A.N. (Alex), Pare, G. (Guillaume), Oostra, B.A. (Ben), Nieminen, M.S. (Markku), Nickerson, D.A. (Deborah), Montgomery, G.W. (Grant), Meitinger, T. (Thomas), McPherson, R. (Ruth), McCarthy, M.I. (Mark), McArdle, W.L. (Wendy), Masson, D. (David), Martin, N.G. (Nicholas), Marroni, F. (Fabio), Mangino, M. (Massimo), Magnusson, P.K. (Patrik), Lucas, G. (Gavin), Luben, R.N. (Robert), Loos, R.J.F. (Ruth), Lokki, M.L., Lettre, G. (Guillaume), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lakatta, E. (Edward), Laaksonen, R. (Reijo), Kyvik, K.O. (Kirsten Ohm), Kronenberg, F. (Florian), König, I.R. (Inke), Khaw, K-T. (Kay-Tee), Kaprio, J. (Jaakko), Kaplan, R.C. (Robert), Johansson, A. (Åsa), Jarvelin, M.-R. (Marjo-Riitta), Cecile, A. (A.), Ingelsson, E. (Erik), Igl, W. (Wilmar), Hovingh, G.K. (Kees), Hottenga, J.J. (Jouke Jan), Hofman, A. (Albert), Hicks, A.A. (Andrew), Hengstenberg, C. (Christian), Heid, I.M. (Iris), Hayward, C. (Caroline), Havulinna, A.S. (Aki), Hastie, N. (Nick), Harris, T.B. (Tamara), Haritunians, T. (Talin), Hall, A.S. (Alistair), Gyllensten, U. (Ulf), Guiducci, C. (Candace), Groop, L. (Leif), Gonzalez, E. (Elena), Gieger, C. (Christian), Freimer, N.B. (Nelson), Ferrucci, L. (Luigi), Erdmann, J. (Jeanette), Elliott, P. (Paul), Ejebe, K.G. (Kenechi), Döring, A. (Angela), Dominiczak, A. (Anna), Demissie, S. (Serkalem), Deloukas, P. (Panagiotis), Geus, E.J.C. (Eco) de, Faire, U. (Ulf) de, Crawford, G. (Gabe), Collins, F.S. (Francis), Chen, C. (Chao), Caulfield, M. (Mark), Campbell, H. (Harry), Burtt, N.P. (Noël), Bonnycastle, L.L. (Lori), Boomsma, D.I. (Dorret), Boekholdt, S.M. (Matthijs), Bergman, R.N. (Richard), Barroso, I.E. (Inês), Bandinelli, S. (Stefania), Ballantyne, C. (Christie), Assimes, T.L. (Themistocles), Quertermous, T. (Thomas), Altshuler, D. (David), Seielstad, M. (Mark), Wong, T.Y. (Tien Yin), Tai, E.S. (Shyong), Feranil, A.B. (Alan), Kuzawa, C.W. (Christopher), Adair, L.S. (Linda), Taylor, H.A. (Herman), Borecki, I.B. (Ingrid), Gabriel, S.B. (Stacey), Holm, H. (Hilma), Thorsteinsdottir, U. (Unnur), Gudnason, V. (Vilmundur), Krauss, R.M. (Ronald), Mohlke, K.L. (Karen), Ordovas, J.M. (Jose), Munroe, P. (Patricia), Kooner, J.S. (Jaspal), Tall, A.R. (Alan), Hegele, R.A. (Robert), Kastelein, J.J.P. (John), Schadt, E.E. (Eric), Rotter, J.I. (Jerome), Boerwinkle, E.A. (Eric), Strachan, D.P. (David), Mooser, V. (Vincent), Zwart, J-A. (John-Anker), Reilly, M.P. (Muredach), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Cupples, L.A. (Adrienne), Sandhu, M.S. (Manjinder), Ridker, P.M. (Paul), Rader, D.J. (Daniel), Tikka-Kleemola, P. (Päivi), Peltonen, L. (Leena Johanna), Abecasis, G.R. (Gonçalo), Boehnke, M. (Michael), Kathiresan, S. (Sekar), and O'Donnell, C.J. (Christopher)

Abstract

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<-10-8), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Published
2010
Full Text
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121. Biological, clinical and population relevance of 95 loci for blood lipids

Author

Teslovich, TM, Musunuru, K, Smith, AV, Edmondson, AC, Stylianou, IM, Koseki, M, Pirruccello, JP, Ripatti, S, Chasman, DI, Willer, CJ, Johansen, CT, Fouchier, SW, Isaacs, A, Peloso, GM, Barbalic, M, Ricketts, SL, Bis, JC, Aulchenko, YS, Thorleifsson, G, Feitosa, MF, Chambers, J, Orho-Melander, M, Melander, O, Johnson, T, Li, X, Guo, X, Li, M, Cho, YS, Go, MJ, Kim, YJ, Lee, J-Y, Park, T, Kim, K, Sim, X, Ong, RT-H, Croteau-Chonka, DC, Lange, LA, Smith, JD, Song, K, Zhao, JH, Yuan, X, Luan, J, Lamina, C, Ziegler, A, Zhang, W, Zee, RYL, Wright, AF, Witteman, JCM, Wilson, JF, Willemsen, G, Wichmann, H-E, Whitfield, JB, Waterworth, DM, Wareham, NJ, Waeber, G, Vollenweider, P, Voight, BF, Vitart, V, Uitterlinden, AG, Uda, M, Tuomilehto, J, Thompson, JR, Tanaka, T, Surakka, I, Stringham, HM, Spector, TD, Soranzo, N, Smit, JH, Sinisalo, J, Silander, K, Sijbrands, EJG, Scuteri, A, Scott, J, Schlessinger, D, Sanna, S, Salomaa, V, Saharinen, J, Sabatti, C, Ruokonen, A, Rudan, I, Rose, LM, Roberts, R, Rieder, M, Psaty, BM, Pramstaller, PP, Pichler, I, Perola, M, Penninx, BWJH, Pedersen, NL, Pattaro, C, Parker, AN, Pare, G, Oostra, BA, O'Donnell, CJ, Nieminen, MS, Nickerson, DA, Montgomery, GW, Meitinger, T, McPherson, R, McCarthy, MI, McArdle, W, Masson, D, Martin, NG, Marroni, F, Mangino, M, Magnusson, PKE, Lucas, G, Luben, R, Loos, RJF, Lokki, M-L, Lettre, G, Langenberg, C, Launer, LJ, Lakatta, EG, Laaksonen, R, Kyvik, KO, Kronenberg, F, Koenig, IR, Khaw, K-T, Kaprio, J, Kaplan, LM, Johansson, A, Jarvelin, M-R, Janssens, ACJW, Ingelsson, E, Igi, W, Hovingh, GK, Hottenga, J-J, Hofman, A, Hicks, AA, Hengstenberg, C, Heid, IM, Hayward, C, Havulinna, AS, Hastie, ND, Harris, TB, Haritunians, T, Hall, AS, Gyllensten, U, Guiducci, C, Groop, LC, Gonzalez, E, Gieger, C, Freimer, NB, Ferrucci, L, Erdmann, J, Elliott, P, Ejebe, KG, Doering, A, Dominiczak, AF, Demissie, S, Deloukas, P, de Geus, EJC, de Faire, U, Crawford, G, Collins, FS, Chen, Y-DI, Caulfield, MJ, Campbell, H, Burtt, NP, Bonnycastle, LL, Boomsma, DI, Boekholdt, SM, Bergman, RN, Barroso, I, Bandinelli, S, Ballantyne, CM, Assimes, TL, Quertermous, T, Altshuler, D, Seielstad, M, Wong, TY, Tai, E-S, Feranil, AB, Kuzawa, CW, Adair, LS, Taylor, HA, Borecki, IB, Gabriel, SB, Wilson, JG, Holm, H, Thorsteinsdottir, U, Gudnason, V, Krauss, RM, Mohlke, KL, Ordovas, JM, Munroe, PB, Kooner, JS, Tall, AR, Hegele, RA, Kastelein, JJP, Schadt, EE, Rotter, JI, Boerwinkle, E, Strachan, DP, Mooser, V, Stefansson, K, Reilly, MP, Samani, NJ, Schunkert, H, Cupples, LA, Sandhu, MS, Ridker, PM, Rader, DJ, van Duijn, CM, Peltonen, L, Abecasis, GR, Boehnke, M, Kathiresan, S, Teslovich, TM, Musunuru, K, Smith, AV, Edmondson, AC, Stylianou, IM, Koseki, M, Pirruccello, JP, Ripatti, S, Chasman, DI, Willer, CJ, Johansen, CT, Fouchier, SW, Isaacs, A, Peloso, GM, Barbalic, M, Ricketts, SL, Bis, JC, Aulchenko, YS, Thorleifsson, G, Feitosa, MF, Chambers, J, Orho-Melander, M, Melander, O, Johnson, T, Li, X, Guo, X, Li, M, Cho, YS, Go, MJ, Kim, YJ, Lee, J-Y, Park, T, Kim, K, Sim, X, Ong, RT-H, Croteau-Chonka, DC, Lange, LA, Smith, JD, Song, K, Zhao, JH, Yuan, X, Luan, J, Lamina, C, Ziegler, A, Zhang, W, Zee, RYL, Wright, AF, Witteman, JCM, Wilson, JF, Willemsen, G, Wichmann, H-E, Whitfield, JB, Waterworth, DM, Wareham, NJ, Waeber, G, Vollenweider, P, Voight, BF, Vitart, V, Uitterlinden, AG, Uda, M, Tuomilehto, J, Thompson, JR, Tanaka, T, Surakka, I, Stringham, HM, Spector, TD, Soranzo, N, Smit, JH, Sinisalo, J, Silander, K, Sijbrands, EJG, Scuteri, A, Scott, J, Schlessinger, D, Sanna, S, Salomaa, V, Saharinen, J, Sabatti, C, Ruokonen, A, Rudan, I, Rose, LM, Roberts, R, Rieder, M, Psaty, BM, Pramstaller, PP, Pichler, I, Perola, M, Penninx, BWJH, Pedersen, NL, Pattaro, C, Parker, AN, Pare, G, Oostra, BA, O'Donnell, CJ, Nieminen, MS, Nickerson, DA, Montgomery, GW, Meitinger, T, McPherson, R, McCarthy, MI, McArdle, W, Masson, D, Martin, NG, Marroni, F, Mangino, M, Magnusson, PKE, Lucas, G, Luben, R, Loos, RJF, Lokki, M-L, Lettre, G, Langenberg, C, Launer, LJ, Lakatta, EG, Laaksonen, R, Kyvik, KO, Kronenberg, F, Koenig, IR, Khaw, K-T, Kaprio, J, Kaplan, LM, Johansson, A, Jarvelin, M-R, Janssens, ACJW, Ingelsson, E, Igi, W, Hovingh, GK, Hottenga, J-J, Hofman, A, Hicks, AA, Hengstenberg, C, Heid, IM, Hayward, C, Havulinna, AS, Hastie, ND, Harris, TB, Haritunians, T, Hall, AS, Gyllensten, U, Guiducci, C, Groop, LC, Gonzalez, E, Gieger, C, Freimer, NB, Ferrucci, L, Erdmann, J, Elliott, P, Ejebe, KG, Doering, A, Dominiczak, AF, Demissie, S, Deloukas, P, de Geus, EJC, de Faire, U, Crawford, G, Collins, FS, Chen, Y-DI, Caulfield, MJ, Campbell, H, Burtt, NP, Bonnycastle, LL, Boomsma, DI, Boekholdt, SM, Bergman, RN, Barroso, I, Bandinelli, S, Ballantyne, CM, Assimes, TL, Quertermous, T, Altshuler, D, Seielstad, M, Wong, TY, Tai, E-S, Feranil, AB, Kuzawa, CW, Adair, LS, Taylor, HA, Borecki, IB, Gabriel, SB, Wilson, JG, Holm, H, Thorsteinsdottir, U, Gudnason, V, Krauss, RM, Mohlke, KL, Ordovas, JM, Munroe, PB, Kooner, JS, Tall, AR, Hegele, RA, Kastelein, JJP, Schadt, EE, Rotter, JI, Boerwinkle, E, Strachan, DP, Mooser, V, Stefansson, K, Reilly, MP, Samani, NJ, Schunkert, H, Cupples, LA, Sandhu, MS, Ridker, PM, Rader, DJ, van Duijn, CM, Peltonen, L, Abecasis, GR, Boehnke, M, and Kathiresan, S

Abstract

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Published
2010

122. The search for putative unifying genetic factors for components of the metabolic syndrome

Author

Sjögren, M, Lyssenko, V, Jonsson, Anna Elisabet, Berglund, G, Nilsson, P, Groop, L, Orho-Melander, M, Sjögren, M, Lyssenko, V, Jonsson, Anna Elisabet, Berglund, G, Nilsson, P, Groop, L, and Orho-Melander, M

Abstract

The metabolic syndrome is a cluster of factors contributing to increased risk of cardiovascular disease and type 2 diabetes but unifying mechanisms have not been identified. Our aim was to study whether common variations in 17 genes previously associated with type 2 diabetes or components of the metabolic syndrome and variants in nine genes with inconsistent association with at least two components of the metabolic syndrome would also predict future development of components of the metabolic syndrome, individually or in combination.

Published
2008

130. Characterization of a naturally occurring mutation (L107I) in the HNF1 alpha (MODY3) gene.

Author

Cervin, C, Orho-Melander, M, Ridderstråle, M, Lehto, M, Barg, S, Groop, L, Cilio, C M, Cervin, C, Orho-Melander, M, Ridderstråle, M, Lehto, M, Barg, S, Groop, L, and Cilio, C M

Abstract

AIMS/HYPOTHESIS: Maturity onset diabetes of the young type 3 (MODY3) is a monogenic form of diabetes mellitus caused by mutations in the gene encoding for hepatocyte nuclear factor 1 alpha, HNF1 alpha. In this study we have examined the in vivo and in vitro effects of a mutation (L107I) outside the DNA binding and dimerization domains in the N terminal part of the HNF1 alpha gene. METHODS: Beta-cell function of the affected family members was assessed by an oral glucose tolerance test. Functional tests were carried out to explain the role of the mutation in vitro by transcriptional activity assay, Western blotting, DNA-binding assays and subcellular localization experiments. RESULTS: Affected family members showed an 86% decreased insulin response to glucose when compared to age-matched healthy control subjects. In vitro the mutation showed a 79% decrease in transcriptional activity as compared to wild type HNF1 alpha in HeLa cells lacking HNF1 alpha. The transcriptional activity was not suppressed when the mutant was co-expressed with wild type HNF1 alpha suggesting that the decreased activity was not mediated by a dominant negative mechanism. The L107I/HNF1alpha protein showed normal nuclear targeting but impaired binding to an HNF1 alpha consensus sequence. CONCLUSION/INTERPRETATION: Our results suggest that the L107I substitution represents a MODY3 mutation which impairs beta-cell function by a loss-of-function mechanism.

Published
2002
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138. FTO, type 2 diabetes, and weight gain throughout adult life: a meta-analysis of 41,504 subjects from the Scandinavian HUNT, MDC, and MPP studies.

Author

Hertel JK, Johansson S, Sonestedt E, Jonsson A, Lie RT, Platou CG, Nilsson PM, Rukh G, Midthjell K, Hveem K, Melander O, Groop L, Lyssenko V, Molven A, Orho-Melander M, Njølstad PR, Hertel, Jens K, Johansson, Stefan, Sonestedt, Emily, and Jonsson, Anna

Abstract

Objective: FTO is the most important polygene identified for obesity. We aimed to investigate whether a variant in FTO affects type 2 diabetes risk entirely through its effect on BMI and how FTO influences BMI across adult life span.Research Design and Methods: Through regression models, we assessed the relationship between the FTO single nucleotide polymorphisms rs9939609, type 2 diabetes, and BMI across life span in subjects from the Norwegian population-based HUNT study using cross-sectional and longitudinal perspectives. For replication and meta-analysis, we used data from the Malmö Diet and Cancer (MDC) and Malmö Preventive Project (MPP) cohorts, comprising a total sample of 41,504 Scandinavians.Results: The meta-analysis revealed a highly significant association for rs9939609 with both type 2 diabetes (OR 1.13; P = 4.5 × 10(-8)) and the risk to develop incident type 2 diabetes (OR 1.16; P = 3.2 × 10(-8)). The associations remained also after correction for BMI and other anthropometric measures. Furthermore, we confirmed the strong effect on BMI (0.28 kg/m(2) per risk allele; P = 2.0 × 10(-26)), with no heterogeneity between different age-groups. We found no differences in change of BMI over time according to rs9939609 risk alleles, neither overall (ΔBMI = 0.0 [-0.05, 0.05]) nor in any individual age stratum, indicating no further weight gain attributable to FTO genotype in adults.Conclusions: We have identified that a variant in FTO alters type 2 diabetes risk partly independent of its observed effect on BMI. The additional weight gain as a result of the FTO risk variant seems to occur before adulthood, and the BMI difference remains stable thereafter. [ABSTRACT FROM AUTHOR]

Published
2011
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139. Plasma copeptin and the risk of diabetes mellitus.

Author

Enhörning S, Wang TJ, Nilsson PM, Almgren P, Hedblad B, Berglund G, Struck J, Morgenthaler NG, Bergmann A, Lindholm E, Groop L, Lyssenko V, Orho-Melander M, Newton-Cheh C, Melander O, Enhörning, Sofia, Wang, Thomas J, Nilsson, Peter M, Almgren, Peter, and Hedblad, Bo

Published
2010
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140. A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans.

Author

Kotronen, A., Johansson, L., Roos, C., Westerbacka, J., Hamsten, A., Bergholm, R., Arkkila, P., Arola, J., Kiviluoto, T., Fisher, R., Ehrenborg, E., Orho-Melander, M., Ridderstråle, M., Groop, L., and Yki-Järvinen, H.

Abstract

It has recently been suggested that the rs738409 G allele in PNPLA3, which encodes adiponutrin, is strongly associated with increased liver fat content in three different ethnic groups. The aims of the present study were as follows: (1) to try to replicate these findings in European individuals with quantitative measures of hepatic fat content; (2) to study whether the polymorphism influences hepatic and adipose tissue insulin sensitivity; and (3) to investigate whether PNPLA3 expression is altered in the human fatty liver. We genotyped 291 Finnish individuals in whom liver fat had been measured using proton magnetic resonance spectroscopy. Hepatic PNPLA3 expression was measured in 32 participants. Hepatic and adipose tissue insulin sensitivities were measured using a euglycaemic–hyperinsulinaemic (insulin infusion 0.3 mU kg−1 min−1) clamp technique combined with infusion of [3-3H]glucose in 109 participants. The rs738409 G allele in PNPLA3 was associated with increased quantitative measures of liver fat content ( p = 0.011) and serum aspartate aminotransferase concentrations ( p = 0.002) independently of age, sex and BMI. Fasting serum insulin and hepatic and adipose tissue insulin sensitivity were related to liver fat content independently of genotype status. PNPLA3 mRNA expression in the liver was positively related to obesity ( r = 0.62, p < 0.0001) and to liver fat content ( r = 0.58, p = 0.025) in participants who were not morbidly obese (BMI < 40 kg/m2). A common variant in PNPLA3 increases the risk of hepatic steatosis in humans. [ABSTRACT FROM AUTHOR]

Published
2009
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142. Genetic prediction of the metabolic syndrome.

Author

Lyssenko, V., Sjögren, M., Almgren, P., Anevski, D., Orho-Melander, M., Isomaa, B., Tuomi, T., Taskinen, M.-R., and Groop, L.

Subjects
METABOLIC syndrome, CARDIOVASCULAR diseases risk factors, TYPE 2 diabetes, HERITABILITY, HUMAN genetic variation, PEROXISOMES, ADRENERGIC receptors, BLOOD plasma
Abstract

Summary: Background: The metabolic syndrome (MetS) is a constellation of factors associated with increased risk of cardiovascular disease (CVD) and type 2 diabetes (T2D). It has been difficult to identify an underlying unifying pathogenic mechanism for the different components. As the syndrome shows high heritability one way to search for such common mechanisms could to be to try to identify genetic variants contributing to MetS. Methods: In total 1937 of 2293 non-diabetic individuals participating in the Botnia prospective study were free of MetS at baseline (M/F: 873/1064; age 44±14 years; BMI 25±4kg/m2; 25% had IFG or IGT or both). Variants in the peroxisome proliferator-activated receptor gamma (PPARG P12A), β1-, β2- and β3-adrenergic receptor (ADRB1 G389R; ADRB2 Q27E; ADRB3 W64R), adiponectin (APM1 SNP −11,377 C>G, 276 G>T, I2019D), and PPARG co-activator-1 alpha (PPARGC1A G482S) genes were studied for their ability to predict MetS defined using the NCEP ATPIII criteria. We also repeated the analyses using the WHO and IDF criteria for defining MetS. Results: During a median 6-year follow-up, 267 (13.8%) persons developed MetS. The PPARG (PP) (HR 1.49 [1.10–3.01], P =0.011) and the ADRB1 G389R (GG/GR) (1.43 [1.14–1.80], P =0.0022) predicted future MetS. ADRB1 G389R and ADRB3 W64R variants showed an interaction effect, implying that the MetS risk was further increased if an individual carried both GG/GR and RR/WR genotypes (2.02 [1.34–3.05], P <0.001). Among the individual MetS components, the PP (PPARG) and GG/GR (ADRB1) genotypes were associated with increase in triglycerides (coefficient 0.016 and 0.0162, P <0.05; respectively). In addition, the GG/GR genotypes (coefficient 0.013, P =0.036) were also associated with increase in fasting glucose concentrations over time. Variants in the ADRB2, APM1 and PPARGC1A genes did not influence risk of future MetS. Conclusion: We demonstrate in a prospective study that variants in the PPARG and ADRB1 genes predict development of MetS and that the risk conferred by the ADRB1 variant is further increased by variants in the ADRB3 gene. [Copyright &y& Elsevier]

Published
2008
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143. The search for putative unifying genetic factors for components of the metabolic syndrome.

Author

Sjögren, M., Lyssenko, V., Jonsson, A., Berglund, G., Nilsson, P., Groop, L., and Orho-Melander, M.

Abstract

The metabolic syndrome is a cluster of factors contributing to increased risk of cardiovascular disease and type 2 diabetes but unifying mechanisms have not been identified. Our aim was to study whether common variations in 17 genes previously associated with type 2 diabetes or components of the metabolic syndrome and variants in nine genes with inconsistent association with at least two components of the metabolic syndrome would also predict future development of components of the metabolic syndrome, individually or in combination. Genetic variants were studied in a large prospective study of 16,143 non-diabetic individuals (mean follow-up time 23 years) from the Malmö Preventive Project. In this study, development of at least three of obesity (BMI ≥ 30 kg/m2), dyslipidaemia (triacylglycerol ≥ 1.7 mmol/l and/or lipid-lowering treatment), hypertension (blood pressure ≥ 140/90 mmHg and/or antihypertensive medication) and hyperglycaemia (fasting plasma glucose ≥ 5.6 mmol/l and/or known diabetes) was defined as development of the metabolic syndrome. The risk of developing at least three components of the metabolic syndrome or the individual components was calculated by logistic regression adjusted for age at baseline, follow-up time and sex. Polymorphisms in TCF7L2 (rs7903146, OR 1.10, 95% CI 1.04–1.17, p = 0.00097), FTO (rs9939609, OR 1.08, 95% CI 1.02–1.14, p = 0.0065), WFS1 (rs10010131, OR 1.07, 95% CI 1.02–1.13, p = 0.0078) and IGF2BP2 (rs4402960, OR 1.07, 95% CI 1.01–1.13, p = 0.021) predicted the development of at least three components of the metabolic syndrome in both univariate and multivariate analysis; in the case of TCF7L2, WFS1 and IGF2BP this was due to their association with hyperglycaemia ( p < 0.00001, p = 0.0033 and p = 0.027, respectively) and for FTO it was due to its association with obesity ( p = 0.004). A polymorphism in the GCKR gene predicted dyslipidaemia (rs1260326, OR 1.15, 95% CI 1.09–1.22, p < 0.00001) but not the metabolic syndrome. None of the studied polymorphisms was associated with more than two components of the metabolic syndrome. A composite genotype score of the 17 polymorphisms associated with type 2 diabetes predicted the development of at least three components of the metabolic syndrome (OR 1.04, p < 0.00001) and the development of hyperglycaemia (OR 1.06, p < 0.00001). Carriers of ≥19 risk alleles had 51 and 72% increased risk of developing at least three components of the metabolic syndrome and hyperglycaemia, respectively, compared with carriers of ≤12 risk alleles ( p < 0.00001 for both). Polymorphisms in susceptibility genes for type 2 diabetes ( TCF7L2, WFS1, IGF2BP2) and obesity ( FTO) predispose to the metabolic syndrome by increasing the risk of one specific component of the metabolic syndrome. The findings argue against a unifying genetic component for the metabolic syndrome. [ABSTRACT FROM AUTHOR]

Published
2008
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144. Parallel manifestation of insulin resistance and beta cell decompensation is compatible with a common defect in Type 2 diabetes Parallel insulin resistance and beta cell decompensation in Type 2 diabetes.

Author

Tripathy, D., Eriksson, K. F., Orho-Melander, M., Fredriksson, J., Ahlqvist, G., and Groop, L.

Subjects
TYPE 2 diabetes, INSULIN resistance, PANCREATIC beta cells, BLOOD sugar, GLUCOSE, GENOTYPE-environment interaction
Abstract

Aims/hypothesis. The aim of the study was to evaluate the relationship between insulin sensitivity, beta cell function and glucose tolerance, and its dependence on variants in the newly identified Type 2 diabetes susceptibility gene, calpain-10 (CAPN10). Methods. We studied 203 men of the same age but with varying degrees of glucose tolerance. These men participated in (i) an oral glucose tolerance test, (ii) a euglycaemic clamp combined with indirect calorimetry and infusion of [3-3H]-glucose and (iii) a stepwise assessment of acute insulin response to arginine (AIR) at three different glucose concentrations (fasting, 14 and 28 mmol/l). Results. There was a linear increase in NEFA levels (p<0.0005) and WHR (p<0.0005) and decrease in glucose uptake due to a reduction in glucose storage over the entire range of glucose tolerance (r=-0.404; p<0.005). No increase in endogenous glucose production (EGP) was seen until patients had manifest diabetes. However, when EGP was expressed relative to fasting insulin concentrations, there was a linear deterioration of basal hepatic insulin sensitivity (r=-0.514; p<0.005). The AIR followed a bell-shaped curve with an initial rise and subsequent decrease. However, AIR adjusted for insulin sensitivity (disposition index) showed a linear decrease with increasing glucose concentrations (r=-0.563; p<0.001) starting already in subjects with normal glucose tolerance. There was an inverse correlation between increase in WHR and NEFA and peripheral as well as hepatic insulin sensitivity. Subjects with the genotype combination of CAPN10 consisting of SNP44 TT and SNP43 GG genotypes had significantly lower insulin-stimulated glucose uptake than carriers of the other genotype combinations (5.3±0.4 vs 7.2±0.4 mg·ffm kg-1·min-1·mU·l-1; p<0.005). Conclusions/interpretation. We conclude that the pre-diabetic state is characterised by a similar linear deterioration of peripheral and hepatic insulin sensitivity as beta cell function and that variants in the CAPN10 gene modify this relationship. These findings are compatible with a common defect in muscle, liver and beta cells in the pathogenesis of Type 2 diabetes. [ABSTRACT FROM AUTHOR]

Published
2004
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145. Characterization of a naturally occurring mutation (L107I) in the HNF1α (MODY3) gene C. Cervin et al.: Characterization of an HNF1α mutation (L107I).

Author

Cervin, C., Orho-Melander, M., Ridderstråle, M., Lehto, M., Barg, S., Groop, L., and Cilio, C.

Subjects
GENETIC mutation, TYPE 2 diabetes, GENE expression, CELL lines, INSULIN, DNA, METABOLISM
Abstract

Aims/hypothesis. Maturity onset diabetes of the young type 3 (MODY3) is a monogenic form of diabetes mellitus caused by mutations in the gene encoding for hepatocyte nuclear factor 1 alpha, HNF1α. In this study we have examined the in vivo and in vitro effects of a mutation (L107I) outside the DNA binding and dimerization domains in the N terminal part of the HNF1α gene. Methods. Beta-cell function of the affected family members was assessed by an oral glucose tolerance test. Functional tests were carried out to explain the role of the mutation in vitro by transcriptional activity assay, Western blotting, DNA-binding assays and subcellular localization experiments. Results. Affected family members showed an 86% decreased insulin response to glucose when compared to age-matched healthy control subjects. In vitro the mutation showed a 79% decrease in transcriptional activity as compared to wild type HNF1α in HeLa cells lacking HNF1α. The transcriptional activity was not suppressed when the mutant was co-expressed with wild type HNF1α suggesting that the decreased activity was not mediated by a dominant negative mechanism. The L107I/HNF1α protein showed normal nuclear targeting but impaired binding to an HNF1α consensus sequence. Conclusion/interpretation. Our results suggest that the L107I substitution represents a MODY3 mutation which impairs beta-cell function by a loss-of-function mechanism. [ABSTRACT FROM AUTHOR]

Published
2002
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146. Polymorphism in the Calpain 10 gene influences glucose metabolism in human fat cells.

Author

Hoffstedt, J., Rydén, M., Löfgren, P., Orho-Melander, M., Groop, L., and Arner, P.

Subjects
TYPE 2 diabetes, CALPAIN, FAT cells, MESSENGER RNA, CYSTEINE proteinases, DIABETES, CONNECTIVE tissue cells, LIPOLYSIS
Abstract

Aims/hypothesis: A common G to A polymorphism (UCSNP-43) in the Calpain 10 gene was recently found to be associated with Type II (non-insulin-dependent) diabetes mellitus and variations in post-absorptive and insulin stimulated glucose metabolism in vivo. We aimed to study the influence of Calpain 10 polymorphism on insulin action in fat cells. Methods:Calpain 10 polymorphism (UCSNP-19, -43 or -63) were set in relation to lipolysis and lipogenesis in isolated subcutaneous adipocytes of 46 apparently healthy non-obese subjects. Results: For UCSNP-43 the G/G genotype had twofold higher basal and insulin stimulated rates as compared with AA/AG genotypes. However, there was no genotype effect on basal or insulin inhibited lipolysis rates in fat cells. The protein amount of GLUT 4 in adipocytes was not influenced by the polymorphism. Fat cells expressed mRNA for the Calpain 10 gene at a relatively high concentration, about 4 amol/μg RNA, which is similar to that of uncoupling protein-2. Neither a UCSNP-19 nor a UCSNP-63 polymorphism in the Calpain 10 gene was found to be associated with basal or insulin-induced adipocyte lipolysis and lipogenesis. None of the polymorphisms influenced body mass index or fasting plasma concentrations of insulin and glucose in 693 non-obese healthy subjects. Conclusions/interpretation: The Calpain 10 gene could be involved in the regulation of glucose metabolism but not lipolysis in human fat cells, although it does not involve adipocyte GLUT-4 protein content. It is possible that the Calpain 10 gene predisposes to diabetes by influencing the glucose metabolism. [Diabetologia (2002) 45: 276–282] [ABSTRACT FROM AUTHOR]

Published
2002
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147. Characterization of the annexin I gene and evaluation of its role in type 2 diabetes.

Author

Lindgren, Cecilia M., Nilsson, Anita, Orho-Melander, Marju, Almgren, Peter, Groop, Leif C., Lindgren, C M, Nilsson, A, Orho-Melander, M, Almgren, P, and Groop, L C

Subjects
ANNEXINS, TYPE 2 diabetes, ALLELES, CALCIUM-binding proteins, COMPARATIVE studies, DNA, DOCUMENTATION, GENES, GENETIC polymorphisms, GENETICS, RESEARCH methodology, MEDICAL cooperation, NUCLEOTIDES, REFERENCE values, RESEARCH, EVALUATION research, SEQUENCE analysis
Abstract

In a previous study, we identified suggestive linkage between type 2 diabetes and a locus on chromosome 9p13-q21. This region contains the gene annexin I (ANXA1), encoding a protein suggested to be involved in both insulin secretion and insulin action. In this study, we sequenced the exon/intron boundaries of the human ANXA1 gene and performed mutation screening in 41 individuals from the initial linkage study. We identified five single nucleotide polymorphisms A58G, A401G, intronic variance sequence (IVS)8-28A/G, IVS11 +31A/G, and IVS12-11T/G, which were further tested for association to diabetes in 197 parent/offspring trios using the transmission disequilibrium test. No significant association with type 2 diabetes was observed, although the common A allele of the +58A/G variant gave a 22:12 transmission distortion (P = 0.12). This variant was further genotyped in 481 case and control subjects, but no difference in allele, genotype, or haplotype frequencies were observed between the groups. Further, a novel polymorphic (CA)(15-25) repeat in intron 11 was genotyped in the subjects included in the initial linkage study. No improvement of the original finding was observed. We therefore concluded that the ANXA1 gene is unlikely to harbor variants that contribute to risk of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Published
2001
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149. Common variants in the β2-(Gln27Glu) and β3-(Trp64Arg) -adrenoceptor genes are associated with elevated serum NEFA concentrations and Type II diabetes.

Author

Carlsson, M., Orho-Melander, M., Hedenbro, J., and Groop, L. C.

Subjects
TYPE 2 diabetes, FATTY acids, ADRENERGIC receptors, INSULIN, LIPOLYSIS, ENZYMES
Abstract

Aims/hypothesis. Higher NEFA concentrations predict Type II (non-insulin-dependent) diabetes mellitus but it is not known whether higher NEFA concentrations are genetically determined or reflect coexisting obesity. To address this question we studied whether common variants in two genes encoding for key regulators of lipolysis, the β2- and β3- adrenoceptors (B2AR and B3AR) are associated with NEFA concentrations and Type II diabetes. Methods. A total of 1054 Swedish subjects with varying degrees of glucose tolerance were genotyped for the Gln27Glu variant in the B2AR and for the Trp64Arg variant in the B3AR genes using PCR-RFLP. Results. The B2AR Gln27 allele was more frequent in 219 Type II diabetic patients than in 237 non-diabetic subjects (59.8 % vs 52.3 %; OR = 1.72, p = 0.02) while there was no significant difference in the frequency of the B3AR Arg64 allele. Subjects homozygous for the protective alleles (Glu27 and Trp64) had, however, a lower prevalence of diabetes than subjects with other genotype combinations (OR = 0.58, p = 0.03). Among sibling pairs discordant for the B2AR Gln27Glu polymorphism, siblings with an excess of the Gln27 allele had higher fasting insulin (n = 217; p = 0.02) and NEFA concentrations (107 sex-matched pairs; p = 0.01) than siblings with an excess of the Glu27 allele. Among sibling pairs discordant for the B3AR Trp64Arg variant, siblings with the Arg64 allele had higher 2 h glucose (n = 48; p = 0.01) and NEFA concentrations (16 pairs matched for sex; p < 0.04) than siblings with the Trp64Trp64 genotype. Conclusions/interpretation. Common variants in the β2- and β3- adrenoceptor genes are associated with increased fasting insulin and NEFA concentrations and could increase susceptibility to Type II diabetes. [Diabetologia (2001) 44: 629–636] [ABSTRACT FROM AUTHOR]

Published
2001
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150. A gene conferring susceptibility to type 2 diabetes in conjunction with obesity is located on chromosome 18p11.

Author

Parker, Alex, Parker, A, Meyer, J, Lewitzky, S, Rennich, J S, Chan, G, Thomas, J D, Orho-Melander, M, Lehtovirta, M, Forsblom, C, Hyrkkö, A, Carlsson, M, Lindgren, C, and Groop, L C

Subjects
CHROMOSOME analysis, TYPE 2 diabetes
Abstract

Genome-wide nonparametric linkage analysis of 480 sib-pairs affected with type 2 diabetes revealed linkage to a previously unreported susceptibility locus on chromosome 18p11. This result improved with stringent subphenotyping using age- and sex-adjusted BMI, ultimately reaching a logarithm of odds of 3.82 (allele sharing 0.6654) at a point between markers D18S976 and D18S391 when the most obese 20% of the sample was analyzed. Several genes on chromosome 18 have been suggested as metabolic disease candidates, but none of these colocalize with our linkage result. We conclude that our results provide support for the presence of a currently uncharacterized gene on chromosome 18p, certain alleles of which confer increased susceptibility to type 2 diabetes in conjunction with obesity. We additionally observed moderate evidence for linkage to chromosome 1, near marker D1S3462; chromosome 4, near marker D4S2361; chromosome 5, near marker D5S1505; and chromosome 17, near marker D17S1301. [ABSTRACT FROM AUTHOR]

Published
2001
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