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

Reilly, M.P.; Li, M.; He, J.; Ferguson, J.F.; Stylianou, I.M.; Mehta, N.N.; Burnett, M.S.; Devaney, J.M.; Knouff, C.W.; Thompson, J.R.; Horne, B.D.; Stewart, A.F.; Assimes, T.L.; Wild, P.S.; Allayee, H.; Nitschke, P.L.; Patel, R.S.; MI Genetics Consortium,; Wellcome Trust Case Control Consortium,; Martinelli, N.; Girelli, D.; Quyyumi, A.A.; Anderson, J.L.; Erdmann, J.; Hall, A.S.; Schunkert, H.; Quertermous, T.; Blankenberg, S.; Hazen, S.L.; Roberts, R.; Kathiresan, S.; Samani, N.J.; Epstein, S.E.; Rader, D.J.; Qasim, A.N.; Derohannessian, S.L.; Qu, L.; Cappola, T.P.; Chen, Z.; Matthai, W.; Hakonarson, H.H.; Wilensky, R.; Kent, K.M.; Lindsay, J.M.; Pichard, A.D.; Satler, L.; Waksman, R.; Knoupf, C.W.; Walker, M.C.; Waterworth, D.M.; Mosser, V.; Thompson, J.R.; Braund, P.S.; Wright, B.; Balmforth, A.J.; Ball, S.G.; Hall, A.S.; Samani, N.J.; Stewart, A.F.; Chen, L.; Wells, G.A.; Mcpherson, R.; Roberts, R.; Wild, P.S.; Lackner, K.; Munzel, T.F.; Schillert, A.; Schnabel, R.; Zeller, T.; Ziegler, A.; Blankenberg, S.; Assimes, T.L.; Absher, D.; Hlatky, M.A.; Iribaren, C.; Knowles, J.W.; Quertermous, T.; Kathiresan, S.; Linsel Nitschke, P.; König, I.R.; Hengstenberg, C.; Nahrstaedt, J.; Peters, A.; Schreiber, S.; Wichmann, E.; Willenborg, C.; Erdmann, J.; Schunkert, H.; Patel, R.S.; Su, S.; Bouzyk, M.; Vaccarino, V.; Zafari, A.M.; Quyyumi, A.A.; Horne, B.D.; Carlquist, J.F.; Muhlestein, J.B.; Anderson, J.L.; Martinelli, N.; Olivieri, O.; Girelli, D.; Barnard, J.; Allayee, H.; Hartiala, J.; Tang, W.H.; Hazen, S.L.; Burton, P.R.; Clayton, D.G.; Cardon, L.R.; Craddock, N.; Deloukas, P.; Duncanson, A.; Kwiatkowski, D.P.; Mccarthy, M.I.; Ouwehand, W.H.; Samani, N.J.; Todd, J.A.; Donnelly, P.; Barrett, J.C.; Burton, P.R.; Davison, D.; Donnelly, P.; Easton, D.; Evans, D.M.; Leung, H.T.; Marchini, J.L.; Morris, A.P.; Spencer, C.C.; Tobin, M.D.; Cardon, L.R.; Clayton, D.G.; Attwood, A.P.; Boorman, J.P.; Cant, B.; Everson, U.; Hussey, J.M.; Jolley, J.D.; Knight, A.S.; Koch, K.; Meech, E.; Nutland, S.; Prowse, C.V.; Stevens, H.E.; Taylor, N.C.; Walters, G.R.; Walker, N.M.; Watkins, N.A.; Winzer, T.; Todd, J.A.; Ouwehand, W.H.; Jones, R.W.; Mcardle, W.L.; Ring, S.M.; Strachan, D.P.; Pembrey, M.; Breen, G.; St Clair, D.; Caesar, S.; Gordon Smith, K.; Jones, L.; Fraser, C.; Green, E.K.; Grozeva, D.; Hamshere, M.L.; Holmans, P.A.; Jones, I.R.; Kirov, G.; Moskvina, V.; Nikolov, I.; O'Donovan, M.C.; Owen, M.J.; Craddock, N.; Collier, D.A.; Elkin, A.; Farmer, A.; Williamson, R.; Mcguffin, P.; Young, A.H.; Ferrier, I.N.; Ball, S.G.; Balmforth, A.J.; Barrett, J.H.; Bishop, D.T.; Iles, M.M.; Maqbool, A.; Yuldasheva, N.; Hall, A.S.; Braund, P.S.; Burton, P.R.; Dixon, R.J.; Mangino, M.; Stevens, S.; Tobin, M.D.; Thompson, J.R.; Samani, N.J.; Bredin, F.; Tremelling, M.; Parkes, M.; Drummond, H.; Lees, C.W.; Nimmo, E.R.; Satsangi, J.; Fisher, S.A.; Forbes, A.; Lewis, C.M.; Onnie, C.M.; Prescott, N.J.; Sanderson, J.; Mathew, C.G.; Barbour, J.; Mohiuddin, M.K.; Todhunter, C.E.; Mansfield, J.C.; Ahmad, T.; Cummings, F.R.; Jewell, D.P.; Webster, J.; Brown, M.J.; Clayton, D.G.; Lathrop, M.; Connell, J.; Dominiczak, A.; Samani, N.J.; Marcano, C.A.; Burke, B.; Dobson, R.; Gungadoo, J.; Lee, K.L.; Munroe, P.B.; Newhouse, S.J.; Onipinla, A.; Wallace, C.; Xue, M.; Caulfield, M.; Farrall, M.; Barton, A.; Bruce, I.N.; Donovan, H.; Eyre, S.; Gilbert, P.D.; Hider, S.L.; Hinks, A.M.; John, S.L.; Potter, C.; Silman, A.J.; Symmons, D.P.; Thomson, W.; Worthington, J.; Clayton, D.G.; Dunger, D.B.; Nutland, S.; Stevens, H.E.; Walker, N.M.; Widmer, B.; Todd, J.A.; Frayling, T.M.; Freathy, R.M.; Lango, H.; Perry, J.R.; Shields, B.M.; Weedon, M.N.; Hattersley, A.T.; Hitman, G.A.; Walker, M.; Elliott, K.S.; Groves, C.J.; Lindgren, C.M.; Rayner, N.W.; Timpson, N.J.; Zeggini, E.; Mccarthy, M.I.; Newport, M.; Sirugo, G.; Lyons, E.; Vannberg, F.; Hill, A.V.; Bradbury, L.A.; Farrar, C.; Pointon, J.J.; Wordsworth, P.; Brown, M.A.; Franklyn, J.A.; Heward, J.M.; Simmonds, M.J.; Gough, S.C.; Seal, S.; Stratton, M.R.; Rahman, N.; Ban, M.; Goris, A.; Sawcer, S.J.; Compston, A.; Conway, D.; Jallow, M.; Newport, M.; Sirugo, G.; Rockett, K.A.; Kwiatkowski, D.P.; Bumpstead, S.J.; Chaney, A.; Downes, K.; Ghori, M.J.; Gwilliam, R.; Hunt, S.E.; Inouye, M.; Keniry, A.; King, E.; Mcginnis, R.; Potter, S.; Ravindrarajah, R.; Whittaker, P.; Widden, C.; Withers, D.; Deloukas, P.; Leung, H.T.; Nutland, S.; Stevens, H.E.; Walker, N.M.; Todd, J.A.; Easton, D.; Clayton, D.G.; Burton, P.R.; Tobin, M.D.; Barrett, J.C.; Evans, D.M.; Morris, A.P.; Cardon, L.R.; Cardin, N.J.; Davison, D.; Ferreira, T.; Pereira Gale, J.; Hallgrimsdóttir, I.B.; Bowie, B.N.; Marchini, J.L.; Spencer, C.C.; Su, Z.; Teo, Y.Y.; Vukcevic, D.; Donnelly, P.; Bentley, D.; Brown, M.A.; Cardon, L.R.; Caulfield, M.; Clayton, D.G.; Compston, A.; Craddock, N.; Deloukas, P.; Donnelly, P.; Farrall, M.; Gough, S.C.; Hall, A.S.; Hattersley, A.T.; Hill, A.V.; Kwiatkowski, D.P.; Mathew, C.G.; Mccarthy, M.I.; Ouwehand, W.H.; Parkes, M.; Pembrey, M.; Rahman, N.; Samani, N.J.; Stratton, M.R.; Todd, J.A.; Worthington, J.; Kathiresan, S.; Meigs, J.B.; Williams, G.; Nathan, D.M.; Macrae, C.A.; O'Donnell, C.J.; Ardissino, D.; Merlini, P.A.; Berzuini, C.; Bernardinelli, L.; Peyvandi, F.; Tubaro, M.; Celli, P.; Ferrario, M.; Fetiveau, R.; Marziliano, N.; Casari, G.; Galli, M.; Ribichini, F.; Rossi, M.; Bernardi, F.; Zonzin, P.; Piazza, A.; Mannucci, P.M.; Schwartz, S.M.; Siscovick, D.S.; Yee, J.; Friedlander, Y.; Elosua, R.; Marrugat, J.; Lucas, G.; Subirana, I.; Sala, J.; Ramos, R.; Salomaa, V.; Havulinna, A.S.; Peltonen, L.; Melander, O.; Berglund, G.; Voight, B.F.; Kathiresan, S.; Hirschhorn, J.N.; Asselta, R.; Duga, S.; Spreafico, M.; Musunuru, K.; Daly, M.J.; Purcell, S.; Schwartz, S.M.; Yee, J.; Kathiresan, S.; Lucas, G.; Subirana, I.; Elosua, R.; Surti, A.; Guiducci, C.; Gianniny, L.; Mirel, D.; Parkin, M.; Burtt, N.; Gabriel, S.B.

doi:10.1016/S0140-6736(10)61996-4

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.

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 / MP. Reilly, M. Li, J. He, JF. Ferguson, IM. Stylianou, NN. Mehta, MS. Burnett, JM. Devaney, CW. Knouff, JR. Thompson, BD. Horne, AF. Stewart, TL. Assimes, PS. Wild, H. Allayee, PL. Nitschke, RS. Patel, MI Genetics Consortium, Wellcome Trust Case Control Consortium, N. Martinelli, D. Girelli, AA. Quyyumi, JL. Anderson, J. Erdmann, AS. Hall, H. Schunkert, T. Quertermous, S. Blankenberg, SL. Hazen, R. Roberts, S. Kathiresan, NJ. Samani, SE. Epstein, DJ. Rader, AN. Qasim, SL. DerOhannessian, L. Qu, TP. Cappola, Z. Chen, W. Matthai, HH. Hakonarson, R. Wilensky, KM. Kent, JM. Lindsay, AD. Pichard, L. Satler, R. Waksman, CW. Knoupf, MC. Walker, DM. Waterworth, V. Mosser, JR. Thompson, PS. Braund, B. Wright, AJ. Balmforth, SG. Ball, AS. Hall, NJ. Samani, AF. Stewart, L. Chen, GA. Wells, R. McPherson, R. Roberts, PS. Wild, K. Lackner, TF. Munzel, A. Schillert, R. Schnabel, T. Zeller, A. Ziegler, S. Blankenberg, TL. Assimes, D. Absher, MA. Hlatky, C. Iribaren, JW. Knowles, T. Quertermous, S. Kathiresan, P. Linsel-Nitschke, IR. König, C. Hengstenberg, J. Nahrstaedt, A. Peters, S. Schreiber, E. Wichmann, C. Willenborg, J. Erdmann, H. Schunkert, RS. Patel, S. Su, M. Bouzyk, V. Vaccarino, AM. Zafari, AA. Quyyumi, BD. Horne, JF. Carlquist, JB. Muhlestein, JL. Anderson, N. Martinelli, O. Olivieri, D. Girelli, J. Barnard, H. Allayee, J. Hartiala, WH. Tang, SL. Hazen, PR. Burton, DG. Clayton, LR. Cardon, N. Craddock, P. Deloukas, A. Duncanson, DP. Kwiatkowski, MI. McCarthy, WH. Ouwehand, NJ. Samani, JA. Todd, P. Donnelly, JC. Barrett, PR. Burton, D. Davison, P. Donnelly, D. Easton, DM. Evans, HT. Leung, JL. Marchini, AP. Morris, CC. Spencer, MD. Tobin, LR. Cardon, DG. Clayton, AP. Attwood, JP. Boorman, B. Cant, U. Everson, JM. Hussey, JD. Jolley, AS. Knight, K. Koch, E. Meech, S. Nutland, CV. Prowse, HE. Stevens, NC. Taylor, GR. Walters, NM. Walker, NA. Watkins, T. Winzer, JA. Todd, WH. Ouwehand, RW. Jones, WL. McArdle, SM. Ring, DP. Strachan, M. Pembrey, G. Breen, D. St Clair, S. Caesar, K. Gordon-Smith, L. Jones, C. Fraser, EK. Green, D. Grozeva, ML. Hamshere, PA. Holmans, IR. Jones, G. Kirov, V. Moskvina, I. Nikolov, MC. O'Donovan, MJ. Owen, N. Craddock, DA. Collier, A. Elkin, A. Farmer, R. Williamson, P. McGuffin, AH. Young, IN. Ferrier, SG. Ball, AJ. Balmforth, JH. Barrett, DT. Bishop, MM. Iles, A. Maqbool, N. Yuldasheva, AS. Hall, PS. Braund, PR. Burton, RJ. Dixon, M. Mangino, S. Stevens, MD. Tobin, JR. Thompson, NJ. Samani, F. Bredin, M. Tremelling, M. Parkes, H. Drummond, CW. Lees, ER. Nimmo, J. Satsangi, SA. Fisher, A. Forbes, CM. Lewis, CM. Onnie, NJ. Prescott, J. Sanderson, CG. Mathew, J. Barbour, MK. Mohiuddin, CE. Todhunter, JC. Mansfield, T. Ahmad, FR. Cummings, DP. Jewell, J. Webster, MJ. Brown, DG. Clayton, M. Lathrop, J. Connell, A. Dominiczak, NJ. Samani, CA. Marcano, B. Burke, R. Dobson, J. Gungadoo, KL. Lee, PB. Munroe, SJ. Newhouse, A. Onipinla, C. Wallace, M. Xue, M. Caulfield, M. Farrall, A. Barton, IN. Bruce, H. Donovan, S. Eyre, PD. Gilbert, SL. Hider, AM. Hinks, SL. John, C. Potter, AJ. Silman, DP. Symmons, W. Thomson, J. Worthington, DG. Clayton, DB. Dunger, S. Nutland, HE. Stevens, NM. Walker, B. Widmer, JA. Todd, TM. Frayling, RM. Freathy, H. Lango, JR. Perry, BM. Shields, MN. Weedon, AT. Hattersley, GA. Hitman, M. Walker, KS. Elliott, CJ. Groves, CM. Lindgren, NW. Rayner, NJ. Timpson, E. Zeggini, MI. McCarthy, M. Newport, G. Sirugo, E. Lyons, F. Vannberg, AV. Hill, LA. Bradbury, C. Farrar, JJ. Pointon, P. Wordsworth, MA. Brown, JA. Franklyn, JM. Heward, MJ. Simmonds, SC. Gough, S. Seal, MR. Stratton, N. Rahman, M. Ban, A. Goris, SJ. Sawcer, A. Compston, D. Conway, M. Jallow, M. Newport, G. Sirugo, KA. Rockett, DP. Kwiatkowski, SJ. Bumpstead, A. Chaney, K. Downes, MJ. Ghori, R. Gwilliam, SE. Hunt, M. Inouye, A. Keniry, E. King, R. McGinnis, S. Potter, R. Ravindrarajah, P. Whittaker, C. Widden, D. Withers, P. Deloukas, HT. Leung, S. Nutland, HE. Stevens, NM. Walker, JA. Todd, D. Easton, DG. Clayton, PR. Burton, MD. Tobin, JC. Barrett, DM. Evans, AP. Morris, LR. Cardon, NJ. Cardin, D. Davison, T. Ferreira, J. Pereira-Gale, IB. Hallgrimsdóttir, BN. Bowie, JL. Marchini, CC. Spencer, Z. Su, YY. Teo, D. Vukcevic, P. Donnelly, D. Bentley, MA. Brown, LR. Cardon, M. Caulfield, DG. Clayton, A. Compston, N. Craddock, P. Deloukas, P. Donnelly, M. Farrall, SC. Gough, AS. Hall, AT. Hattersley, AV. Hill, DP. Kwiatkowski, CG. Mathew, MI. McCarthy, WH. Ouwehand, M. Parkes, M. Pembrey, N. Rahman, NJ. Samani, MR. Stratton, JA. Todd, J. Worthington, S. Kathiresan, JB. Meigs, G. Williams, DM. Nathan, CA. MacRae, CJ. O'Donnell, D. Ardissino, PA. Merlini, C. Berzuini, L. Bernardinelli, F. Peyvandi, M. Tubaro, P. Celli, M. Ferrario, R. Fetiveau, N. Marziliano, G. Casari, M. Galli, F. Ribichini, M. Rossi, F. Bernardi, P. Zonzin, A. Piazza, PM. Mannucci, SM. Schwartz, DS. Siscovick, J. Yee, Y. Friedlander, R. Elosua, J. Marrugat, G. Lucas, I. Subirana, J. Sala, R. Ramos, V. Salomaa, AS. Havulinna, L. Peltonen, O. Melander, G. Berglund, BF. Voight, S. Kathiresan, JN. Hirschhorn, R. Asselta, S. Duga, M. Spreafico, K. Musunuru, MJ. Daly, S. Purcell, SM. Schwartz, J. Yee, S. Kathiresan, G. Lucas, I. Subirana, R. Elosua, A. Surti, C. Guiducci, L. Gianniny, D. Mirel, M. Parkin, N. Burtt, SB. Gabriel. - In: THE LANCET. - ISSN 0140-6736. - 377:9763(2011 Jan 29), pp. 383-392. [10.1016/S0140-6736(10)61996-4]

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

M.P. Reilly;M. Li;J. He;J.F. Ferguson;I.M. Stylianou;N.N. Mehta;M.S. Burnett;J.M. Devaney;C.W. Knouff;J.R. Thompson;B.D. Horne;A.F. Stewart;T.L. Assimes;P.S. Wild;H. Allayee;P.L. Nitschke;R.S. Patel;MI Genetics Consortium;Wellcome Trust Case Control Consortium;N. Martinelli;D. Girelli;A.A. Quyyumi;J.L. Anderson;J. Erdmann;A.S. Hall;H. Schunkert;T. Quertermous;S. Blankenberg;S.L. Hazen;R. Roberts;S. Kathiresan;N.J. Samani;S.E. Epstein;D.J. Rader;A.N. Qasim;S.L. DerOhannessian;L. Qu;T.P. Cappola;Z. Chen;W. Matthai;H.H. Hakonarson;R. Wilensky;K.M. Kent;J.M. Lindsay;A.D. Pichard;L. Satler;R. Waksman;C.W. Knoupf;M.C. Walker;D.M. Waterworth;V. Mosser;J.R. Thompson;P.S. Braund;B. Wright;A.J. Balmforth;S.G. Ball;A.S. Hall;N.J. Samani;A.F. Stewart;L. Chen;G.A. Wells;R. McPherson;R. Roberts;P.S. Wild;K. Lackner;T.F. Munzel;A. Schillert;R. Schnabel;T. Zeller;A. Ziegler;S. Blankenberg;T.L. Assimes;D. Absher;M.A. Hlatky;C. Iribaren;J.W. Knowles;T. Quertermous;S. Kathiresan;P. Linsel Nitschke;I.R. König;C. Hengstenberg;J. Nahrstaedt;A. Peters;S. Schreiber;E. Wichmann;C. Willenborg;J. Erdmann;H. Schunkert;R.S. Patel;S. Su;M. Bouzyk;V. Vaccarino;A.M. Zafari;A.A. Quyyumi;B.D. Horne;J.F. Carlquist;J.B. Muhlestein;J.L. Anderson;N. Martinelli;O. Olivieri;D. Girelli;J. Barnard;H. Allayee;J. Hartiala;W.H. Tang;S.L. Hazen;P.R. Burton;D.G. Clayton;L.R. Cardon;N. Craddock;P. Deloukas;A. Duncanson;D.P. Kwiatkowski;M.I. McCarthy;W.H. Ouwehand;N.J. Samani;J.A. Todd;P. Donnelly;J.C. Barrett;P.R. Burton;D. Davison;P. Donnelly;D. Easton;D.M. Evans;H.T. Leung;J.L. Marchini;A.P. Morris;C.C. Spencer;M.D. Tobin;L.R. Cardon;D.G. Clayton;A.P. Attwood;J.P. Boorman;B. Cant;U. Everson;J.M. Hussey;J.D. Jolley;A.S. Knight;K. Koch;E. Meech;S. Nutland;C.V. Prowse;H.E. Stevens;N.C. Taylor;G.R. Walters;N.M. Walker;N.A. Watkins;T. Winzer;J.A. Todd;W.H. Ouwehand;R.W. Jones;W.L. McArdle;S.M. Ring;D.P. Strachan;M. Pembrey;G. Breen;D. St Clair;S. Caesar;K. Gordon Smith;L. Jones;C. Fraser;E.K. Green;D. Grozeva;M.L. Hamshere;P.A. Holmans;I.R. Jones;G. Kirov;V. Moskvina;I. Nikolov;M.C. O'Donovan;M.J. Owen;N. Craddock;D.A. Collier;A. Elkin;A. Farmer;R. Williamson;P. McGuffin;A.H. Young;I.N. Ferrier;S.G. Ball;A.J. Balmforth;J.H. Barrett;D.T. Bishop;M.M. Iles;A. Maqbool;N. Yuldasheva;A.S. Hall;P.S. Braund;P.R. Burton;R.J. Dixon;M. Mangino;S. Stevens;M.D. Tobin;J.R. Thompson;N.J. Samani;F. Bredin;M. Tremelling;M. Parkes;H. Drummond;C.W. Lees;E.R. Nimmo;J. Satsangi;S.A. Fisher;A. Forbes;C.M. Lewis;C.M. Onnie;N.J. Prescott;J. Sanderson;C.G. Mathew;J. Barbour;M.K. Mohiuddin;C.E. Todhunter;J.C. Mansfield;T. Ahmad;F.R. Cummings;D.P. Jewell;J. Webster;M.J. Brown;D.G. Clayton;M. Lathrop;J. Connell;A. Dominiczak;N.J. Samani;C.A. Marcano;B. Burke;R. Dobson;J. Gungadoo;K.L. Lee;P.B. Munroe;S.J. Newhouse;A. Onipinla;C. Wallace;M. Xue;M. Caulfield;M. Farrall;A. Barton;I.N. Bruce;H. Donovan;S. Eyre;P.D. Gilbert;S.L. Hider;A.M. Hinks;S.L. John;C. Potter;A.J. Silman;D.P. Symmons;W. Thomson;J. Worthington;D.G. Clayton;D.B. Dunger;S. Nutland;H.E. Stevens;N.M. Walker;B. Widmer;J.A. Todd;T.M. Frayling;R.M. Freathy;H. Lango;J.R. Perry;B.M. Shields;M.N. Weedon;A.T. Hattersley;G.A. Hitman;M. Walker;K.S. Elliott;C.J. Groves;C.M. Lindgren;N.W. Rayner;N.J. Timpson;E. Zeggini;M.I. McCarthy;M. Newport;G. Sirugo;E. Lyons;F. Vannberg;A.V. Hill;L.A. Bradbury;C. Farrar;J.J. Pointon;P. Wordsworth;M.A. Brown;J.A. Franklyn;J.M. Heward;M.J. Simmonds;S.C. Gough;S. Seal;M.R. Stratton;N. Rahman;M. Ban;A. Goris;S.J. Sawcer;A. Compston;D. Conway;M. Jallow;M. Newport;G. Sirugo;K.A. Rockett;D.P. Kwiatkowski;S.J. Bumpstead;A. Chaney;K. Downes;M.J. Ghori;R. Gwilliam;S.E. Hunt;M. Inouye;A. Keniry;E. King;R. McGinnis;S. Potter;R. Ravindrarajah;P. Whittaker;C. Widden;D. Withers;P. Deloukas;H.T. Leung;S. Nutland;H.E. Stevens;N.M. Walker;J.A. Todd;D. Easton;D.G. Clayton;P.R. Burton;M.D. Tobin;J.C. Barrett;D.M. Evans;A.P. Morris;L.R. Cardon;N.J. Cardin;D. Davison;T. Ferreira;J. Pereira Gale;I.B. Hallgrimsdóttir;B.N. Bowie;J.L. Marchini;C.C. Spencer;Z. Su;Y.Y. Teo;D. Vukcevic;P. Donnelly;D. Bentley;M.A. Brown;L.R. Cardon;M. Caulfield;D.G. Clayton;A. Compston;N. Craddock;P. Deloukas;P. Donnelly;M. Farrall;S.C. Gough;A.S. Hall;A.T. Hattersley;A.V. Hill;D.P. Kwiatkowski;C.G. Mathew;M.I. McCarthy;W.H. Ouwehand;M. Parkes;M. Pembrey;N. Rahman;N.J. Samani;M.R. Stratton;J.A. Todd;J. Worthington;S. Kathiresan;J.B. Meigs;G. Williams;D.M. Nathan;C.A. MacRae;C.J. O'Donnell;D. Ardissino;P.A. Merlini;C. Berzuini;L. Bernardinelli;F. Peyvandi;M. Tubaro;P. Celli;M. Ferrario;R. Fetiveau;N. Marziliano;G. Casari;M. Galli;F. Ribichini;M. Rossi;F. Bernardi;P. Zonzin;A. Piazza;P.M. Mannucci;S.M. Schwartz;D.S. Siscovick;J. Yee;Y. Friedlander;R. Elosua;J. Marrugat;G. Lucas;I. Subirana;J. Sala;R. Ramos;V. Salomaa;A.S. Havulinna;L. Peltonen;O. Melander;G. Berglund;B.F. Voight;S. Kathiresan;J.N. Hirschhorn;R. Asselta;S. Duga;M. Spreafico;K. Musunuru;M.J. Daly;S. Purcell;S.M. Schwartz;J. Yee;S. Kathiresan;G. Lucas;I. Subirana;R. Elosua;A. Surti;C. Guiducci;L. Gianniny;D. Mirel;M. Parkin;N. Burtt;S.B. Gabriel

2011

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.

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	Settori scientifico-disciplinari dell'articolo
	
			Settore BIO/11 - Biologia Molecolare
Settore MED/09 - Medicina Interna
		
	Data di pubblicazione
	
			29-gen-2011
		
	Rivista in ANCE
	
			THE LANCET
		
	DOI
	
			https://dx.doi.org/10.1016/S0140-6736(10)61996-4
		
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			Article (author)
		
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			01 - Articolo su periodico

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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/292287

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