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1. Large-scale gene-centric analysis identifies novel variants for coronary artery disease

Author

Butterworth, As, Braund, Ps, Farrall, M, Hardwick, Rj, Saleheen, D, Peden, Jf, Soranzo, N, Chambers, Jc, Sivapalaratnam, S, Kleber, Me, Keating, B, Qasim, A, Klopp, N, Erdmann, J, Assimes, Tl, Ball, Sg, Balmforth, Aj, Barnes, Ta, Basart, H, Baumert, J, Bezzina, Cr, Boerwinkle, E, Boehm, Bo, Brocheton, J, Bugert, P, Cambien, F, Clarke, R, Codd, V, Collins, R, Couper, D, Cupples, La, de Jong JS, Diemert, P, Ejebe, K, Elbers, Cc, Elliott, P, Fornage, M, Franzosi, Mg, Frossard, P, Garner, S, Goel, A, Goodall, Ah, Hengstenberg, C, Hunt, Se, Kastelein, Jj, Klungel, Oh, Klüter, H, Koch, K, König, Ir, Kooner, As, Laaksonen, R, Lathrop, M, Li, M, Liu, K, Mcpherson, R, Musameh, Md, Musani, S, Nelson, Cp, O'Donnell, Cj, Ongen, H, Papanicolaou, G, Peters, A, Peters, Bj, Potter, S, Psaty, Bm, Qu, L, Rader, Dj, Rasheed, A, Rice, C, Scott, J, Seedorf, U, Sehmi, Js, Sotoodehnia, N, Stark, K, Stephens, J, van der Schoot CE, van der Schouw YT, Thorsteinsdottir, U, Tomaszewski, M, van der Harst, P, Vasan, Rs, Wilde, Aa, Willenborg, C, Winkelmann, Br, Zaidi, M, Zhang, W, Ziegler, A, de Bakker PI, Koenig, W, Mätz, W, Trip, Md, Reilly, Mp, Kathiresan, S, Schunkert, H, Hamsten, A, Hall, As, Kooner, Js, Thompson, Sg, Thompson, Jr, Deloukas, P, Ouwehand, Wh, Watkins, H, Danesh, J, Samani, Nj, Barnes, T, Rafelt, S, Bruinsma, N, Dekker, Lr, Henriques, Jp, Koch, Kt, de Winter RJ, Alings, M, Allaart, Cf, Gorgels, Ap, Verheugt, Fw, Mueller, M, Meisinger, C, Derohannessian, S, Mehta, Nn, Ferguson, J, Hakonarson, H, Matthai, W, Wilensky, R, Hopewell, Jc, Parish, S, Linksted, P, Notman, J, Gonzalez, H, Young, A, Ostley, T, Munday, A, Goodwin, N, Verdon, V, Shah, S, Cobb, L, Edwards, C, Mathews, C, Gunter, R, Benham, J, Davies, C, Cobb, M, Crowther, J, Richards, A, Silver, M, Tochlin, S, Mozley, S, Clark, S, Radley, M, Kourellias, K, Silveira, A, Söderholm, B, Olsson, P, Barlera, S, Tognoni, G, Rust, S, Assmann, G, Heath, S, Zelenika, D, Gut, I, Green, F, Peden, J, Aly, A, Anner, K, Björklund, K, Blomgren, G, Cederschiöld, B, Danell Toverud, K, Eriksson, P, Grundstedt, U, Heinonen, M, Hellénius, Ml, van't Hooft, F, Husman, K, Lagercrantz, J, Larsson, A, Larsson, M, Mossfeldt, M, Mälarstig, A, Olsson, G, Sabater Lleal, M, Sennblad, B, Strawbridge, R, Öhrvik, J, Zaman, Ks, Mallick, Nh, Azhar, M, Samad, A, Ishaq, M, Shah, N, Samuel, M, Reilly, M, Holm, H, Preuss, M, Stewart, Af, Barbalic, M, Gieger, C, Absher, D, Aherrahrou, Z, Allayee, H, Altshuler, D, Anand, S, Andersen, K, Anderson, Jl, Ardissino, D, Becker, Lc, Becker, Dm, Berger, K, Bis, Jc, Boekholdt, Sm, Brown, Mj, Burnett, Ms, Buysschaert, I, Carlquist, Jf, Chen, L, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, J, Do, R, Doering, A, El Mokhtari NE, Ellis, Sg, Elosua, R, Engert, Jc, Epstein, S, de Faire, U, Fischer, M, Folsom, Ar, Freyer, J, Gigante, B, Girelli, D, Gretarsdottir, S, Gudnason, V, Gulcher, Jr, Tennstedt, S, Halperin, E, Hammond, N, Hazen, Sl, Hofman, A, Horne, Bd, Illig, T, Iribarren, C, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kaplan, Lm, Khaw, Kt, Knowles, Jw, Kolovou, G, Kong, A, Lambrechts, D, Leander, K, Lieb, W, Lettre, G, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meitinger, T, Melander, O, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Musunuru, K, Nahrstaedt, J, Nöthen, Mm, Olivieri, Oliviero, Peyvandi, F, Patel, Rs, Patterson, Cc, Quyyumi, Aa, Rallidis, Ls, Roosendaal, Fr, Rubin, D, Salomaa, V, Sampietro, Ml, Sandhu, Ms, Schadt, E, Schäfer, A, Schillert, A, Schreiber, S, Schrezenmeir, J, Schwartz, Sm, Siscovick, Ds, Sivananthan, M, Smith, Av, Smith, Tb, Snoep, Jd, Spertus, Ja, Stefansson, K, Stirrups, K, Stoll, M, Tang, Wh, Thorgeirsson, G, Thorleifsson, G, Uitterlinden, Ag, van Rij AM, Voight, Bf, Wareham, Nj, Awells, G, Wichmann, He, Witteman, Jc, Wright, Bj, Ye, S, Quertermous, T, März, W, Blankenberg, S, Roberts, R, Onland Moret NC, van Setten, J, Verschuren, Wm, Boer, Jm, Wijmenga, C, Hofker, Mh, Maitland van der Zee AH, de Boer, A, Grobbee, De, Attwood, T, Belz, S, Braund, P, Cooper, J, Crisp Hihn, A, Foad, N, Gracey, J, Gray, E, Gwilliams, R, Heimerl, S, Jolley, J, Krishnan, U, Lloyd Jones, H, Lugauer, I, Lundmark, P, Moore, Js, Muir, D, Murray, E, Neudert, J, Niblett, D, O'Leary, K, Pollard, H, Rankin, A, Rice, Cm, Sager, H, Sambrook, J, Schmitz, G, Scholz, M, Schroeder, L, Syvannen, Ac, Wallace, C., Cardiologie, RS: CAPHRI School for Public Health and Primary Care, Vascular Medicine, Other departments, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Landsteiner Laboratory, Clinical Haematology, Pulmonology, and Medical Research Council (MRC)

Subjects
Male, Cancer Research, Candidate gene, Epidemiology, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Cardiovascular, 0302 clinical medicine, GENETICS & HEREDITY, Genetics (clinical), Genetics, 0303 health sciences, Cardiovascular diseases [NCEBP 14], Middle Aged, 3. Good health, CYP17A1, Genetic Epidemiology, Genome-wide association, Myocardial-infarction, Susceptibility loci, Risk, Atherosclerosis, Metanalysis, Lipoprotein, Medicine, Female, Life Sciences & Biomedicine, Research Article, Asian Continental Ancestry Group, Adult, SUSCEPTIBILITY LOCI, lcsh:QH426-470, European Continental Ancestry Group, Biology, Polymorphism, Single Nucleotide, coronary artery disease, genetics, White People, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Asian People, Genetic variation, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Allele, Molecular Biology, Gene, METAANALYSIS, Ecology, Evolution, Behavior and Systematics, Genetic Association Studies, Cardiovascular Disease Epidemiology, Alleles, 030304 developmental biology, Aged, 0604 Genetics, Science & Technology, Case-control study, Genetic Variation, Human Genetics, Odds ratio, large-scale gene analysis, lcsh:Genetics, LIPOPROTEIN, MYOCARDIAL-INFARCTION, ATHEROSCLEROSIS, Case-Control Studies, Genetics of Disease, IBC 50K CAD Consortium, Developmental Biology, Genome-Wide Association Study
Abstract

Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p, Author Summary Coronary artery disease (CAD) has a strong genetic basis that remains poorly characterised. Using a custom-designed array, we tested the association with CAD of almost 50,000 common and low frequency variants in ∼2,000 genes of known or suspected cardiovascular relevance. We genotyped the array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin) and attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. We report the novel association of variants in or near four genes with CAD and in additional studies identify potential mechanisms by which some of these novel variants affect CAD risk. Interestingly, we found that these variants, as well as the majority of previously reported CAD variants, have similar associations in Europeans and South Asians. Contrary to prior expectations, many previously suggested candidate genes did not show evidence of any effect on CAD risk, and neither did we identify any novel low frequency alleles with strong effects amongst the genes tested. Discovery of novel genes associated with heart disease may help to further understand the aetiology of cardiovascular disease and identify new targets for therapeutic interventions.

Published
2016

2. Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies

Author

Reilly MP, Li M, He J, Ferguson JF, Stylianou IM, Mehta NN, Burnett MS, Devaney JM, Knouff CW, Thompson JR, Horne BD, Stewart AF, Assimes TL, Wild PS, Allayee H, Nitschke PL, Patel RS, Myocardial Infarction Genetics Consortium, Wellcome Trust Case Control Consortium, Martinelli N, Girelli D, Quyyumi AA, Anderson JL, Erdmann J, Hall AS, Schunkert H, Quertermous T, Blankenberg S, Hazen SL, Roberts R, Kathiresan S, Samani NJ, Epstein SE, Rader DJ, Qasim AN, DerOhannessian SL, Qu L, Cappola TP, Chen Z, Matthai W, Hakonarson HH, Wilensky R, Kent KM, Lindsay JM, Pichard AD, Satler L, Waksman R, Knoupf CW, Walker MC, Waterworth DM, Mosser V, Braund PS, Wright B, Balmforth AJ, Ball SG, Chen L, Wells GA, McPherson R, Lackner K, Munzel TF, Schillert A, Schnabel R, Zeller T, Ziegler A, Absher D, Hlatky MA, Iribaren C, Knowles JW, Linsel Nitschke P, König IR, Hengstenberg C, Nahrstaedt J, Peters A, Schreiber S, Wichmann E, Willenborg C, Su S, Bouzyk M, Vaccarino V, Zafari AM, Carlquist JF, Muhlestein JB, Olivieri O, Barnard J, Hartiala J, Tang WH, Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI, Ouwehand WH, Todd JA, Donnelly P, Barrett JC, Davison D, Easton D, Evans DM, Leung HT, Marchini JL, Morris AP, Spencer CC, Tobin MD, Attwood AP, Boorman JP, Cant B, Everson U, Hussey JM, Jolley JD, Knight AS, Koch K, Meech E, Nutland S, Prowse CV, Stevens HE, Taylor NC, Walters GR, Walker NM, Watkins NA, Winzer T, Jones RW, McArdle WL, Ring SM, Strachan DP, Pembrey M, Breen G, St Clair D, Caesar S, Gordon Smith K, Jones L, Fraser C, Green EK, Grozeva D, Hamshere ML, Holmans PA, Jones IR, Kirov G, Moskvina V, Nikolov I, O'Donovan MC, Owen MJ, Collier DA, Elkin A, Farmer A, Williamson R, McGuffin P, Young AH, Ferrier IN, Barrett JH, Bishop DT, Iles MM, Maqbool A, Yuldasheva N, Dixon RJ, Mangino M, Stevens S, Bredin F, Tremelling M, Parkes M, Drummond H, Lees CW, Nimmo ER, Satsangi J, Fisher SA, Forbes A, Lewis CM, Onnie CM, Prescott NJ, Sanderson J, Mathew CG, Barbour J, Mohiuddin MK, Todhunter CE, Mansfield JC, Ahmad T, Cummings FR, Jewell DP, Webster J, Brown MJ, Lathrop M, Connell J, Dominiczak A, Marcano CA, Burke B, Dobson R, Gungadoo J, Lee KL, Munroe PB, Newhouse SJ, Onipinla A, Wallace C, Xue M, Caulfield M, Farrall M, Barton A, Bruce IN, Donovan H, Eyre S, Gilbert PD, Hider SL, Hinks AM, John SL, Potter C, Silman AJ, Symmons DP, Thomson W, Worthington J, Dunger DB, Widmer B, Frayling TM, Freathy RM, Lango H, Perry JR, Shields BM, Weedon MN, Hattersley AT, Hitman GA, Walker M, Elliott KS, Groves CJ, Lindgren CM, Rayner NW, Timpson NJ, Zeggini E, Newport M, Sirugo G, Lyons E, Vannberg F, Hill AV, Bradbury LA, Farrar C, Pointon JJ, Wordsworth P, Brown MA, Franklyn JA, Heward JM, Simmonds MJ, Gough SC, Seal S, Stratton MR, Rahman N, Ban M, Goris A, Sawcer SJ, Compston A, Conway D, Jallow M, Rockett KA, Bumpstead SJ, Chaney A, Downes K, Ghori MJ, Gwilliam R, Hunt SE, Inouye M, Keniry A, King E, McGinnis R, Potter S, Ravindrarajah R, Whittaker P, Widden C, Withers D, Cardin NJ, Ferreira T, Pereira Gale J, Hallgrimsdóttir IB, Bowie BN, Su Z, Teo YY, Vukcevic D, Bentley D, Meigs JB, Williams G, Nathan DM, MacRae CA, O'Donnell CJ, Ardissino D, Merlini PA, Berzuini C, Bernardinelli L, Peyvandi F, Tubaro M, Celli P, Ferrario M, Fetiveau R, Marziliano N, Galli M, Ribichini F, Rossi M, Bernardi F, Zonzin P, Piazza A, Mannucci PM, Schwartz SM, Siscovick DS, Yee J, Friedlander Y, Elosua R, Marrugat J, Lucas G, Subirana I, Sala J, Ramos R, Salomaa V, Havulinna AS, Peltonen L, Melander O, Berglund G, Voight BF, Hirschhorn JN, Asselta R, Duga S, Spreafico M, Musunuru K, Daly MJ, Purcell S, Surti A, Guiducci C, Gianniny L, Mirel D, Parkin M, Burtt N, Gabriel SB, CASARI , GIORGIO NEVIO, Reilly, Mp, Li, M, He, J, Ferguson, Jf, Stylianou, Im, Mehta, Nn, Burnett, M, Devaney, Jm, Knouff, Cw, Thompson, Jr, Horne, Bd, Stewart, Af, Assimes, Tl, Wild, P, Allayee, H, Nitschke, Pl, Patel, R, Myocardial Infarction Genetics, Consortium, Wellcome Trust Case Control, Consortium, Martinelli, N, Girelli, D, Quyyumi, Aa, Anderson, Jl, Erdmann, J, Hall, A, Schunkert, H, Quertermous, T, Blankenberg, S, Hazen, Sl, Roberts, R, Kathiresan, S, Samani, Nj, Epstein, Se, Rader, Dj, Qasim, An, Derohannessian, Sl, Qu, L, Cappola, Tp, Chen, Z, Matthai, W, Hakonarson, Hh, Wilensky, R, Kent, Km, Lindsay, Jm, Pichard, Ad, Satler, L, Waksman, R, Knoupf, Cw, Walker, Mc, Waterworth, Dm, Mosser, V, Braund, P, Wright, B, Balmforth, Aj, Ball, Sg, Chen, L, Wells, Ga, Mcpherson, R, Lackner, K, Munzel, Tf, Schillert, A, Schnabel, R, Zeller, T, Ziegler, A, Absher, D, Hlatky, Ma, Iribaren, C, Knowles, Jw, Linsel Nitschke, P, König, Ir, Hengstenberg, C, Nahrstaedt, J, Peters, A, Schreiber, S, Wichmann, E, Willenborg, C, Su, S, Bouzyk, M, Vaccarino, V, Zafari, Am, Carlquist, Jf, Muhlestein, Jb, Olivieri, O, Barnard, J, Hartiala, J, Tang, Wh, Burton, Pr, Clayton, Dg, Cardon, Lr, Craddock, N, Deloukas, P, Duncanson, A, Kwiatkowski, Dp, Mccarthy, Mi, Ouwehand, Wh, Todd, Ja, Donnelly, P, Barrett, Jc, Davison, D, Easton, D, Evans, Dm, Leung, Ht, Marchini, Jl, Morris, Ap, Spencer, Cc, Tobin, Md, Attwood, Ap, Boorman, Jp, Cant, B, Everson, U, Hussey, Jm, Jolley, Jd, Knight, A, Koch, K, Meech, E, Nutland, S, Prowse, Cv, Stevens, He, Taylor, Nc, Walters, Gr, Walker, Nm, Watkins, Na, Winzer, T, Jones, Rw, Mcardle, Wl, Ring, Sm, Strachan, Dp, Pembrey, M, Breen, G, St Clair, D, Caesar, S, Gordon Smith, K, Jones, L, Fraser, C, Green, Ek, Grozeva, D, Hamshere, Ml, Holmans, Pa, Jones, Ir, Kirov, G, Moskvina, V, Nikolov, I, O'Donovan, Mc, Owen, Mj, Collier, Da, Elkin, A, Farmer, A, Williamson, R, Mcguffin, P, Young, Ah, Ferrier, In, Barrett, Jh, Bishop, Dt, Iles, Mm, Maqbool, A, Yuldasheva, N, Dixon, Rj, Mangino, M, Stevens, S, Bredin, F, Tremelling, M, Parkes, M, Drummond, H, Lees, Cw, Nimmo, Er, Satsangi, J, Fisher, Sa, Forbes, A, Lewis, Cm, Onnie, Cm, Prescott, Nj, Sanderson, J, Mathew, Cg, Barbour, J, Mohiuddin, Mk, Todhunter, Ce, Mansfield, Jc, Ahmad, T, Cummings, Fr, Jewell, Dp, Webster, J, Brown, Mj, Lathrop, M, Connell, J, Dominiczak, A, Marcano, Ca, Burke, B, Dobson, R, Gungadoo, J, Lee, Kl, Munroe, Pb, Newhouse, Sj, Onipinla, A, Wallace, C, Xue, M, Caulfield, M, Farrall, M, Barton, A, Bruce, In, Donovan, H, Eyre, S, Gilbert, Pd, Hider, Sl, Hinks, Am, John, Sl, Potter, C, Silman, Aj, Symmons, Dp, Thomson, W, Worthington, J, Dunger, Db, Widmer, B, Frayling, Tm, Freathy, Rm, Lango, H, Perry, Jr, Shields, Bm, Weedon, Mn, Hattersley, At, Hitman, Ga, Walker, M, Elliott, K, Groves, Cj, Lindgren, Cm, Rayner, Nw, Timpson, Nj, Zeggini, E, Newport, M, Sirugo, G, Lyons, E, Vannberg, F, Hill, Av, Bradbury, La, Farrar, C, Pointon, Jj, Wordsworth, P, Brown, Ma, Franklyn, Ja, Heward, Jm, Simmonds, Mj, Gough, Sc, Seal, S, Stratton, Mr, Rahman, N, Ban, M, Goris, A, Sawcer, Sj, Compston, A, Conway, D, Jallow, M, Rockett, Ka, Bumpstead, Sj, Chaney, A, Downes, K, Ghori, Mj, Gwilliam, R, Hunt, Se, Inouye, M, Keniry, A, King, E, Mcginnis, R, Potter, S, Ravindrarajah, R, Whittaker, P, Widden, C, Withers, D, Cardin, Nj, Ferreira, T, Pereira Gale, J, Hallgrimsdóttir, Ib, Bowie, Bn, Su, Z, Teo, Yy, Vukcevic, D, Bentley, D, Meigs, Jb, Williams, G, Nathan, Dm, Macrae, Ca, O'Donnell, Cj, Ardissino, D, Merlini, Pa, Berzuini, C, Bernardinelli, L, Peyvandi, F, Tubaro, M, Celli, P, Ferrario, M, Fetiveau, R, Marziliano, N, Casari, GIORGIO NEVIO, Galli, M, Ribichini, F, Rossi, M, Bernardi, F, Zonzin, P, Piazza, A, Mannucci, Pm, Schwartz, Sm, Siscovick, D, Yee, J, Friedlander, Y, Elosua, R, Marrugat, J, Lucas, G, Subirana, I, Sala, J, Ramos, R, Salomaa, V, Havulinna, A, Peltonen, L, Melander, O, Berglund, G, Voight, Bf, Hirschhorn, Jn, Asselta, R, Duga, S, Spreafico, M, Musunuru, K, Daly, Mj, Purcell, S, Surti, A, Guiducci, C, Gianniny, L, Mirel, D, Parkin, M, Burtt, N, and Gabriel, Sb

Subjects
Adult, Male, medicine.medical_specialty, Linkage disequilibrium, ABO, ADAMTS7 Protein, ADAMTS7, Genome-wide association study, Coronary Angiography, Polymorphism, Single Nucleotide, Linkage Disequilibrium, ABO Blood-Group System, Coronary artery disease, Gene Frequency, ABO blood group system, Internal medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Myocardial infarction, Genetic risk factor, genetic locus, Coronary atherosclerosis, Aged, business.industry, coronary atherosclerosis, General Medicine, Middle Aged, medicine.disease, ADAM Proteins, myocardial infarction, Genetic Loci, Cardiology, Myocardial infarction complications, Female, business, coronary artery disease, Genome-Wide Association Study
Abstract

BACKGROUND: We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis. METHODS: We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12,393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644). FINDINGS: In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4·98×10(-13)). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7·62×10(-9)). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction. INTERPRETATION: Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD. FUNDING: The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix.

Published
2011

3. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

Strawbridge, Rj, Dupuis, J, Prokopenko, I, Barker, A, Ahlqvist, E, Rybin, D, Petrie, Jr, Travers, Me, Bouatia Naji, N, Dimas, As, Nica, A, Wheeler, E, Chen, H, Voight, Bf, Taneera, J, Kanoni, S, Peden, Jf, Turrini, F, Gustafsson, S, Zabena, C, Almgren, P, Barker, Dj, Barnes, D, Dennison, Em, Eriksson, Jg, Eriksson, P, Eury, E, Folkersen, L, Fox, Cs, Frayling, Tm, Goel, A, Gu, Hf, Horikoshi, M, Isomaa, B, Jackson, Au, Jameson, Ka, Kajantie, E, Kerr Conte, J, Kuulasmaa, T, Kuusisto, J, Loos, Rj, Luan, J, Makrilakis, K, Manning, Ak, Martínez Larrad MT, Narisu, N, Nastase Mannila, M, Ohrvik, J, Osmond, C, Pascoe, L, Payne, F, Sayer, Aa, Sennblad, B, Silveira, A, Stancáková, A, Stirrups, K, Swift, Aj, Syvänen, Ac, Tuomi, T, van 't Hooft FM, Walker, M, Weedon, Mn, Xie, W, Zethelius, B, Diagram, Consortium, Giant, Consortium, Muther, Consortium, Cardiogram, Consortium, C4d, Consortium, Ongen, H, Mälarstig, A, Hopewell, Jc, Saleheen, D, Chambers, J, Parish, S, Danesh, J, Kooner, J, Ostenson, Cg, Lind, L, Cooper, Cc, Serrano Ríos, M, Ferrannini, E, Forsen, Tj, Clarke, R, Franzosi, Mg, Seedorf, U, Watkins, H, Froguel, P, Johnson, P, Deloukas, P, Collins, Fs, Laakso, M, Dermitzakis, Et, Boehnke, M, Mccarthy, Mi, Wareham, Nj, Groop, L, Pattou, F, Gloyn, Al, Dedoussis, Gv, Lyssenko, V, Meigs, Jb, Barroso, I, Watanabe, Rm, Ingelsson, E, Langenberg, C, Hamsten, A, Voight BF, Florez J. C., Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Ys, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Hofmann, Om, Qi, L, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Bengtsson Boström, K, Bravenboer, B, Bumpstead, S, Burtt, P, Charpentier, G, Chines, Ps, Cornelis, M, Couper, Dj, Crawford, G, Doney, As, Elliott, Ks, Elliott, Al, Erdos, Mr, Franklin, Cs, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Nilsson, P, Owen, Kr, Perry, Jr, Petersen, K, Platou, C, Proença, C, Rathmann, W, William Rayner, N, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Thorand, B, Tichet, J, van Dam RM, van Haeften TW, van Herpt, T, van Vliet JV, Bragi Walters, G, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Pankow, Js, Pedersen, O, Wichmann, E, Florez, Jc, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Stefansson, K, Altshuler, D, Speliotes, Ek, Berndt, Si, Monda, Kl, Allen, Hl, Mägi, R, Randall, Jc, Vedantam, S, Winkler, Tw, Workalemahu, T, Heid, Im, Wood, Ar, Weyant, Rj, Estrada, K, Liang, L, Nemesh, J, Park, Jh, Kilpeläinen, To, Yang, J, Esko, T, Feitosa, Mf, Kutalik, Z, Mangino, M, Scherag, A, Smith, Av, Welch, R, Zhao, Jh, Aben, Kk, Absher, Dm, Dixon, Al, Fisher, E, Glazer, Nl, Goddard, Me, Heard Costa NL, Hoesel, V, Hottenga, Jj, Johansson, Å, Johnson, T, Ketkar, S, Lamina, C, Li, S, Moffatt, Mf, Myers, Rh, Peters, Mj, Preuss, M, Ripatti, S, Rivadeneira, F, Sandholt, C, Timpson, Nj, Tyrer, Jp, van Wingerden, S, White, Cc, Wiklund, F, Barlassina, C, Chasman, Di, Cooper, Mn, Jansson, Jo, Lawrence, Rw, Pellikka, N, Shi, J, Thiering, E, Alavere, H, Alibrandi, Mt, Arnold, Am, Aspelund, T, Atwood, Ld, Balmforth, Aj, Ben Shlomo, Y, Bergmann, S, Biebermann, H, Blakemore, Ai, Boes, T, Bornstein, Sr, Brown, Mj, Buchanan, Ta, Busonero, F, Cappuccio, Fp, Cavalcanti Proença, C, Ida Chen YD, Chen, Cm, Coin, L, Connell, J, Day, In, den Heijer, M, Duan, J, Ebrahim, S, Elliott, P, Elosua, R, Eiriksdottir, G, Facheris, Mf, Felix, Sb, Fischer Posovszky, P, Folsom, Ar, Friedrich, N, Freimer, Nb, Fu, M, Gaget, S, Gejman, Pv, Geus, Ej, Gjesing, Ap, Goyette, P, Grässler, J, Greenawalt, Dm, Gudnason, V, Hartikainen, Al, Hall, As, Havulinna, As, Hayward, C, Heath, Ac, Hengstenberg, C, Hicks, Aa, Hinney, A, Homuth, G, Hui, J, Igl, W, Iribarren, C, Jacobs, Kb, Jarick, I, Jewell, E, John, U, Jousilahti, P, Jula, A, Kaakinen, M, Kaplan, Lm, Kathiresan, S, Kettunen, J, Kinnunen, L, Knowles, Jw, Kolcic, I, König, Ir, Koskinen, S, Kovacs, P, Kvaløy, K, Laitinen, J, Lantieri, O, Lanzani, C, Launer, Lj, Lecoeur, C, Terho, L, Lettre, G, Liu, J, Lokki, Ml, Lorentzon, M, Luben, Rn, Ludwig, B, Magic, Manunta, P, Marek, D, Martin, Ng, Mcardle, Wl, Mccarthy, A, Mcknight, B, Melander, O, Meyre, D, Montgomery, Gw, Mulic, R, Ngwa, Js, Nelis, M, Neville, Mj, Nyholt, Dr, O'Donnell, Cj, O'Rahilly, S, Ong, Kk, Oostra, B, Paré, G, Parker, An, Perola, M, Pichler, I, Pietiläinen, Kh, Platou, Cg, Polasek, O, Pouta, A, Rafelt, S, Raitakari, O, Rayner, Nw, Ridderstråle, M, Rief, W, Ruokonen, A, Rzehak, P, Salomaa, V, Sanders, Ar, Sandhu, Ms, Sanna, S, Saramies, J, Savolainen, Mj, Scherag, S, Schipf, S, Schreiber, S, Schunkert, H, Silander, K, Sinisalo, J, Siscovick, Ds, Smit, Jh, Soranzo, N, Sovio, U, Stephens, J, Surakka, I, Tammesoo, Ml, Tardif, Jc, Teder Laving, M, Teslovich, Tm, Thompson, Jr, Thomson, B, Tönjes, A, van Meurs JB, van Ommen GJ, Vatin, V, Viikari, J, Visvikis Siest, S, Vitart, V, Vogel, Ci, Waite, Ll, Wallaschofski, H, Walters, Gb, Widen, E, Wiegand, S, Wild, Sh, Willemsen, G, Witte, Dr, Witteman, Jc, Xu, J, Zhang, Q, Zgaga, L, Ziegler, A, Zitting, P, Beilby, Jp, Farooqi, Is, Hebebrand, J, Huikuri, Hv, James, Al, Kähönen, M, Levinson, Df, Macciardi, F, Nieminen, Ms, Ohlsson, C, Palmer, Lj, Ridker, Pm, Stumvoll, M, Beckmann, Js, Boeing, H, Dorret, I. B., Caulfield, Mj, Chanock, Sj, Cupples, La, Smith, Gd, Erdmann, J, Grönberg, H, Hall, P, Harris, Tb, Hayes, Rb, Heinrich, J, Jarvelin, Mr, Kaprio, J, Karpe, F, Khaw, Kt, Kiemeney, La, Krude, H, Lawlor, Da, Metspalu, A, Munroe, Pb, Ouwehand, Wh, Penninx, Bw, Peters, A, Quertermous, T, Reinehr, T, Rissanen, A, Samani, Nj, Schwarz, Pe, Shuldiner, Ar, Spector, Td, Uda, M, Valle, Tt, Wabitsch, M, Waeber, G, Shaun, P, Eric, E. S., Peter, M. V., Assimes, Tl, Borecki, Ib, Groop, Lc, Haritunians, T, Kaplan, Rc, O'Connell, Jr, Peltonen, L, Schlessinger, D, Strachan, Dp, van Duijn CM, Barroso, H, North, Ke, Hirschhorn, Jn, Nica, Ac, Parts, L, Glass, D, Nisbet, J, Barrett, A, Sekowska, M, Travers, M, Potter, S, Grundberg, E, Small, K, Hedman, Åk, Bataille, V, Bell, Jt, Surdulescu, G, Ingle, C, Nestle, Fo, di Meglio, P, Min, Jl, Wilk, A, Hammond, Cj, Yang, Tp, Montgomery, Sb, Zondervan, Kt, Durbin, R, Ahmadi, K, Reilly, Mp, Holm, H, Stewart, Af, Barbalic, M, Absher, D, Aherrahrou, Z, Allayee, H, Anand, Ss, Andersen, K, Anderson, Jl, Ardissino, D, Ball, Sg, Barnes, Ta, Becker, Dm, Becker, Lc, Berger, K, Bis, Jc, Boekholdt, Sm, Braund, Ps, Burnett, Ms, Buysschaert, I, Cardiogenics, Carlquist, Jf, Chen, L, Cichon, S, Codd, V, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, Jm, Diemert, P, Do, R, Doering, A, Eifert, S, El Mokhtari NE, Ellis, Sg, Engert, Jc, Epstein, Se, de Faire, U, Fischer, M, Freyer, J, Gigante, B, Girelli, Domenico, Gretarsdottir, S, Gulcher, Jr, Halperin, E, Hammond, N, Hazen, Sl, Horne, Bd, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kastelein, Jj, Kolovou, G, Laaksonen, R, Lambrechts, D, Leander, K, Lieb, W, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meisinger, C, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Münzel, T, Musunuru, K, Nahrstaedt, J, Nelson, Cp, Nöthen, Mm, Olivieri, Oliviero, Patel, Rs, Patterson, Cc, Peyvandi, F, Qu, L, Quyyumi, Aa, Rader, Dj, Rallidis, Ls, Rice, C, Rosendaal, Fr, Rubin, D, Sampietro, Ml, Schadt, E, Schäfer, A, Schillert, A, Schrezenmeir, J, Schwartz, Sm, Sivananthan, M, Sivapalaratnam, S, Smith, A, Smith, Tb, Snoep, Jd, Spertus, Ja, Stark, K, Stoll, M, Tang, Wh, Tennstedt, S, Thorgeirsson, G, Tomaszewski, M, Uitterlinden, Ag, van Rij AM, Wells, Ga, Wichmann, He, Wild, Ps, Willenborg, C, Wright, Bj, Ye, S, Zeller, T, Cambien, F, Goodall, Ah, März, W, Blankenberg, S, Roberts, R, Mcpherson, R, Nilesh, J. S., Medical Research Council (MRC), Nica, Alexandra, Ongen, Halit, Dermitzakis, Emmanouil, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Vascular Medicine, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Scherag, Andre (Beitragende*r), Hinney, Anke (Beitragende*r), Scherag, S. (Beitragende*r), Vogel, C (Beitragende*r), Hebebrand, Johannes (Beitragende*r), University of Groningen, Wheeler, Eleanor [0000-0002-8616-6444], Barnes, Daniel [0000-0002-3781-7570], Luan, Jian'an [0000-0003-3137-6337], Johnson, Kathleen [0000-0002-6823-3252], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository

Subjects
Male, Netherlands Twin Register (NTR), endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Medizin, Genome-wide association study, Type 2 diabetes, CORONARY HEART-DISEASE, Fasting/blood, 0302 clinical medicine, Insulin, Glucose homeostasis, ddc:576.5, Genome-wide, Diabetes Mellitus, Type 2/blood/genetics/metabolism, CARDIoGRAM Consortium, POPULATION, Proinsulin, RISK, Genetics, 0303 health sciences, INSULIN SENSITIVITY, 11 Medical And Health Sciences, Fasting, Polymorphism, Single Nucleotide/genetics, OBESITY, Female, type 2 diabetes, Life Sciences & Biomedicine, hormones, hormone substitutes, and hormone antagonists, Insulin processing, Adult, medicine.medical_specialty, endocrine system, ENDOCRINOLOGY & METABOLISM, SUSCEPTIBILITY LOCI, Genotype, 030209 endocrinology & metabolism, DIAGRAM Consortium, Biology, C4D Consortium, Polymorphism, Single Nucleotide, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Insulin resistance, BETA-CELL FUNCTION, SDG 3 - Good Health and Well-being, Internal medicine, GIANT Consortium, Internal Medicine, medicine, Humans, METAANALYSIS, 030304 developmental biology, Science & Technology, Genome, Human, Hormonal regulation [IGMD 6], Genetic Variation, nutritional and metabolic diseases, proinsulin, medicine.disease, Proinsulin/blood, TCF7L2, Endocrinology, Diabetes Mellitus, Type 2, MuTHER Consortium, GLUCOSE-HOMEOSTASIS, Insulin/blood
Abstract

OBJECTIVE Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Published
2011
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4. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease

Author

Schunkert, H. König, I.R. Kathiresan, S. Reilly, M.P. Assimes, T.L. Holm, H. Preuss, M. Stewart, A.F.R. Barbalic, M. Gieger, C. Absher, D. Aherrahrou, Z. Allayee, H. Altshuler, D. Anand, S.S. Andersen, K. Anderson, J.L. Ardissino, D. Ball, S.G. Balmforth, A.J. Barnes, T.A. Becker, D.M. Becker, L.C. Berger, K. Bis, J.C. Boekholdt, S.M. Boerwinkle, E. Braund, P.S. Brown, M.J. Burnett, M.S. Buysschaert, I. Carlquist, J.F. Chen, L. Cichon, S. Codd, V. Davies, R.W. Dedoussis, G. Dehghan, A. Demissie, S. Devaney, J.M. Diemert, P. Do, R. Doering, A. Eifert, S. Mokhtari, N.E.E. Ellis, S.G. Elosua, R. Engert, J.C. Epstein, S.E. De Faire, U. Fischer, M. Folsom, A.R. Freyer, J. Gigante, B. Girelli, D. Gretarsdottir, S. Gudnason, V. Gulcher, J.R. Halperin, E. Hammond, N. Hazen, S.L. Hofman, A. Horne, B.D. Illig, T. Iribarren, C. Jones, G.T. Jukema, J.W. Kaiser, M.A. Kaplan, L.M. Kastelein, J.J.P. Khaw, K.-T. Knowles, J.W. Kolovou, G. Kong, A. Laaksonen, R. Lambrechts, D. Leander, K. Lettre, G. Li, M. Lieb, W. Loley, C. Lotery, A.J. Mannucci, P.M. Maouche, S. Martinelli, N. McKeown, P.P. Meisinger, C. Meitinger, T. Melander, O. Merlini, P.A. Mooser, V. Morgan, T. Mühleisen, T.W. Muhlestein, J.B. Münzel, T. Musunuru, K. Nahrstaedt, J. Nelson, C.P. Nöthen, M.M. Olivieri, O. Patel, R.S. Patterson, C.C. Peters, A. Peyvandi, F. Qu, L. Quyyumi, A.A. Rader, D.J. Rallidis, L.S. Rice, C. Rosendaal, F.R. Rubin, D. Salomaa, V. Sampietro, M.L. Sandhu, M.S. Schadt, E. Scḧsignfer, A. Schillert, A. Schreiber, S. Schrezenmeir, J. Schwartz, S.M. Siscovick, D.S. Sivananthan, M. Sivapalaratnam, S. Smith, A. Smith, T.B. Snoep, J.D. Soranzo, N. Spertus, J.A. Stark, K. Stirrups, K. Stoll, M. Tang, W.H.W. Tennstedt, S. Thorgeirsson, G. Thorleifsson, G. Tomaszewski, M. Uitterlinden, A.G. Van Rij, A.M. Voight, B.F. Wareham, N.J. Wells, G.A. Wichmann, H.-E. Wild, P.S. Willenborg, C. Witteman, J.C.M. Wright, B.J. Ye, S. Zeller, T. Ziegler, A. Cambien, F. Goodall, A.H. Cupples, L.A. Quertermous, T. Mäsignrz, W. Hengstenberg, C. Blankenberg, S. Ouwehand, W.H. Hall, A.S. Deloukas, P. Thompson, J.R. Stefansson, K. Roberts, R. Thorsteinsdottir, U. O'Donnell, C.J. McPherson, R. Erdmann, J. Samani, N.J.

Subjects
cardiovascular diseases
Abstract

We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 - 10'8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits. © 2011 Nature America, Inc. All rights reserved.

Published
2011

5. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

Strawbridge, R.J. Dupuis, J. Prokopenko, I. Barker, A. Ahlqvist, E. Rybin, D. Petrie, J.R. Travers, M.E. Bouatia-Naji, N. Dimas, A.S. Nica, A.C. Wheeler, E. Chen, H. Voight, B.F. Taneera, J. Kanoni, S. Peden, J.F. Turrini, F. Gustafsson, S. Zabena, C. Almgren, P. Barker, D.J.P. Barnes, D. Dennison, E.M. Eriksson, J.G. Eriksson, P. Eury, E. Folkersen, L. Fox, C.S. Frayling, T.M. Goel, A. Gu, H.F. Horikoshi, M. Isomaa, B. Jackson, A.U. Jameson, K.A. Kajantie, E. Kerr-Conte, J. Kuulasmaa, T. Kuusisto, J. Loos, R.J.F. Luan, J. Makrilakis, K. Manning, A.K. Martínez-Larrad, M.T. Narisu, N. Mannila, M.N. Öhrvik, J. Osmond, C. Pascoe, L. Payne, F. Sayer, A.A. Sennblad, B. Silveira, A. Stančcáková, A. Stirrups, K. Swift, A.J. Syvänen, A.-C. Tuomi, T. Van't Hooft, F.M. Walker, M. Weedon, M.N. Xie, W. Zethelius, B. Scott, L.J. Steinthorsdottir, V. Morris, A.P. 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. Qi, L. Segre, A.V. Van Hoek, M. Navarro, P. Ardlie, K. Balkau, B. Benediktsson, R. Bennett, A.J. Blagieva, R. Boerwinkle, E. Bonnycastle, L.L. Bostrom, K.B. Bravenboer, B. Bumpstead, S. Burtt, N.P. Charpentier, G. Chines, P.S. Cornelis, M. Couper, D.J. Crawford, G. Doney, A.S.F. Elliott, K.S. Elliott, A.L. Erdos, M.R. Franklin, C.S. Ganser, M. Gieger, C. Grarup, N. Green, T. Griffin, S. Groves, C.J. Guiducci, C. Hadjadj, S. Hassanali, N. Herder, C. Johnson, P.R.V. Jorgensen, T. Kao, W.H.L. Klopp, N. Kong, A. Kraft, P. Lauritzen, T. Li, M. Lieverse, A. Lindgren, C.M. Lyssenko, V. Marre, M. Meitinger, T. Midthjell, K. Morken, M.A. Nilsson, P. Owen, K.R. Perry, J.R.B. Petersen, A.-K. Platou, C. Proenca, C. Rathmann, W. Rayner, N.W. Robertson, N.R. Rocheleau, G. Roden, M. Sampson, M.J. Saxena, R. Shields, B.M. Shrader, P. Sigurdsson, G. Sparso, T. Strassburger, K. Stringham, H.M. Sun, Q. Thorand, B. Tichet, J. Van Dam, R.M. Van Haeften, T.W. Van Herpt, T. Van Vliet-Ostaptchouk, J.V. Walters, G.B. Wijmenga, C. Witteman, J.C.M. 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. Mohlke, K.L. Morris, A.D. Palmer, C.N.A. Pramstaller, P.P. Rudan, I. Sijbrands, E. Stein, L.D. Tuomilehto, J. Uitterlinden, A.G. Wareham, N.J. Watanabe, R.M. Abecasis, G.R. Boehm, B.O. Campbell, H. Daly, M.J. Hattersley, A.T. Hu, F.B. Meigs, J.B. Pankow, J.S. Pedersen, O. Wichmann, H.-E. 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. Speliotes, E.K. Berndt, S.I. Monda, K.L. Allen, H.L. Magi, R. Randall, J.C. Vedantam, S. Winkler, T.W. Workalemahu, T. Heid, I.M. Wood, A.R. Weyant, R.J. Estrada, K. Liang, L. Nemesh, J. Park, J.-H. Kilpelainen, T.O. Yang, J. Esko, T. Feitosa, M.F. Kutalik, Z. Mangino, M. Scherag, A. Smith, A.V. Zhao, J.H. Aben, K.K. Absher, D.M. Dixon, A.L. Fisher, E. Glazer, N.L. Goddard, M.E. Heard-Costa, N.L. Hoesel, V. Hottenga, J.-J. Johansson, A. Johnson, T. Ketkar, S. Lamina, C. Li, S. Moffatt, M.F. Myers, R.H. Peters, M.J. Preuss, M. Ripatti, S. Rivadeneira, F. Sandholt, C. Timpson, N.J. Tyrer, J.P. Van Wingerden, S. White, C.C. Wiklund, F. Barlassina, C. Chasman, D.I. Cooper, M.N. Jansson, J.-O. Lawrence, R.W. Pellikka, N. Shi, J. Thiering, E. Alavere, H. Alibrandi, M.T.S. Arnold, A.M. Aspelund, T. Atwood, L.D. Balmforth, A.J. Ben-Shlomo, Y. Bergmann, S. Biebermann, H. Blakemore, A.I.F. Boes, T. Bornstein, S.R. Brown, M.J. Buchanan, T.A. Busonero, F. Cappuccio, F.P. Cavalcanti-Proenca, C. Chen, Y.-D.I. Chen, C.-M. Clarke, R. Coin, L. Connell, J. Day, I.N.M. Den Heijer, M. Duan, J. Ebrahim, S. Elliott, P. Elosua, R. Eiriksdottir, G. Facheris, M.F. Felix, S.B. Fischer-Posovszky, P. Folsom, A.R. Friedrich, N. Freimer, N.B. Fu, M. Gaget, S. Gejman, P.V. Geus, E.J.C. Gjesing, A.P. Goyette, P. Grasler, J. Greenawalt, D.M. Gudnason, V. Hartikainen, A.-L. Hall, A.S. Havulinna, A.S. Hayward, C. Heath, A.C. Hengstenberg, C. Hicks, A.A. Hinney, A. Homuth, G. Hui, J. Igl, W. Iribarren, C. Jacobs, K.B. Jarick, I. Jewell, E. John, U. Jousilahti, P. Jula, A. Kaakinen, M. Kaplan, L.M. Kathiresan, S. Kettunen, J. Kinnunen, L. Knowles, J.W. Kolcic, I. König, I.R. Koskinen, S. Kovacs, P. Kvaloy, K. Laitinen, J. Lantieri, O. Lanzani, C. Launer, L.J. Lecoeur, C. Lehtimaki, T. Lettre, G. Liu, J. Lokki, M.-L. Lorentzon, M. Luben, R.N. Ludwig, B. Manunta, P. Marek, D. Martin, N.G. McArdle, W.L. McCarthy, A. McKnight, B. Melander, O. Meyre, D. Montgomery, G.W. Mulic, R. Ngwa, J.S. Nelis, M. Neville, M.J. Nyholt, D.R. O'Donnell, C.J. O'Rahilly, S. Ong, K.K. Oostra, B. Pare, G. Parker, A.N. Perola, M. Pichler, I. Pietilainen, K.H. Platou, C.G.P. Polasek, O. Pouta, A. Rafelt, S. Raitakari, O. Rayner, N.W. Ridderstrale, M. Rief, W. Ruokonen, A. Rzehak, P. Salomaa, V. Sanders, A.R. Sandhu, M.S. Sanna, S. Saramies, J. Savolainen, M.J. Scherag, S. Schipf, S. Schreiber, S. Schunkert, H. Silander, K. Sinisalo, J. Siscovick, D.S. Smit, J.H. Soranzo, N. Sovio, U. Stephens, J. Surakka, I. Tammesoo, M.-L. Tardif, J.-C. Teder-Laving, M. Teslovich, T.M. Thompson, J.R. Thomson, B. Tonjes, A. Van Meurs, J.B.J. Van Ommen, G.-J. Vatin, V. Viikari, J. Visvikis-Siest, S. Vitart, V. Vogel, C.I.G. Waite, L.L. Wallaschofski, H. Widen, E. Wiegand, S. Wild, S.H. Willemsen, G. Witte, D.R. Xu, J. Zhang, Q. Zgaga, L. Ziegler, A. Zitting, P. Beilby, J.P. Farooqi, I.S. Hebebrand, J. Huikuri, H.V. James, A.L. Kahonen, M. Levinson, D.F. Macciardi, F. Nieminen, M.S. Ohlsson, C. Palmer, L.J. Ridker, P.M. Stumvoll, M. Beckmann, J.S. Boeing, H. Boomsma, D.I. Caulfield, M.J. Chanock, S.J. Cupples, L.A. Smith, G.D. Erdmann, J. Gronberg, H. Hall, P. Harris, T.B. Hayes, R.B. Heinrich, J. Jarvelin, M.-R. Kaprio, J. Karpe, F. Khaw, K.-T. Kiemeney, L.A. Krude, H. Lawlor, D.A. Metspalu, A. Munroe, P.B. Ouwehand, W.H. Penninx, B.W. Peters, A. Quertermous, T. Reinehr, T. Rissanen, A. Samani, N.J. Schwarz, P.E.H. Shuldiner, A.R. Spector, T.D. Uda, M. Valle, T.T. Wabitsch, M. Waeber, G. Watkins, H. Wright, A.F. Zillikens, M.C. Chatterjee, N. Purcell, S. Schadt, E.E. Visscher, P.M. Assimes, T.L. Borecki, I.B. Deloukas, P. Haritunians, T. Kaplan, R.C. O'Connell, J.R. Peltonen, L. Schlessinger, D. Strachan, D.P. North, K.E. Hirschhorn, J.N. Ingelsson, E. Parts, L. Glass, D. Nisbet, J. Barrett, A. Sekowska, M. Potter, S. Grundberg, E. Small, K. Hedman, A.K. Bataille, V. Bell, J.T. Surdulescu, G. Ingle, C. Nestle, F.O. Di Meglio, P. Min, J.L. Wilk, A. Hammond, C.J. Yang, T.-P. Montgomery, S.B. Zondervan, K.T. Durbin, R. Ahmadi, K. Dermitzakis, E.T. Reilly, M.P. Holm, H. Stewart, A.F.R. Barbalic, M. Aherrahrou, Z. Allayee, H. Anand, S.S. Andersen, K. Anderson, J.L. Ardissino, D. Ball, S.G. Barnes, T.A. Becker, D.M. Becker, L.C. Berger, K. Bis, J.C. Boekholdt, S.M. Braund, P.S. Burnett, M.S. Buysschaert, I. Carlquist, J.F. Chen, L. Codd, V. Davies, R.W. Cichon, S. Dedoussis, G.V. Demissie, S. Dehghan, A. Devaney, J.M. Diemert, P. Do, R. Doering, A. Eifert, S. El Mokhtari, N.E. Ellis, S.G. Engert, J.C. Epstein, S.E. De Faire, U. Fischer, M. Freyer, J. Gigante, B. Girelli, D. Gretarsdottir, S. Gulcher, J.R. Halperin, E. Hammond, N. Hazen, S.L. Horne, B.D. Jones, G.T. Jukema, J.W. Kaiser, M.A. Kastelein, J.J.P. Kolovou, G. Laaksonen, R. Lambrechts, D. Leander, K. Li, M. Lieb, W. Loley, C. Lotery, A.J. Mannucci, P.M. Maouche, S. Martinelli, N. McKeown, P.P. Meisinger, C. Merlini, P.A. Mooser, V. Morgan, T. Mühleisen, T.W. Muhlestein, J.B. Münzel, T. Musunuru, K. Nahrstaedt, J. Nelson, C.P. Nöthen, M.M. Olivieri, O. Patel, R.S. Patterson, C.C. Peyvandi, F. Qu, L. Quyyumi, A.A. Rader, D.J. Rallidis, L.S. Rice, C. Rosendaal, F.R. Rubin, D. Sampietro, M.L. Sandhu, M.S. Schadt, E. Schäfer, A. Schillert, A. Schrezenmeir, J. Schwartz, S.M. Sivananthan, M. Sivapalaratnam, S. Smith, T.B. Snoep, J.D. Spertus, J.A. Stark, K. Stoll, M. Wilson Tang, W.H. Tennstedt, S. Thorgeirsson, G. Tomaszewski, M. Van Rij, A.M. Wells, G.A. Wild, P.S. Willenborg, C. Wright, B.J. Ye, S. Zeller, T. Cambien, F. Goodall, A.H. Marz, W. Blankenberg, S. Roberts, R. McPherson, R. Hopewell, J.C. Parish, S. Offer, A. Bowman, L. Sleight, P. Armitage, J. Peto, R. Collins, R. Chambers, J.C. Ahmed, N. Donnelly, P. Kooner, A.S. Scott, J. Sehmi, J. Zhang, W. Kooner, J. Sabater-Lleal, M. Mälarstig, A. Hellénius, M.-L. Olsson, G. Rust, S. Assmann, G. Seedorf, U. Barlera, S. Tognoni, G. Franzosi, M.G. Linksted, P. Ongen, H. Kyriakou, T. Green, F. Farrall, M. Saleheen, D. Rasheed, A. Zaidi, M. Shah, N. Samuel, M. Mallick, N. Azhar, M. Zaman, K. Samad, A. Ishaq, M. Gardezi, A. Memon, F.-U.-R. Frossard, P. Danesh, J. Östenson, C.-G. Lind, L. Cooper, C.C. Serrano-Ríos, M. Ferrannini, E. Forsen, T.J. Pattou, F. Langenberg, C. Hamsten, A. Florez, J.C.

Subjects
endocrine system, endocrine system diseases, nutritional and metabolic diseases
Abstract

OBJECTIVE - Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired b-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS - We have conducted a meta-analysis of genome-wide association tests of ;2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS - Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10-8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/ C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 3 10-4), improved b-cell function (P = 1.1 × 10-5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10-6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS - We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. © 2011 by the American Diabetes Association.

Published
2011

6. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease

Author

Schunkert, H, König, Ir, Kathiresan, S, Reilly, Mp, Assimes, Tl, Holm, H, Preuss, M, Stewart, Af, Barbalic, M, Gieger, C, Absher, D, Aherrahrou, Z, Allayee, H, Altshuler, D, Anand, Ss, Andersen, K, Anderson, Jl, Ardissino, D, Ball, Sg, Balmforth, Aj, Barnes, Ta, Becker, Dm, Becker, Lc, Berger, K, Bis, Jc, Boekholdt, Sm, Boerwinkle, E, Braund, Ps, Brown, Mj, Burnett, Ms, Buysschaert, I, Cardiogenics, Carlquist, Jf, Chen, L, Cichon, S, Codd, V, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, Jm, Diemert, P, Do, R, Doering, A, Eifert, S, Mokhtari, Ne, Ellis, Sg, Elosua, R, Engert, Jc, Epstein, Se, de Faire, U, Fischer, M, Folsom, Ar, Freyer, J, Gigante, B, Girelli, Domenico, Gretarsdottir, S, Gudnason, V, Gulcher, Jr, Halperin, E, Hammond, N, Hazen, Sl, Hofman, A, Horne, Bd, Illig, T, Iribarren, C, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kaplan, Lm, Kastelein, Jj, Khaw, Kt, Knowles, Jw, Kolovou, G, Kong, A, Laaksonen, R, Lambrechts, D, Leander, K, Lettre, G, Li, M, Lieb, W, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meisinger, C, Meitinger, T, Melander, O, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Münzel, T, Musunuru, K, Nahrstaedt, J, Nelson, Cp, Nöthen, Mm, Olivieri, Oliviero, Patel, Rs, Patterson, Cc, Peters, A, Peyvandi, F, Qu, L, Quyyumi, Aa, Rader, Dj, Rallidis, Ls, Rice, C, Rosendaal, Fr, Rubin, D, Salomaa, V, Sampietro, Ml, Sandhu, Ms, Schadt, E, Schäfer, A, Schillert, A, Schreiber, S, Schrezenmeir, J, Schwartz, Sm, Siscovick, Ds, Sivananthan, M, Sivapalaratnam, S, Smith, A, Smith, Tb, Snoep, Jd, Soranzo, N, Spertus, Ja, Stark, K, Stirrups, K, Stoll, M, Tang, Wh, Tennstedt, S, Thorgeirsson, G, Thorleifsson, G, Tomaszewski, M, Uitterlinden, Ag, van Rij AM, Voight, Bf, Wareham, Nj, Wells, Ga, Wichmann, He, Wild, Ps, Willenborg, C, Witteman, Jc, Wright, Bj, Ye, S, Zeller, T, Ziegler, A, Cambien, F, Goodall, Ah, Cupples, La, Quertermous, T, März, W, Hengstenberg, C, Blankenberg, S, Ouwehand, Wh, Hall, As, Deloukas, P, Thompson, Jr, Stefansson, K, Roberts, R, Thorsteinsdottir, U, O'Donnell, Cj, Mcpherson, R, Erdmann, J, the CARDIoGRAM Consortium, Samani, N. J., Epidemiology, Internal Medicine, ACS - Amsterdam Cardiovascular Sciences, Cardiology, and Vascular Medicine

Subjects
Adult, Male, Multifunction cardiogram, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Coronary Artery Disease, Biology, Polymorphism, Single Nucleotide, Genetic determinism, artery disease, Article, Coronary artery disease, Gene Frequency, SDG 3 - Good Health and Well-being, Risk Factors, Genetics, medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Allele, Genotyping, Allele frequency, coronary, Alleles, Genetics (clinical), Aged, Genetic association, business.industry, Case-control study, Middle Aged, medicine.disease, coronary artery disease, Large-scale association analysis, Case-Control Studies, Female, Cardiology and Cardiovascular Medicine, business, Genome-Wide Association Study
Abstract

1. The CARDIoGRAM Consortium. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nature Genetics. 2011;43:333–338. ### Study Hypothesis Recently, genome-wide association studies (GWAS) have identified several common variants that are associated with risk of coronary artery disease (CAD) and myocardial infarction (MI). The authors state that the current loci discovered in CAD and MI GWAS explain only a small fraction of the heritability of this complex disease. The authors hypothesized that a larger study would provide more power to discover common variants with modest effect sizes. Therefore, they formed the Coronary ARtery DIsease Genome-wide Replication And Meta-analysis (CARDIoGRAM) consortium, which consisted of data from 14 GWAS of CAD and MI.1 ### How Was the Hypothesis Tested? The authors performed a meta-analysis of 14 GWAS of CAD comprising 22 233 cases and 64 762 control subjects, all of European ancestry. CAD was defined angiographically in a subset (n=7364) and by history in the entire sample. Presence of MI ranged from 48.1% to 100% of each cohort. After the meta-analysis, they genotyped the lead single-nucleotide polymorphisms (SNPs) within the most promising (defined a priori as P 90% power to detect effect sizes observed in the GWAS meta-analysis. Finally, to understand potential mechanisms and intermediate pathways by which novel loci may mediate risk, the authors interrogated 3 genome-wide studies that also assessed gene expression in multiple tissues, using human cell lines, a genome-wide map of allelic expression imbalance, and other human disease traits. ### Principal Findings The analysis of approximately 135 000 individuals more than doubled the number of loci with CAD association, yielding 13 previously unidentified loci and confirming at …

Published
2011

7. Large-scale gene-centric analysis identifies novel variants for coronary artery disease

Author

Butterworth, A.S., Braund, P.S., Hardwick, R.J., Saleheen, D., Peden, J.F., Soranzo, N., Chambers, J.C., Kleber, M.E., Keating, B., Qasim, A., Klopp, N., Erdmann, J., Basart, H., Baumert, J.H., Bezzina, C.R., Boehm, B.O., Brocheton, J., Bugert, P., Cambien, F., Collins, R., Couper, D., Jong, J.S. de, Diemert, P., Ejebe, K., Elbers, C.C., Elliott, P., Fornage, M., Frossard, P., Garner, S., Hunt, S.E., Kastelein, J.J., Klungel, O.H., Kluter, H., Koch, K., Konig, I.R., Kooner, A.S., Liu, K., McPherson, R., Musameh, M.D., Musani, S., Papanicolaou, G., Peters, A., Peters, B.J., Potter, S., Psaty, B.M., Rasheed, A., Scott, J., Seedorf, U., Sehmi, J.S., Sotoodehnia, N., Stark, K., Stephens, J., Schoot, C.E. van der, Schouw, Y.T. van der, Harst, P. van der, Vasan, R.S., Wilde, A.A., Willenborg, C., Winkelmann, B.R., Zaidi, M., Zhang, W., Ziegler, A., Koenig, W., Matz, W., Trip, M.D., Reilly, M.P., Kathiresan, S., Schunkert, H., Hamsten, A., Hall, A.S., Kooner, J.S., Thompson, S.G., Thompson, J.R., Watkins, H., Danesh, J., Barnes, T., Rafelt, S., Codd, V., Bruinsma, N., Dekker, L.R., Henriques, J.P., Koch, K.T., Winter, R.J. de, Alings, M., Allaart, C.F., Gorgels, A.P., Verheugt, F.W.A., Mueller, M., Meisinger, C., DerOhannessian, S., Mehta, N.N., Ferguson, J., Hakonarson, H., Matthai, W., Wilensky, R., Hopewell, J.C., Parish, S., Linksted, P., Notman, J., Gonzalez, H., Young, A., Ostley, T., Munday, A., Goodwin, N., Verdon, V., Shah, S., Edwards, C., Mathews, C., Gunter, R., Benham, J., Davies, C., Cobb, M., Cobb, L., Crowther, J., Richards, A., Silver, M., Tochlin, S., Mozley, S., Clark, S., Radley, M., Kourellias, K., Olsson, P., Barlera, S., Tognoni, G., Rust, S., Assmann, G., Heath, S., Zelenika, D., Gut, I., Green, F., Farrall, M., Goel, A., Ongen, H., Franzosi, M.G., Lathrop, M., Clarke, R., Aly, A., Anner, K., Bjorklund, K., Blomgren, G., Cederschiold, B., Danell-Toverud, K., Eriksson, P., Grundstedt, U., Heinonen, M., Hellenius, M.L., Hooft, F. van 't, Husman, K., Lagercrantz, J., Larsson, A., Larsson, M., Mossfeldt, M., Malarstig, A., Olsson, G., Sabater-Lleal, M., Sennblad, B., Silveira, A., Strawbridge, R., Soderholm, B., Ohrvik, J., Zaman, K.S., Mallick, N.H., Azhar, M., Samad, A., Ishaq, M., Shah, N., Samuel, M., Kathiresan, S.C., Assimes, T.L., Holm, H., Preuss, M., Stewart, A.F., Barbalic, M., Gieger, C., Absher, D., Aherrahrou, Z., Allayee, H., Altshuler, D., Anand, S., Andersen, K., Anderson, J.L., Ardissino, D., Ball, S.G., Balmforth, A.J., Barnes, T.A., Becker, L.C., Becker, D.M., Berger, K., Bis, J.C., Boekholdt, S.M., Boerwinkle, E., Brown, M.J., Burnett, M.S., Buysschaert, I., Carlquist, J.F., Chen, L., Davies, R.W., Dedoussis, G., Dehghan, A., Demissie, S., Devaney, J., Do, R., Doering, A., El Mokhtari, N.E., Ellis, S.G., Elosua, R., Engert, J.C., Epstein, S., Faire, U. de, Fischer, M., Folsom, A.R., Freyer, J., Gigante, B., Girelli, D., Gretarsdottir, S., Gudnason, V., Gulcher, J.R., Tennstedt, S., Halperin, E., Hammond, N., Hazen, S.L., Hofman, A., Horne, B.D., Illig, T., Iribarren, C., Jones, G.T., Jukema, J.W., Kaiser, M.A., Kaplan, L.M., Khaw, K.T., Knowles, J.W., Kolovou, G., Kong, A., Laaksonen, R., Lambrechts, D., Leander, K., Li, M., Lieb, W., Lettre, G., Loley, C., Lotery, A.J., Mannucci, P.M., Martinelli, N., McKeown, P.P., Meitinger, T., Melander, O., Merlini, P.A., Mooser, V., Morgan, T., Muhleisen T.W., ., Muhlestein, J.B., Musunuru, K., Nahrstaedt, J., Nothen, Markus, Olivieri, O., Peyvandi, F., Patel, R.S., Patterson, C.C., Qu, L., Quyyumi, A.A., Rader, D.J., Rallidis, L.S., Rice, C., Roosendaal, F.R., Rubin, D., Salomaa, V., Sampietro, M.L., Sandhu, M.S., Schadt, E., Schafer, A., Schillert, A., Schreiber, S., Schrezenmeir, J., Schwartz, S.M., Siscovick, D.S., Sivananthan, M., Sivapalaratnam, S., Smith, A.V., Smith, T.B., Snoep, J.D., Spertus, J.A., Stefansson, K., Stirrups, K., Stoll, M., Tang, W.H., Thorgeirsson, G., Thorleifsson, G., Tomaszewski, M., Uitterlinden, A.G., Rij, A.M. van, Voight, B.F., Wareham, N.J., AWells, G., Wichmann, H.E., Witteman, J.C., Wright, B.J., Ye, S., Cupples, L.A., Quertermous, T., Marz, W., Blankenberg, S., Thorsteinsdottir, U., Roberts, R., O'Donnell, C.J., Onland-Moret, N.C., Setten, J. van, Bakker, P.I. de, Verschuren, W.M., Boer, J.M., Wijmenga, C., Hofker, M.H., Maitland-van der Zee, A.H., Boer, A. de, Grobbee, D.E., Attwood, T., Belz, S., Cooper, J., Crisp-Hihn, A., Deloukas, P., Foad, N., Goodall, A.H., Gracey, J., Gray, E., Gwilliams, R., Heimerl, S., Hengstenberg, C., Jolley, J., Krishnan, U., Lloyd-Jones, H., Lugauer, I., Lundmark, P., Maouche, S., Moore, J.S., Muir, D., Murray, E., Nelson, C.P., Neudert, J., Niblett, D., O'Leary, K., Ouwehand, W.H., Pollard, H., Rankin, A., Rice, C.M., Sager, H., Samani, N.J., Sambrook, J., Schmitz, G., Scholz, M., Schroeder, L., Syvannen, A.C., Wallace, C., Butterworth, A.S., Braund, P.S., Hardwick, R.J., Saleheen, D., Peden, J.F., Soranzo, N., Chambers, J.C., Kleber, M.E., Keating, B., Qasim, A., Klopp, N., Erdmann, J., Basart, H., Baumert, J.H., Bezzina, C.R., Boehm, B.O., Brocheton, J., Bugert, P., Cambien, F., Collins, R., Couper, D., Jong, J.S. de, Diemert, P., Ejebe, K., Elbers, C.C., Elliott, P., Fornage, M., Frossard, P., Garner, S., Hunt, S.E., Kastelein, J.J., Klungel, O.H., Kluter, H., Koch, K., Konig, I.R., Kooner, A.S., Liu, K., McPherson, R., Musameh, M.D., Musani, S., Papanicolaou, G., Peters, A., Peters, B.J., Potter, S., Psaty, B.M., Rasheed, A., Scott, J., Seedorf, U., Sehmi, J.S., Sotoodehnia, N., Stark, K., Stephens, J., Schoot, C.E. van der, Schouw, Y.T. van der, Harst, P. van der, Vasan, R.S., Wilde, A.A., Willenborg, C., Winkelmann, B.R., Zaidi, M., Zhang, W., Ziegler, A., Koenig, W., Matz, W., Trip, M.D., Reilly, M.P., Kathiresan, S., Schunkert, H., Hamsten, A., Hall, A.S., Kooner, J.S., Thompson, S.G., Thompson, J.R., Watkins, H., Danesh, J., Barnes, T., Rafelt, S., Codd, V., Bruinsma, N., Dekker, L.R., Henriques, J.P., Koch, K.T., Winter, R.J. de, Alings, M., Allaart, C.F., Gorgels, A.P., Verheugt, F.W.A., Mueller, M., Meisinger, C., DerOhannessian, S., Mehta, N.N., Ferguson, J., Hakonarson, H., Matthai, W., Wilensky, R., Hopewell, J.C., Parish, S., Linksted, P., Notman, J., Gonzalez, H., Young, A., Ostley, T., Munday, A., Goodwin, N., Verdon, V., Shah, S., Edwards, C., Mathews, C., Gunter, R., Benham, J., Davies, C., Cobb, M., Cobb, L., Crowther, J., Richards, A., Silver, M., Tochlin, S., Mozley, S., Clark, S., Radley, M., Kourellias, K., Olsson, P., Barlera, S., Tognoni, G., Rust, S., Assmann, G., Heath, S., Zelenika, D., Gut, I., Green, F., Farrall, M., Goel, A., Ongen, H., Franzosi, M.G., Lathrop, M., Clarke, R., Aly, A., Anner, K., Bjorklund, K., Blomgren, G., Cederschiold, B., Danell-Toverud, K., Eriksson, P., Grundstedt, U., Heinonen, M., Hellenius, M.L., Hooft, F. van 't, Husman, K., Lagercrantz, J., Larsson, A., Larsson, M., Mossfeldt, M., Malarstig, A., Olsson, G., Sabater-Lleal, M., Sennblad, B., Silveira, A., Strawbridge, R., Soderholm, B., Ohrvik, J., Zaman, K.S., Mallick, N.H., Azhar, M., Samad, A., Ishaq, M., Shah, N., Samuel, M., Kathiresan, S.C., Assimes, T.L., Holm, H., Preuss, M., Stewart, A.F., Barbalic, M., Gieger, C., Absher, D., Aherrahrou, Z., Allayee, H., Altshuler, D., Anand, S., Andersen, K., Anderson, J.L., Ardissino, D., Ball, S.G., Balmforth, A.J., Barnes, T.A., Becker, L.C., Becker, D.M., Berger, K., Bis, J.C., Boekholdt, S.M., Boerwinkle, E., Brown, M.J., Burnett, M.S., Buysschaert, I., Carlquist, J.F., Chen, L., Davies, R.W., Dedoussis, G., Dehghan, A., Demissie, S., Devaney, J., Do, R., Doering, A., El Mokhtari, N.E., Ellis, S.G., Elosua, R., Engert, J.C., Epstein, S., Faire, U. de, Fischer, M., Folsom, A.R., Freyer, J., Gigante, B., Girelli, D., Gretarsdottir, S., Gudnason, V., Gulcher, J.R., Tennstedt, S., Halperin, E., Hammond, N., Hazen, S.L., Hofman, A., Horne, B.D., Illig, T., Iribarren, C., Jones, G.T., Jukema, J.W., Kaiser, M.A., Kaplan, L.M., Khaw, K.T., Knowles, J.W., Kolovou, G., Kong, A., Laaksonen, R., Lambrechts, D., Leander, K., Li, M., Lieb, W., Lettre, G., Loley, C., Lotery, A.J., Mannucci, P.M., Martinelli, N., McKeown, P.P., Meitinger, T., Melander, O., Merlini, P.A., Mooser, V., Morgan, T., Muhleisen T.W., ., Muhlestein, J.B., Musunuru, K., Nahrstaedt, J., Nothen, Markus, Olivieri, O., Peyvandi, F., Patel, R.S., Patterson, C.C., Qu, L., Quyyumi, A.A., Rader, D.J., Rallidis, L.S., Rice, C., Roosendaal, F.R., Rubin, D., Salomaa, V., Sampietro, M.L., Sandhu, M.S., Schadt, E., Schafer, A., Schillert, A., Schreiber, S., Schrezenmeir, J., Schwartz, S.M., Siscovick, D.S., Sivananthan, M., Sivapalaratnam, S., Smith, A.V., Smith, T.B., Snoep, J.D., Spertus, J.A., Stefansson, K., Stirrups, K., Stoll, M., Tang, W.H., Thorgeirsson, G., Thorleifsson, G., Tomaszewski, M., Uitterlinden, A.G., Rij, A.M. van, Voight, B.F., Wareham, N.J., AWells, G., Wichmann, H.E., Witteman, J.C., Wright, B.J., Ye, S., Cupples, L.A., Quertermous, T., Marz, W., Blankenberg, S., Thorsteinsdottir, U., Roberts, R., O'Donnell, C.J., Onland-Moret, N.C., Setten, J. van, Bakker, P.I. de, Verschuren, W.M., Boer, J.M., Wijmenga, C., Hofker, M.H., Maitland-van der Zee, A.H., Boer, A. de, Grobbee, D.E., Attwood, T., Belz, S., Cooper, J., Crisp-Hihn, A., Deloukas, P., Foad, N., Goodall, A.H., Gracey, J., Gray, E., Gwilliams, R., Heimerl, S., Hengstenberg, C., Jolley, J., Krishnan, U., Lloyd-Jones, H., Lugauer, I., Lundmark, P., Maouche, S., Moore, J.S., Muir, D., Murray, E., Nelson, C.P., Neudert, J., Niblett, D., O'Leary, K., Ouwehand, W.H., Pollard, H., Rankin, A., Rice, C.M., Sager, H., Samani, N.J., Sambrook, J., Schmitz, G., Scholz, M., Schroeder, L., Syvannen, A.C., and Wallace, C.

Abstract

Contains fulltext : 98050.pdf (publisher's version ) (Open Access), Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in approximately 2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5x10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other approximately 4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular f

Published
2011

8. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease

Author

Schunkert, H. (Heribert), König, I.R. (Inke), Kathiresan, S. (Sekar), Reilly, M.P. (Muredach), Assimes, T.L. (Themistocles), Holm, H. (Hilma), Preuss, M. (Michael), Stewart, A.F.R. (Alexandre), Barbalic, M. (maja), Gieger, C. (Christian), Absher, D. (Devin), Aherrahrou, Z. (Zouhair), Allayee, H. (Hooman), Altshuler, D. (David), Anand, S.S. (Sonia), Andersen, K.K. (Karl), Anderson, J.L. (Jeffrey), Ardissino, D. (Diego), Ball, S.G. (Stephen), Balmforth, A.J. (Anthony), Barnes, T.A. (Timothy), Becker, D.M. (Diane), Berger, K. (Klaus), Bis, J.C. (Joshua), Boekholdt, S.M. (Matthijs), Boerwinkle, E.A. (Eric), Braund, P.S. (Peter), Brown, M.J. (Morris), Burnett, M.S., Buysschaert, I. (Ian), Carlquist, J.F. (John), Chen, L. (Li), Cichon, S. (Sven), Codd, V. (Veryan), Davies, R.W. (Robert), Dedoussis, G.V. (George), Dehghan, A. (Abbas), Demissie, S. (Serkalem), Devaney, J. (Joseph), Diemert, P. (Patrick), Do, R. (Ron), Doering, A. (Angela), Eifert, S. (Sandra), Mokhtari, N.E.E., Ellis, S.G. (Stephen), Elosua, R. (Roberto), Engert, J.C. (James), Epstein, S.E. (Stephen), Faire, U. (Ulf) de, Fischer, M. (Marcus), Folsom, A.R. (Aaron), Freyer, J. (Jennifer), Gigante, B. (Bruna), Girelli, D. (Domenico), Gretarsdottir, S. (Solveig), Gudnason, V. (Vilmundur), Gulcher, J.R. (Jeffrey), Halperin, E. (Eran), Hammond, N. (Naomi), Hazen, S.L. (Stanley), Hofman, A. (Albert), Horne, B.D. (Benjamin), Illig, T. (Thomas), Iribarren, C. (Carlos), Jones, G.T. (Gregory), Jukema, J.W. (Jan Wouter), Kaiser, M.A. (Michael), Kaplan, R.C. (Robert), Khaw, K-T. (Kay-Tee), Knowles, J.W. (Joshua), Kolovou, G. (Genovefa), Kong, A. (Augustine), Laaksonen, R. (Reijo), Lambrechts, D. (Diether), Leander, K. (Karin), Lettre, G. (Guillaume), Lieb, W. (Wolfgang), Loley, C. (Christina), Lotery, A.J. (Andrew), Mannucci, P.M. (Pier), Maouche, S. (Seraya), Martinelli, N. (Nicola), McKeown, P.P. (Pascal), Meisinger, C. (Christa), Meitinger, T. (Thomas), Melander, O. (Olle), Merlini, P.A., Mooser, V. (Vincent), Morgan, T. (Thomas), Mühleisen, T.W. (Thomas), Muhlestein, J.B. (Joseph), Münzel, T. (Thomas), Musunuru, K. (Kiran), Nahrstaedt, J. (Janja), Nelson, C.P. (Christopher P.), Nöthen, M.M. (Markus), Olivieri, O. (Oliviero), Patel, R.S. (Riyaz), Patterson, C.C. (Chris), Peters, A. (Annette), Peyvandi, F. (Flora), Qu, L. (Liming), Quyyumi, A.A. (Arshed), Rader, D.J. (Daniel), Rallidis, L.S. (Loukianos), Rice, C. (Catherine), Rosendaal, F.R. (Frits), Rubin, D. (Diana), Salomaa, V. (Veikko), Sampietro, M.L. (Maria Lourdes), Sandhu, M.S. (Manj), Schadt, E.E. (Eric), Schillert, A. (Arne), Schreiber, S. (Stefan), Schrezenmeir, J. (Jürgen), Schwartz, S.M. (Stephen), Siscovick, D.S. (David), Sivananthan, M. (Mohan), Sivapalaratnam, S. (Suthesh), Smith, A.V. (Albert Vernon), Snoep, J.D. (Jaapjan), Soranzo, N. (Nicole), Spertus, J.A. (John), Stark, K. (Klaus), Stirrups, K. (Kathy), Stoll, M. (Monika), Tang, W.H.W. (Wilson), Tennstedt, S. (Stephanie), Thorgeirsson, G. (Gudmundur), Thorleifsson, G. (Gudmar), Tomaszewski, M. (Maciej), Uitterlinden, A.G. (André), Rij, A.M. (Andre) van, Voight, B.F. (Benjamin), Wareham, N.J. (Nick), Wells, G.A. (George), Wichmann, H.E. (Heinz Erich), Wild, P.S. (Philipp), Willenborg, C. (Christina), Witteman, J.C.M. (Jacqueline), Wright, B.J. (Benjamin), Ye, S. (Shu), Zeller, T. (Tanja), Ziegler, A. (Andreas), Cambien, F. (François), Goodall, A.H. (Alison), Cupples, L.A. (Adrienne), Quertermous, T. (Thomas), Mäsignrz, W. (Winfried), Hengstenberg, C. (Christian), Blankenberg, S. (Stefan), Ouwehand, W.H. (Willem), Hall, A.S. (Alistair), Kastelein, J.J.P. (John), Deloukas, P. (Panagiotis), Thompson, J.R. (John), Stefansson, K. (Kari), Roberts, R. (Robert), Li, M. (Mingyao), Thorsteinsdottir, U. (Unnur), O'Donnell, C.J. (Christopher), McPherson, R. (Ruth), Erdmann, J. (Jeanette), Samani, N.J. (Nilesh), Schäffer, A. (Arne), Schunkert, H. (Heribert), König, I.R. (Inke), Kathiresan, S. (Sekar), Reilly, M.P. (Muredach), Assimes, T.L. (Themistocles), Holm, H. (Hilma), Preuss, M. (Michael), Stewart, A.F.R. (Alexandre), Barbalic, M. (maja), Gieger, C. (Christian), Absher, D. (Devin), Aherrahrou, Z. (Zouhair), Allayee, H. (Hooman), Altshuler, D. (David), Anand, S.S. (Sonia), Andersen, K.K. (Karl), Anderson, J.L. (Jeffrey), Ardissino, D. (Diego), Ball, S.G. (Stephen), Balmforth, A.J. (Anthony), Barnes, T.A. (Timothy), Becker, D.M. (Diane), Berger, K. (Klaus), Bis, J.C. (Joshua), Boekholdt, S.M. (Matthijs), Boerwinkle, E.A. (Eric), Braund, P.S. (Peter), Brown, M.J. (Morris), Burnett, M.S., Buysschaert, I. (Ian), Carlquist, J.F. (John), Chen, L. (Li), Cichon, S. (Sven), Codd, V. (Veryan), Davies, R.W. (Robert), Dedoussis, G.V. (George), Dehghan, A. (Abbas), Demissie, S. (Serkalem), Devaney, J. (Joseph), Diemert, P. (Patrick), Do, R. (Ron), Doering, A. (Angela), Eifert, S. (Sandra), Mokhtari, N.E.E., Ellis, S.G. (Stephen), Elosua, R. (Roberto), Engert, J.C. (James), Epstein, S.E. (Stephen), Faire, U. (Ulf) de, Fischer, M. (Marcus), Folsom, A.R. (Aaron), Freyer, J. (Jennifer), Gigante, B. (Bruna), Girelli, D. (Domenico), Gretarsdottir, S. (Solveig), Gudnason, V. (Vilmundur), Gulcher, J.R. (Jeffrey), Halperin, E. (Eran), Hammond, N. (Naomi), Hazen, S.L. (Stanley), Hofman, A. (Albert), Horne, B.D. (Benjamin), Illig, T. (Thomas), Iribarren, C. (Carlos), Jones, G.T. (Gregory), Jukema, J.W. (Jan Wouter), Kaiser, M.A. (Michael), Kaplan, R.C. (Robert), Khaw, K-T. (Kay-Tee), Knowles, J.W. (Joshua), Kolovou, G. (Genovefa), Kong, A. (Augustine), Laaksonen, R. (Reijo), Lambrechts, D. (Diether), Leander, K. (Karin), Lettre, G. (Guillaume), Lieb, W. (Wolfgang), Loley, C. (Christina), Lotery, A.J. (Andrew), Mannucci, P.M. (Pier), Maouche, S. (Seraya), Martinelli, N. (Nicola), McKeown, P.P. (Pascal), Meisinger, C. (Christa), Meitinger, T. (Thomas), Melander, O. (Olle), Merlini, P.A., Mooser, V. (Vincent), Morgan, T. (Thomas), Mühleisen, T.W. (Thomas), Muhlestein, J.B. (Joseph), Münzel, T. (Thomas), Musunuru, K. (Kiran), Nahrstaedt, J. (Janja), Nelson, C.P. (Christopher P.), Nöthen, M.M. (Markus), Olivieri, O. (Oliviero), Patel, R.S. (Riyaz), Patterson, C.C. (Chris), Peters, A. (Annette), Peyvandi, F. (Flora), Qu, L. (Liming), Quyyumi, A.A. (Arshed), Rader, D.J. (Daniel), Rallidis, L.S. (Loukianos), Rice, C. (Catherine), Rosendaal, F.R. (Frits), Rubin, D. (Diana), Salomaa, V. (Veikko), Sampietro, M.L. (Maria Lourdes), Sandhu, M.S. (Manj), Schadt, E.E. (Eric), Schillert, A. (Arne), Schreiber, S. (Stefan), Schrezenmeir, J. (Jürgen), Schwartz, S.M. (Stephen), Siscovick, D.S. (David), Sivananthan, M. (Mohan), Sivapalaratnam, S. (Suthesh), Smith, A.V. (Albert Vernon), Snoep, J.D. (Jaapjan), Soranzo, N. (Nicole), Spertus, J.A. (John), Stark, K. (Klaus), Stirrups, K. (Kathy), Stoll, M. (Monika), Tang, W.H.W. (Wilson), Tennstedt, S. (Stephanie), Thorgeirsson, G. (Gudmundur), Thorleifsson, G. (Gudmar), Tomaszewski, M. (Maciej), Uitterlinden, A.G. (André), Rij, A.M. (Andre) van, Voight, B.F. (Benjamin), Wareham, N.J. (Nick), Wells, G.A. (George), Wichmann, H.E. (Heinz Erich), Wild, P.S. (Philipp), Willenborg, C. (Christina), Witteman, J.C.M. (Jacqueline), Wright, B.J. (Benjamin), Ye, S. (Shu), Zeller, T. (Tanja), Ziegler, A. (Andreas), Cambien, F. (François), Goodall, A.H. (Alison), Cupples, L.A. (Adrienne), Quertermous, T. (Thomas), Mäsignrz, W. (Winfried), Hengstenberg, C. (Christian), Blankenberg, S. (Stefan), Ouwehand, W.H. (Willem), Hall, A.S. (Alistair), Kastelein, J.J.P. (John), Deloukas, P. (Panagiotis), Thompson, J.R. (John), Stefansson, K. (Kari), Roberts, R. (Robert), Li, M. (Mingyao), Thorsteinsdottir, U. (Unnur), O'Donnell, C.J. (Christopher), McPherson, R. (Ruth), Erdmann, J. (Jeanette), Samani, N.J. (Nilesh), and Schäffer, A. (Arne)

Abstract

We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 - 10'8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

Published
2011
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9. Genome-wide association study identifies a new locus for coronary artery disease on chromosome 10p11.23

Author

Erdmann, J., primary, Willenborg, C., additional, Nahrstaedt, J., additional, Preuss, M., additional, Konig, I. R., additional, Baumert, J., additional, Linsel-Nitschke, P., additional, Gieger, C., additional, Tennstedt, S., additional, Belcredi, P., additional, Aherrahrou, Z., additional, Klopp, N., additional, Loley, C., additional, Stark, K., additional, Hengstenberg, C., additional, Bruse, P., additional, Freyer, J., additional, Wagner, A. K., additional, Medack, A., additional, Lieb, W., additional, Grosshennig, A., additional, Sager, H. B., additional, Reinhardt, A., additional, Schafer, A., additional, Schreiber, S., additional, El Mokhtari, N. E., additional, Raaz-Schrauder, D., additional, Illig, T., additional, Garlichs, C. D., additional, Ekici, A. B., additional, Reis, A., additional, Schrezenmeir, J., additional, Rubin, D., additional, Ziegler, A., additional, Wichmann, H.- E., additional, Doering, A., additional, Meisinger, C., additional, Meitinger, T., additional, Peters, A., additional, and Schunkert, H., additional

Published
2010
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12. Dysfunctional nitric oxide signalling increases risk of myocardial infarction.

Author

Erdmann J, Stark K, Esslinger UB, Rumpf PM, Koesling D, de Wit C, Kaiser FJ, Braunholz D, Medack A, Fischer M, Zimmermann ME, Tennstedt S, Graf E, Eck S, Aherrahrou Z, Nahrstaedt J, Willenborg C, Bruse P, Brænne I, Nöthen MM, Hofmann P, Braund PS, Mergia E, Reinhard W, Burgdorf C, Schreiber S, Balmforth AJ, Hall AS, Bertram L, Steinhagen-Thiessen E, Li SC, März W, Reilly M, Kathiresan S, McPherson R, Walter U, Ott J, Samani NJ, Strom TM, Meitinger T, Hengstenberg C, and Schunkert H

Subjects
Animals, Chaperonin Containing TCP-1 genetics, Chaperonin Containing TCP-1 metabolism, Cyclic GMP metabolism, Exome genetics, Female, Genetic Predisposition to Disease, Guanylate Cyclase deficiency, Guanylate Cyclase genetics, Guanylate Cyclase metabolism, HEK293 Cells, Humans, Male, Mice, Mutation genetics, Myocardial Infarction genetics, Myocardial Infarction physiopathology, Pedigree, Platelet Activation, Receptors, Cytoplasmic and Nuclear deficiency, Receptors, Cytoplasmic and Nuclear genetics, Receptors, Cytoplasmic and Nuclear metabolism, Reproducibility of Results, Solubility, Soluble Guanylyl Cyclase, Thrombosis metabolism, Vasodilation, Disease Susceptibility metabolism, Myocardial Infarction metabolism, Nitric Oxide metabolism, Signal Transduction
Abstract

Myocardial infarction, a leading cause of death in the Western world, usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery. The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history. Next-generation sequencing in families with several affected individuals has revolutionized mutation identification. Here we report the segregation of two private, heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the α1 subunit of soluble guanylyl cyclase (α1-sGC), and CCT7 encodes CCTη, a member of the tailless complex polypeptide 1 ring complex, which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation. We demonstrate in vitro that mutations in both GUCY1A3 and CCT7 severely reduce α1-sGC as well as β1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxide-induced cGMP formation. Mice deficient in α1-sGC protein displayed accelerated thrombus formation in the microcirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.

Published
2013
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13. A genome-wide association study for coronary artery disease identifies a novel susceptibility locus in the major histocompatibility complex.

Author

Davies RW, Wells GA, Stewart AF, Erdmann J, Shah SH, Ferguson JF, Hall AS, Anand SS, Burnett MS, Epstein SE, Dandona S, Chen L, Nahrstaedt J, Loley C, König IR, Kraus WE, Granger CB, Engert JC, Hengstenberg C, Wichmann HE, Schreiber S, Tang WH, Ellis SG, Rader DJ, Hazen SL, Reilly MP, Samani NJ, Schunkert H, Roberts R, and McPherson R

Subjects
Adult, Aged, Alleles, Female, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, White People genetics, Coronary Artery Disease genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Histocompatibility Antigens Class I genetics
Abstract

Background: Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with coronary artery disease (CAD) and/or myocardial infarction risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered., Methods and Results: We performed a discovery meta-analysis of 5 GWAS involving 13 949 subjects (7123 cases, 6826 control subjects) imputed at approximately 5 million single nucleotide polymorphisms, using pilot 1000 Genomes-based haplotypes. Promising loci were followed up in an additional 5 studies with 11 032 subjects (5211 cases, 5821 control subjects). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome-wide significance in the combined analysis (rs3869109; p(discovery)=3.3×10(-7), p(replication)=5.3×10(-4)p(combined)=1.12×10(-9)). A subanalysis combining discovery GWAS showed an attenuation of significance when stringent corrections for European population structure were used (P=4.1×10(-10) versus 3.2×10(-7)), suggesting that the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity, and self-cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association., Conclusions: We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T-cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).

Published
2012
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14. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease.

Author

Schunkert H, König IR, Kathiresan S, Reilly MP, Assimes TL, Holm H, Preuss M, Stewart AF, Barbalic M, Gieger C, Absher D, Aherrahrou Z, Allayee H, Altshuler D, Anand SS, Andersen K, Anderson JL, Ardissino D, Ball SG, Balmforth AJ, Barnes TA, Becker DM, Becker LC, Berger K, Bis JC, Boekholdt SM, Boerwinkle E, Braund PS, Brown MJ, Burnett MS, Buysschaert I, Carlquist JF, Chen L, Cichon S, Codd V, Davies RW, Dedoussis G, Dehghan A, Demissie S, Devaney JM, Diemert P, Do R, Doering A, Eifert S, Mokhtari NE, Ellis SG, Elosua R, Engert JC, Epstein SE, de Faire U, Fischer M, Folsom AR, Freyer J, Gigante B, Girelli D, Gretarsdottir S, Gudnason V, Gulcher JR, Halperin E, Hammond N, Hazen SL, Hofman A, Horne BD, Illig T, Iribarren C, Jones GT, Jukema JW, Kaiser MA, Kaplan LM, Kastelein JJ, Khaw KT, Knowles JW, Kolovou G, Kong A, Laaksonen R, Lambrechts D, Leander K, Lettre G, Li M, Lieb W, Loley C, Lotery AJ, Mannucci PM, Maouche S, Martinelli N, McKeown PP, Meisinger C, Meitinger T, Melander O, Merlini PA, Mooser V, Morgan T, Mühleisen TW, Muhlestein JB, Münzel T, Musunuru K, Nahrstaedt J, Nelson CP, Nöthen MM, Olivieri O, Patel RS, Patterson CC, Peters A, Peyvandi F, Qu L, Quyyumi AA, Rader DJ, Rallidis LS, Rice C, Rosendaal FR, Rubin D, Salomaa V, Sampietro ML, Sandhu MS, Schadt E, Schäfer A, Schillert A, Schreiber S, Schrezenmeir J, Schwartz SM, Siscovick DS, Sivananthan M, Sivapalaratnam S, Smith A, Smith TB, Snoep JD, Soranzo N, Spertus JA, Stark K, Stirrups K, Stoll M, Tang WH, Tennstedt S, Thorgeirsson G, Thorleifsson G, Tomaszewski M, Uitterlinden AG, van Rij AM, Voight BF, Wareham NJ, Wells GA, Wichmann HE, Wild PS, Willenborg C, Witteman JC, Wright BJ, Ye S, Zeller T, Ziegler A, Cambien F, Goodall AH, Cupples LA, Quertermous T, März W, Hengstenberg C, Blankenberg S, Ouwehand WH, Hall AS, Deloukas P, Thompson JR, Stefansson K, Roberts R, Thorsteinsdottir U, O'Donnell CJ, McPherson R, Erdmann J, and Samani NJ

Subjects
Adult, Aged, Alleles, Case-Control Studies, Coronary Artery Disease etiology, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Coronary Artery Disease genetics
Abstract

We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10⁻⁸ and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

Published
2011
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15. Genome-wide association study identifies a new locus for coronary artery disease on chromosome 10p11.23.

Author

Erdmann J, Willenborg C, Nahrstaedt J, Preuss M, König IR, Baumert J, Linsel-Nitschke P, Gieger C, Tennstedt S, Belcredi P, Aherrahrou Z, Klopp N, Loley C, Stark K, Hengstenberg C, Bruse P, Freyer J, Wagner AK, Medack A, Lieb W, Grosshennig A, Sager HB, Reinhardt A, Schäfer A, Schreiber S, El Mokhtari NE, Raaz-Schrauder D, Illig T, Garlichs CD, Ekici AB, Reis A, Schrezenmeir J, Rubin D, Ziegler A, Wichmann HE, Doering A, Meisinger C, Meitinger T, Peters A, and Schunkert H

Subjects
Adult, Cell Adhesion Molecules genetics, Chromosomes, Human, Pair 9 genetics, Female, Genome-Wide Association Study, Genotype, Genotyping Techniques methods, Humans, Male, Middle Aged, Pedigree, Risk Factors, Young Adult, Chromosomes, Human, Pair 10 genetics, Coronary Artery Disease genetics, Myocardial Infarction genetics, Polymorphism, Single Nucleotide genetics
Abstract

Aims: Recent genome-wide association (GWA) studies identified 10 chromosomal loci for coronary artery disease (CAD) or myocardial infarction (MI). However, these loci explain only a small proportion of the genetic variability of these pertinent diseases. We sought to identify additional CAD/MI loci by applying a three-stage approach., Methods and Results: We genotyped n = 1157 MI cases and n = 1748 controls from a population-based study population [German MI Family Study (GerMIFS) III (KORA)] with genome-wide SNP arrays. At this first stage, n = 462 SNPs showed association with MI at P<1 × 10(-3) in two-sided logistic regression. In a second stage, 415 of these SNPs were evaluated in silico in two independent GWA samples, the GerMIFS I (875 cases/1644 controls) and GerMIFS II (1222 cases/1298 controls). Nine SNPs, representing three regions, displayed consistent replication in this in silico analysis (P<0.05 for each GWA sample): five SNPs at 9p21.3, a well-known CAD/MI locus, two SNPs at 10p11.21, and two SNPs at 2p24.3. Wet-lab replication, i.e. the third stage, of SNP rs3739998 (representing the novel locus at 10p11.21, p.S1002T in the KIAA1462 gene) in additional 5790 cases and 5302 controls confirmed the association (P=9.54 × 10(-4)), but not for the 2p24.3 locus. The combined P-value across all stages for SNP rs3739998 is P=1.27 × 10(-11) [odds ratio (OR) = 1.15 (1.11-1.20)]., Conclusion: Analysis of a GWA study followed by in silico and wet-lab replication steps identified the KIAA1462 gene, encoding a yet uncharacterized protein, on chromosome 10p11.23 with genome-wide significant association for CAD/MI. Further studies are needed to characterize the functional role of this locus in the aetiology of these diseases.

Published
2011
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