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

Butterworth, A.S.; Braund, P.S.; Farrall, M.; Hardwick, R.J.; Saleheen, D.; Peden, J.F.; Soranzo, N.; Chambers, J.C.; Sivapalaratnam, S.; Kleber, M.E.; Keating, B.; Qasim, A.; Klopp, N.; Erdmann, J.; Assimes, T.L.; Ball, S.G.; Balmforth, A.J.; Barnes, T.A.; Basart, H.; Baumert, J.; Bezzina, C.R.; Boerwinkle, E.; Boehm, B.O.; Brocheton, J.; Bugert, P.; Cambien, F.; Clarke, R.; Codd, V.; Collins, R.; Couper, D.; Cupples, L.A.; De Jong, J.S.; Diemert, P.; Ejebe, K.; Elbers, C.C.; Elliott, P.; Fornage, M.; Franzosi, M.G.; Frossard, P.; Garner, S.; Goel, A.; Goodall, A.H.; Hengstenberg, C.; Hunt, S.E.; Kastelein, J.J.; Klungel, O.H.; Klüter, H.; Koch, K.; König, I.R.; Kooner, A.S.; Laaksonen, R.; Lathrop, M.; Li, M.; Liu, K.; Mcpherson, R.; Musameh, M.D.; Musani, S.; Nelson, C.P.; O'Donnell, C.J.; Ongen, H.; Papanicolaou, G.; Peters, A.; Peters, B.J.; Potter, S.; Psaty, B.M.; Qu, L.; Rader, D.J.; Rasheed, A.; Rice, C.; Scott, J.; Seedorf, U.; Sehmi, J.S.; Sotoodehnia, N.; Stark, K.; Stephens, J.; Van Der Schoot, C.E.; Van Der Schouw, Y.T.; Thorsteinsdottir, U.; Tomaszewski, M.; Van Der Harst, P.; Vasan, R.S.; Wilde, A.A.; Willenborg, C.; Winkelmann, B.R.; Zaidi, M.; Zhang, W.; Ziegler, A.; De Bakker, P.I.; Koenig, W.; Mätz, 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.; Deloukas, P.; Ouwehand, W.H.; Watkins, H.; Danesh, J.; Samani, N.J.; Barnes, T.; Rafelt, S.; Codd, V.; Tomaszewski, M.; Ouwehand, W.H.; Bruinsma, N.; Dekker, L.R.; Henriques, J.P.; Koch, K.T.; De Winter, R.J.; Alings, M.; Allaart, C.F.; Gorgels, A.P.; Verheugt, F.W.; Braund, P.S.; Thompson, J.R.; Samani, N.J.; 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.; Cobb, L.; 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.; Silveira, A.; Söderholm, B.; Olsson, P.; Barlera, S.; Tognoni, G.; Rust, S.; Assmann, G.; Heath, S.; Zelenika, D.; Gut, I.; Green, F.; Farrall, M.; Peden, J.; Goel, A.; Ongen, H.; Franzosi, M.G.; Lathrop, M.; Seedorf, U.; Clarke, R.; Collins, R.; Hamsten, A.; Watkins, H.; Aly, A.; Anner, K.; Björklund, K.; Blomgren, G.; Cederschiöld, B.; Danell Toverud, K.; Eriksson, P.; Grundstedt, U.; Hamsten, A.; Heinonen, M.; Hellénius, M.L.; Hooft, F.V.; Husman, K.; Lagercrantz, J.; Larsson, A.; Larsson, M.; Mossfeldt, M.; Mälarstig, A.; Olsson, G.; Sabater Lleal, M.; Sennblad, B.; Silveira, A.; Strawbridge, R.; Söderholm, B.; Öhrvik, J.; Zaman, K.S.; Mallick, N.H.; Azhar, M.; Samad, A.; Ishaq, M.; Shah, N.; Samuel, M.; Schunkert, H.; König, I.R.; Kathiresan, S.; Reilly, M.; 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.; Braund, P.S.; Brown, M.J.; Burnett, M.S.; Buysschaert, I.; Carlquist, J.F.; Chen, L.; Codd, V.; 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.; De Faire, U.; 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.; Kastelein, J.J.; Khaw, K.T.; Knowles, J.W.; Kolovou, G.; Kong, A.; Laaksonen, R.; Lambrechts, D.; Leander, K.; Li, M.; Lieb, W.; Diemert, P.; Lettre, G.; 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.; Musunuru, K.; Nahrstaedt, J.; Nelson, C.P.; Nöthen, M.M.; Olivieri, O.; Peyvandi, F.; Patel, R.S.; Patterson, C.C.; Peters, A.; 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.; Schäfer, 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.; Soranzo, N.; Spertus, J.A.; Stark, K.; Stefansson, K.; Stirrups, K.; Stoll, M.; Tang, W.H.; Thorgeirsson, G.; Thorleifsson, G.; Tomaszewski, M.; Uitterlinden, A.G.; Van Rij, A.M.; Voight, B.F.; Wareham, N.J.; Wells, G.; Wichmann, H.E.; Willenborg, C.; Witteman, J.C.; Wright, B.J.; Ye, S.; Ziegler, A.; Cambien, F.; Goodall, A.H.; Cupples, L.A.; Quertermous, T.; März, W.; Hengstenberg, C.; Blankenberg, S.; Ouwehand, W.H.; Hall, A.S.; Deloukas, P.; Thorsteinsdottir, U.; Roberts, R.; Thompson, J.R.; O'Donnell, C.J.; Mcpherson, R.; Erdmann, J.; Samani, N.J.; Onland Moret, N.C.; Van Setten, J.; De Bakker, P.I.; Verschuren, W.M.; Boer, J.M.; Wijmenga, C.; Hofker, M.H.; Maitland Van Der Zee, A.H.; De Boer, A.; Grobbee, D.E.; Attwood, T.; Belz, S.; Braund, P.; Cambien, F.; Cooper, J.; Crisp Hihn, A.; Diemert, P.; Deloukas, P.; Foad, N.; Erdmann, J.; 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.; Schunkert, H.; Syvannen, A.C.; Tennstedt, S.; Wallace, C.

doi:10.1371/journal.pgen.1002260

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<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10(-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 ∼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 functions and clarified the literature with regard to many previously suggested genes

Large-scale gene-centric analysis identifies novel variants for coronary artery disease / A.S. Butterworth, P.S. Braund, M. Farrall, R.J. Hardwick, D. Saleheen, J.F. Peden, N. Soranzo, J.C. Chambers, S. Sivapalaratnam, M.E. Kleber, B. Keating, A. Qasim, N. Klopp, J. Erdmann, T.L. Assimes, S.G. Ball, A.J. Balmforth, T.A. Barnes, H. Basart, J. Baumert, C.R. Bezzina, E. Boerwinkle, B.O. Boehm, J. Brocheton, P. Bugert, F. Cambien, R. Clarke, V. Codd, R. Collins, D. Couper, L.A. Cupples, J.S. de Jong, P. Diemert, K. Ejebe, C.C. Elbers, P. Elliott, M. Fornage, M.G. Franzosi, P. Frossard, S. Garner, A. Goel, A.H. Goodall, C. Hengstenberg, S.E. Hunt, J.J. Kastelein, O.H. Klungel, H. Klüter, K. Koch, I.R. König, A.S. Kooner, R. Laaksonen, M. Lathrop, M. Li, K. Liu, R. McPherson, M.D. Musameh, S. Musani, C.P. Nelson, C.J. O'Donnell, H. Ongen, G. Papanicolaou, A. Peters, B.J. Peters, S. Potter, B.M. Psaty, L. Qu, D.J. Rader, A. Rasheed, C. Rice, J. Scott, U. Seedorf, J.S. Sehmi, N. Sotoodehnia, K. Stark, J. Stephens, C.E. van der Schoot, Y.T. van der Schouw, U. Thorsteinsdottir, M. Tomaszewski, P. van der Harst, R.S. Vasan, A.A. Wilde, C. Willenborg, B.R. Winkelmann, M. Zaidi, W. Zhang, A. Ziegler, P.I. de Bakker, W. Koenig, W. Mätz, M.D. Trip, M.P. Reilly, S. Kathiresan, H. Schunkert, A. Hamsten, A.S. Hall, J.S. Kooner, S.G. Thompson, J.R. Thompson, P. Deloukas, W.H. Ouwehand, H. Watkins, J. Danesh, N.J. Samani, T. Barnes, S. Rafelt, V. Codd, M. Tomaszewski, W.H. Ouwehand, N. Bruinsma, L.R. Dekker, J.P. Henriques, K.T. Koch, R.J. de Winter, M. Alings, C.F. Allaart, A.P. Gorgels, F.W. Verheugt, P.S. Braund, J.R. Thompson, N.J. Samani, M. Mueller, C. Meisinger, S. DerOhannessian, N.N. Mehta, J. Ferguson, H. Hakonarson, W. Matthai, R. Wilensky, J.C. Hopewell, S. Parish, P. Linksted, J. Notman, H. Gonzalez, A. Young, T. Ostley, A. Munday, N. Goodwin, V. Verdon, S. Shah, L. Cobb, C. Edwards, C. Mathews, R. Gunter, J. Benham, C. Davies, M. Cobb, L. Cobb, J. Crowther, A. Richards, M. Silver, S. Tochlin, S. Mozley, S. Clark, M. Radley, K. Kourellias, A. Silveira, B. Söderholm, P. Olsson, S. Barlera, G. Tognoni, S. Rust, G. Assmann, S. Heath, D. Zelenika, I. Gut, F. Green, M. Farrall, J. Peden, A. Goel, H. Ongen, M.G. Franzosi, M. Lathrop, U. Seedorf, R. Clarke, R. Collins, A. Hamsten, H. Watkins, A. Aly, K. Anner, K. Björklund, G. Blomgren, B. Cederschiöld, K. Danell-Toverud, P. Eriksson, U. Grundstedt, A. Hamsten, M. Heinonen, M.L. Hellénius, F. van't Hooft, K. Husman, J. Lagercrantz, A. Larsson, M. Larsson, M. Mossfeldt, A. Mälarstig, G. Olsson, M. Sabater-Lleal, B. Sennblad, A. Silveira, R. Strawbridge, B. Söderholm, J. Öhrvik, K.S. Zaman, N.H. Mallick, M. Azhar, A. Samad, M. Ishaq, N. Shah, M. Samuel, H. Schunkert, I.R. König, S. Kathiresan, M. Reilly, T.L. Assimes, H. Holm, M. Preuss, A.F. Stewart, M. Barbalic, C. Gieger, D. Absher, Z. Aherrahrou, H. Allayee, D. Altshuler, S. Anand, K. Andersen, J.L. Anderson, D. Ardissino, S.G. Ball, A.J. Balmforth, T.A. Barnes, L.C. Becker, D.M. Becker, K. Berger, J.C. Bis, S.M. Boekholdt, E. Boerwinkle, P.S. Braund, M.J. Brown, M.S. Burnett, I. Buysschaert, J.F. Carlquist, L. Chen, V. Codd, R.W. Davies, G. Dedoussis, A. Dehghan, S. Demissie, J Devaney, R. Do, A. Doering, N.E. El Mokhtari, S.G. Ellis, R. Elosua, J.C Engert, S. Epstein, U. de Faire, M. Fischer, A.R. Folsom, J. Freyer, B. Gigante, D. Girelli, S. Gretarsdottir, V. Gudnason, J.R. Gulcher, S. Tennstedt, E. Halperin, N. Hammond, S.L. Hazen, A. Hofman, B.D. Horne, T. Illig, C. Iribarren, G.T. Jones, J.W. Jukema, M.A. Kaiser, L.M. Kaplan, J.J. Kastelein, K.T. Khaw, J.W. Knowles, G. Kolovou, A. Kong, R. Laaksonen, D. Lambrechts, K. Leander, M. Li, W. Lieb, P. Diemert, G. Lettre, C. Loley, A.J. Lotery, P.M. Mannucci, S. Maouche, N. Martinelli, P.P. McKeown, C. Meisinger, T. Meitinger, O. Melander, P.A. Merlini, V. Mooser, T. Morgan, T.W. Mühleisen, J.B. Muhlestein, K. Musunuru, J. Nahrstaedt, C.P. Nelson, M.M. Nöthen, O. Olivieri, F. Peyvandi, R.S. Patel, C.C. Patterson, A. Peters, L. Qu, A.A. Quyyumi, D.J. Rader, L.S. Rallidis, C. Rice, F.R. Roosendaal, D. Rubin, V. Salomaa, M.L. Sampietro, M.S. Sandhu, E. Schadt, A. Schäfer, A. Schillert, S. Schreiber, J. Schrezenmeir, S.M. Schwartz, D.S. Siscovick, M. Sivananthan, S. Sivapalaratnam, A.V. Smith, T.B. Smith, J.D. Snoep, N. Soranzo, J.A. Spertus, K. Stark, K. Stefansson, K. Stirrups, M. Stoll, W.H. Tang, G. Thorgeirsson, G. Thorleifsson, M. Tomaszewski, A.G. Uitterlinden, A.M. van Rij, B.F. Voight, N.J. Wareham, G. Wells, H.E. Wichmann, C. Willenborg, J.C. Witteman, B.J. Wright, S. Ye, A. Ziegler, F. Cambien, A.H. Goodall, L.A. Cupples, T. Quertermous, W. März, C. Hengstenberg, S. Blankenberg, W.H. Ouwehand, A.S. Hall, P. Deloukas, U. Thorsteinsdottir, R. Roberts, J.R. Thompson, C.J. O'Donnell, R. McPherson, J. Erdmann, N.J. Samani, N.C. Onland-Moret, J. van Setten, P.I. de Bakker, W.M. Verschuren, J.M. Boer, C. Wijmenga, M.H. Hofker, A.H. Maitland-van der Zee, A. de Boer, D.E. Grobbee, T. Attwood, S. Belz, P. Braund, F. Cambien, J. Cooper, A. Crisp-Hihn, P. Diemert, P. Deloukas, N. Foad, J. Erdmann, A.H. Goodall, J. Gracey, E. Gray, R. Gwilliams, S. Heimerl, C. Hengstenberg, J. Jolley, U. Krishnan, H. Lloyd-Jones, I. Lugauer, P. Lundmark, S. Maouche, J.S. Moore, D. Muir, E. Murray, C.P. Nelson, J. Neudert, D. Niblett, K. O'Leary, W.H. Ouwehand, H. Pollard, A. Rankin, C.M. Rice, H. Sager, N.J. Samani, J. Sambrook, G. Schmitz, M. Scholz, L. Schroeder, H. Schunkert, A.C. Syvannen, S. Tennstedt, C. Wallace. - In: PLOS GENETICS. - ISSN 1553-7390. - 7:9(2011 Sep), pp. e1002260.e1002260-e1002260.e1002260.

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

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

2011

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<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10(-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 ∼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 functions and clarified the literature with regard to many previously suggested genes

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	Lingua dell'articolo
	
				English
			
	Settori scientifico-disciplinari dell'articolo (sola visualizzazione)
	
				Settore MED/09 - Medicina Interna
			
	Tipo
	
				Articolo
			
	Revisione (peer review)
	
				Esperti anonimi
			
	Data di pubblicazione
	
				set-2011
			
	Rivista in ANCE
	
				PLOS GENETICS
			
	Volume o annata
	
				7
			
	Fascicolo
	
				9
			
	Numero dell'articolo
	
				e1002260
			
	Pagina iniziale
	
				e1002260
			
	Pagina finale
	
				e1002260
			
	Stato di pubblicazione
	
				Pubblicato
			
	Rilevanza del periodico
	
				Periodico con rilevanza internazionale
			
	DOI
	
				https://dx.doi.org/10.1371/journal.pgen.1002260
			
	Identificativo ISI
	
				WOS:000295419100015
			
	Identificativo SCOPUS
	
				2-s2.0-80053452394
			
	Tipologia
	
				info:eu-repo/semantics/article
			
	Citazione
	
				Large-scale gene-centric analysis identifies novel variants for coronary artery disease / A.S. Butterworth, P.S. Braund, M. Farrall, R.J. Hardwick, D. Saleheen, J.F. Peden, N. Soranzo, J.C. Chambers, S. Sivapalaratnam, M.E. Kleber, B. Keating, A. Qasim, N. Klopp, J. Erdmann, T.L. Assimes, S.G. Ball, A.J. Balmforth, T.A. Barnes, H. Basart, J. Baumert, C.R. Bezzina, E. Boerwinkle, B.O. Boehm, J. Brocheton, P. Bugert, F. Cambien, R. Clarke, V. Codd, R. Collins, D. Couper, L.A. Cupples, J.S. de Jong, P. Diemert, K. Ejebe, C.C. Elbers, P. Elliott, M. Fornage, M.G. Franzosi, P. Frossard, S. Garner, A. Goel, A.H. Goodall, C. Hengstenberg, S.E. Hunt, J.J. Kastelein, O.H. Klungel, H. Klüter, K. Koch, I.R. König, A.S. Kooner, R. Laaksonen, M. Lathrop, M. Li, K. Liu, R. McPherson, M.D. Musameh, S. Musani, C.P. Nelson, C.J. O'Donnell, H. Ongen, G. Papanicolaou, A. Peters, B.J. Peters, S. Potter, B.M. Psaty, L. Qu, D.J. Rader, A. Rasheed, C. Rice, J. Scott, U. Seedorf, J.S. Sehmi, N. Sotoodehnia, K. Stark, J. Stephens, C.E. van der Schoot, Y.T. van der Schouw, U. Thorsteinsdottir, M. Tomaszewski, P. van der Harst, R.S. Vasan, A.A. Wilde, C. Willenborg, B.R. Winkelmann, M. Zaidi, W. Zhang, A. Ziegler, P.I. de Bakker, W. Koenig, W. Mätz, M.D. Trip, M.P. Reilly, S. Kathiresan, H. Schunkert, A. Hamsten, A.S. Hall, J.S. Kooner, S.G. Thompson, J.R. Thompson, P. Deloukas, W.H. Ouwehand, H. Watkins, J. Danesh, N.J. Samani, T. Barnes, S. Rafelt, V. Codd, M. Tomaszewski, W.H. Ouwehand, N. Bruinsma, L.R. Dekker, J.P. Henriques, K.T. Koch, R.J. de Winter, M. Alings, C.F. Allaart, A.P. Gorgels, F.W. Verheugt, P.S. Braund, J.R. Thompson, N.J. Samani, M. Mueller, C. Meisinger, S. DerOhannessian, N.N. Mehta, J. Ferguson, H. Hakonarson, W. Matthai, R. Wilensky, J.C. Hopewell, S. Parish, P. Linksted, J. Notman, H. Gonzalez, A. Young, T. Ostley, A. Munday, N. Goodwin, V. Verdon, S. Shah, L. Cobb, C. Edwards, C. Mathews, R. Gunter, J. Benham, C. Davies, M. Cobb, L. Cobb, J. Crowther, A. Richards, M. Silver, S. Tochlin, S. Mozley, S. Clark, M. Radley, K. Kourellias, A. Silveira, B. Söderholm, P. Olsson, S. Barlera, G. Tognoni, S. Rust, G. Assmann, S. Heath, D. Zelenika, I. Gut, F. Green, M. Farrall, J. Peden, A. Goel, H. Ongen, M.G. Franzosi, M. Lathrop, U. Seedorf, R. Clarke, R. Collins, A. Hamsten, H. Watkins, A. Aly, K. Anner, K. Björklund, G. Blomgren, B. Cederschiöld, K. Danell-Toverud, P. Eriksson, U. Grundstedt, A. Hamsten, M. Heinonen, M.L. Hellénius, F. van't Hooft, K. Husman, J. Lagercrantz, A. Larsson, M. Larsson, M. Mossfeldt, A. Mälarstig, G. Olsson, M. Sabater-Lleal, B. Sennblad, A. Silveira, R. Strawbridge, B. Söderholm, J. Öhrvik, K.S. Zaman, N.H. Mallick, M. Azhar, A. Samad, M. Ishaq, N. Shah, M. Samuel, H. Schunkert, I.R. König, S. Kathiresan, M. Reilly, T.L. Assimes, H. Holm, M. Preuss, A.F. Stewart, M. Barbalic, C. Gieger, D. Absher, Z. Aherrahrou, H. Allayee, D. Altshuler, S. Anand, K. Andersen, J.L. Anderson, D. Ardissino, S.G. Ball, A.J. Balmforth, T.A. Barnes, L.C. Becker, D.M. Becker, K. Berger, J.C. Bis, S.M. Boekholdt, E. Boerwinkle, P.S. Braund, M.J. Brown, M.S. Burnett, I. Buysschaert, J.F. Carlquist, L. Chen, V. Codd, R.W. Davies, G. Dedoussis, A. Dehghan, S. Demissie, J Devaney, R. Do, A. Doering, N.E. El Mokhtari, S.G. Ellis, R. Elosua, J.C Engert, S. Epstein, U. de Faire, M. Fischer, A.R. Folsom, J. Freyer, B. Gigante, D. Girelli, S. Gretarsdottir, V. Gudnason, J.R. Gulcher, S. Tennstedt, E. Halperin, N. Hammond, S.L. Hazen, A. Hofman, B.D. Horne, T. Illig, C. Iribarren, G.T. Jones, J.W. Jukema, M.A. Kaiser, L.M. Kaplan, J.J. Kastelein, K.T. Khaw, J.W. Knowles, G. Kolovou, A. Kong, R. Laaksonen, D. Lambrechts, K. Leander, M. Li, W. Lieb, P. Diemert, G. Lettre, C. Loley, A.J. Lotery, P.M. Mannucci, S. Maouche, N. Martinelli, P.P. McKeown, C. Meisinger, T. Meitinger, O. Melander, P.A. Merlini, V. Mooser, T. Morgan, T.W. Mühleisen, J.B. Muhlestein, K. Musunuru, J. Nahrstaedt, C.P. Nelson, M.M. Nöthen, O. Olivieri, F. Peyvandi, R.S. Patel, C.C. Patterson, A. Peters, L. Qu, A.A. Quyyumi, D.J. Rader, L.S. Rallidis, C. Rice, F.R. Roosendaal, D. Rubin, V. Salomaa, M.L. Sampietro, M.S. Sandhu, E. Schadt, A. Schäfer, A. Schillert, S. Schreiber, J. Schrezenmeir, S.M. Schwartz, D.S. Siscovick, M. Sivananthan, S. Sivapalaratnam, A.V. Smith, T.B. Smith, J.D. Snoep, N. Soranzo, J.A. Spertus, K. Stark, K. Stefansson, K. Stirrups, M. Stoll, W.H. Tang, G. Thorgeirsson, G. Thorleifsson, M. Tomaszewski, A.G. Uitterlinden, A.M. van Rij, B.F. Voight, N.J. Wareham, G. Wells, H.E. Wichmann, C. Willenborg, J.C. Witteman, B.J. Wright, S. Ye, A. Ziegler, F. Cambien, A.H. Goodall, L.A. Cupples, T. Quertermous, W. März, C. Hengstenberg, S. Blankenberg, W.H. Ouwehand, A.S. Hall, P. Deloukas, U. Thorsteinsdottir, R. Roberts, J.R. Thompson, C.J. O'Donnell, R. McPherson, J. Erdmann, N.J. Samani, N.C. Onland-Moret, J. van Setten, P.I. de Bakker, W.M. Verschuren, J.M. Boer, C. Wijmenga, M.H. Hofker, A.H. Maitland-van der Zee, A. de Boer, D.E. Grobbee, T. Attwood, S. Belz, P. Braund, F. Cambien, J. Cooper, A. Crisp-Hihn, P. Diemert, P. Deloukas, N. Foad, J. Erdmann, A.H. Goodall, J. Gracey, E. Gray, R. Gwilliams, S. Heimerl, C. Hengstenberg, J. Jolley, U. Krishnan, H. Lloyd-Jones, I. Lugauer, P. Lundmark, S. Maouche, J.S. Moore, D. Muir, E. Murray, C.P. Nelson, J. Neudert, D. Niblett, K. O'Leary, W.H. Ouwehand, H. Pollard, A. Rankin, C.M. Rice, H. Sager, N.J. Samani, J. Sambrook, G. Schmitz, M. Scholz, L. Schroeder, H. Schunkert, A.C. Syvannen, S. Tennstedt, C. Wallace. - In: PLOS GENETICS. - ISSN 1553-7390. - 7:9(2011 Sep), pp. e1002260.e1002260-e1002260.e1002260.
			
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						A.S. Butterworth, P.S. Braund, M. Farrall, R.J. Hardwick, D. Saleheen, J.F. Peden, N. Soranzo, J.C. Chambers, S. Sivapalaratnam, M.E. Kleber, B. Keati...espandi
						
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