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

Butterworth, AS, Saleheen, D, Thompson, SG, Danesh, J, Braund, PS, Hardwick, RJ, Barnes, TA, Codd, V, Goodall, AH, Musameh, MD, Nelson, CP, Tomaszewski, M, van der Harst, P, Samani, NJ, Farrall, M, Peden, JF, Goel, A, Ongen, H, Watkins, H, Frossard, P, Rasheed, A, Zaidi, M, Soranzo, N, Hunt, SE, Potter, S, Rice, C, Deloukas, P, Ouwehand, WH, Chambers, JC, Zhang, W, Sivapalaratnam, S, Basart, H, Kastelein, JJP, Trip, MD, Kleber, ME, Keating, B, Qasim, A, Rader, DJ, Reilly, MP, Klopp, N, Baumert, J, Peters, A, Erdmann, J, Diemert, P, Willenborg, C, Schunkert, H, Assimes, TL, Ball, SG, Balmforth, AJ, Bezzina, CR, de Jong, JS, Wilde, AAM, Boerwinkle, E, Boehm, BO, Brocheton, J, Cambien, F, Bugert, P, Klüterr, H, Clarke, R, Collins, R, Couper, D, Adrienne Cupples, L, O'Donnell, CJ, Ejebe, K, Kathiresan, S, Elbers, CC, van der Schouw, YT, de Bakker, PIW, Elliott, P, Fornage, M, Franzosi, M-G, Garner, S, Koch, K, Stephens, J, Hengstenberg, C, Stark, K, Klungel, OH, Peters, BJM, König, IR, Ziegler, A, Kooner, AS, Scott, J, Sehmi, JS, Kooner, JS, Laaksonen, R, Lathrop, M, Li, M, Qu, L, Liu, K, McPherson, R, Musani, S, Papanicolaou, G, Psaty, BM, Seedorf, U, Sotoodehnia, N, van der Schoot, CE, Thorsteinsdottir, U, Vasan, RS, Winkelmann, BR, Koenig, W, März, W, Hamsten, A, Hall, AS, Thompson, JR, 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, 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, M-L, van't Hooft, F, 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, Shah Zaman, K, Hayat Mallick, N, Azhar, M, Samad, A, Ishaq, M, Shah, N, Samuel, M, Reilly, M, Holm, H, Preuss, M, Stewart, AFR, 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, Matthijs Boekholdt, S, Brown, MJ, Susan Burnett, M, 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, Wouter Jukema, J, Kaiser, MA, Kaplan, LM, Khaw, K-T, Knowles, JW, Kolovou, G, Kong, A, Lambrechts, D, Leander, K, Lieb, W, Lettre, G, Loley, C, Lotery, AJ, Mannucci, PM, Maouche, S, Martinelli, N, McKeown, PP, Meitinger, T, Melander, O, Angelica Merlini, P, Mooser, V, Morgan, T, Mühleisen, TW, Muhlestein, JB, Musunuru, K, Nahrstaedt, J, Nöthen, MM, Olivieri, O, Peyvandi, F, Patel, RS, Patterson, CC, Quyyumi, AA, Rallidis, LS, Roosendaal, FR, Rubin, D, Salomaa, V, Lourdes Sampietro, M, 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, Wilson Tang, WH, Thorgeirsson, G, Thorleifsson, G, Uitterlinden, AG, van Rij, AM, Voight, BF, Wareham, NJ, Wells, GA, Wichmann, H-E, Witteman, JCM, Wright, BJ, Ye, S, Quertermous, T, Blankenberg, S, Roberts, R, Onland-Moret, NC, van Setten, J, Monique Verschuren, WM, Boer, JMA, Wijmenga, C, Hofker, MH, Maitland-van der Zee, A-H, 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 and Niblett, D (2011) Large-scale gene-centric analysis identifies novel variants for coronary artery disease PLoS Genetics, 7 (9).

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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; LPA:p<10; 1p13.3:p<10) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10). 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. © 2011 Butterworth et al.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences
Authors :
AuthorsEmailORCID
Butterworth, ASUNSPECIFIEDUNSPECIFIED
Saleheen, DUNSPECIFIEDUNSPECIFIED
Thompson, SGUNSPECIFIEDUNSPECIFIED
Danesh, JUNSPECIFIEDUNSPECIFIED
Braund, PSUNSPECIFIEDUNSPECIFIED
Hardwick, RJUNSPECIFIEDUNSPECIFIED
Barnes, TAUNSPECIFIEDUNSPECIFIED
Codd, VUNSPECIFIEDUNSPECIFIED
Goodall, AHUNSPECIFIEDUNSPECIFIED
Musameh, MDUNSPECIFIEDUNSPECIFIED
Nelson, CPUNSPECIFIEDUNSPECIFIED
Tomaszewski, MUNSPECIFIEDUNSPECIFIED
van der Harst, PUNSPECIFIEDUNSPECIFIED
Samani, NJUNSPECIFIEDUNSPECIFIED
Farrall, MUNSPECIFIEDUNSPECIFIED
Peden, JFUNSPECIFIEDUNSPECIFIED
Goel, AUNSPECIFIEDUNSPECIFIED
Ongen, HUNSPECIFIEDUNSPECIFIED
Watkins, HUNSPECIFIEDUNSPECIFIED
Frossard, PUNSPECIFIEDUNSPECIFIED
Rasheed, AUNSPECIFIEDUNSPECIFIED
Zaidi, MUNSPECIFIEDUNSPECIFIED
Soranzo, NUNSPECIFIEDUNSPECIFIED
Hunt, SEUNSPECIFIEDUNSPECIFIED
Potter, SUNSPECIFIEDUNSPECIFIED
Rice, CUNSPECIFIEDUNSPECIFIED
Deloukas, PUNSPECIFIEDUNSPECIFIED
Ouwehand, WHUNSPECIFIEDUNSPECIFIED
Chambers, JCUNSPECIFIEDUNSPECIFIED
Zhang, WUNSPECIFIEDUNSPECIFIED
Sivapalaratnam, SUNSPECIFIEDUNSPECIFIED
Basart, HUNSPECIFIEDUNSPECIFIED
Kastelein, JJPUNSPECIFIEDUNSPECIFIED
Trip, MDUNSPECIFIEDUNSPECIFIED
Kleber, MEUNSPECIFIEDUNSPECIFIED
Keating, BUNSPECIFIEDUNSPECIFIED
Qasim, AUNSPECIFIEDUNSPECIFIED
Rader, DJUNSPECIFIEDUNSPECIFIED
Reilly, MPUNSPECIFIEDUNSPECIFIED
Klopp, NUNSPECIFIEDUNSPECIFIED
Baumert, JUNSPECIFIEDUNSPECIFIED
Peters, AUNSPECIFIEDUNSPECIFIED
Erdmann, JUNSPECIFIEDUNSPECIFIED
Diemert, PUNSPECIFIEDUNSPECIFIED
Willenborg, CUNSPECIFIEDUNSPECIFIED
Schunkert, HUNSPECIFIEDUNSPECIFIED
Assimes, TLUNSPECIFIEDUNSPECIFIED
Ball, SGUNSPECIFIEDUNSPECIFIED
Balmforth, AJUNSPECIFIEDUNSPECIFIED
Bezzina, CRUNSPECIFIEDUNSPECIFIED
de Jong, JSUNSPECIFIEDUNSPECIFIED
Wilde, AAMUNSPECIFIEDUNSPECIFIED
Boerwinkle, EUNSPECIFIEDUNSPECIFIED
Boehm, BOUNSPECIFIEDUNSPECIFIED
Brocheton, JUNSPECIFIEDUNSPECIFIED
Cambien, FUNSPECIFIEDUNSPECIFIED
Bugert, PUNSPECIFIEDUNSPECIFIED
Klüterr, HUNSPECIFIEDUNSPECIFIED
Clarke, RUNSPECIFIEDUNSPECIFIED
Collins, RUNSPECIFIEDUNSPECIFIED
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O'Donnell, CJUNSPECIFIEDUNSPECIFIED
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Kathiresan, SUNSPECIFIEDUNSPECIFIED
Elbers, CCUNSPECIFIEDUNSPECIFIED
van der Schouw, YTUNSPECIFIEDUNSPECIFIED
de Bakker, PIWUNSPECIFIEDUNSPECIFIED
Elliott, PUNSPECIFIEDUNSPECIFIED
Fornage, MUNSPECIFIEDUNSPECIFIED
Franzosi, M-GUNSPECIFIEDUNSPECIFIED
Garner, SUNSPECIFIEDUNSPECIFIED
Koch, KUNSPECIFIEDUNSPECIFIED
Stephens, JUNSPECIFIEDUNSPECIFIED
Hengstenberg, CUNSPECIFIEDUNSPECIFIED
Stark, KUNSPECIFIEDUNSPECIFIED
Klungel, OHUNSPECIFIEDUNSPECIFIED
Peters, BJMUNSPECIFIEDUNSPECIFIED
König, IRUNSPECIFIEDUNSPECIFIED
Ziegler, AUNSPECIFIEDUNSPECIFIED
Kooner, ASUNSPECIFIEDUNSPECIFIED
Scott, JUNSPECIFIEDUNSPECIFIED
Sehmi, JSUNSPECIFIEDUNSPECIFIED
Kooner, JSUNSPECIFIEDUNSPECIFIED
Laaksonen, RUNSPECIFIEDUNSPECIFIED
Lathrop, MUNSPECIFIEDUNSPECIFIED
Li, MUNSPECIFIEDUNSPECIFIED
Qu, LUNSPECIFIEDUNSPECIFIED
Liu, KUNSPECIFIEDUNSPECIFIED
McPherson, RUNSPECIFIEDUNSPECIFIED
Musani, SUNSPECIFIEDUNSPECIFIED
Papanicolaou, GUNSPECIFIEDUNSPECIFIED
Psaty, BMUNSPECIFIEDUNSPECIFIED
Seedorf, UUNSPECIFIEDUNSPECIFIED
Sotoodehnia, NUNSPECIFIEDUNSPECIFIED
van der Schoot, CEUNSPECIFIEDUNSPECIFIED
Thorsteinsdottir, UUNSPECIFIEDUNSPECIFIED
Vasan, RSUNSPECIFIEDUNSPECIFIED
Winkelmann, BRUNSPECIFIEDUNSPECIFIED
Koenig, WUNSPECIFIEDUNSPECIFIED
März, WUNSPECIFIEDUNSPECIFIED
Hamsten, AUNSPECIFIEDUNSPECIFIED
Hall, ASUNSPECIFIEDUNSPECIFIED
Thompson, JRUNSPECIFIEDUNSPECIFIED
Barnes, TUNSPECIFIEDUNSPECIFIED
Rafelt, SUNSPECIFIEDUNSPECIFIED
Bruinsma, NUNSPECIFIEDUNSPECIFIED
Dekker, LRUNSPECIFIEDUNSPECIFIED
Henriques, JPUNSPECIFIEDUNSPECIFIED
Koch, KTUNSPECIFIEDUNSPECIFIED
de Winter, RJUNSPECIFIEDUNSPECIFIED
Alings, MUNSPECIFIEDUNSPECIFIED
Allaart, CFUNSPECIFIEDUNSPECIFIED
Gorgels, APUNSPECIFIEDUNSPECIFIED
Verheugt, FWUNSPECIFIEDUNSPECIFIED
Mueller, MUNSPECIFIEDUNSPECIFIED
Meisinger, CUNSPECIFIEDUNSPECIFIED
DerOhannessian, SUNSPECIFIEDUNSPECIFIED
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Ferguson, JUNSPECIFIEDUNSPECIFIED
Hakonarson, HUNSPECIFIEDUNSPECIFIED
Matthai, WUNSPECIFIEDUNSPECIFIED
Wilensky, RUNSPECIFIEDUNSPECIFIED
Hopewell, JCUNSPECIFIEDUNSPECIFIED
Parish, SUNSPECIFIEDUNSPECIFIED
Linksted, PUNSPECIFIEDUNSPECIFIED
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Ostley, TUNSPECIFIEDUNSPECIFIED
Munday, AUNSPECIFIEDUNSPECIFIED
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Cobb, MUNSPECIFIEDUNSPECIFIED
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Richards, AUNSPECIFIEDUNSPECIFIED
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Maitland-van der Zee, A-HUNSPECIFIEDUNSPECIFIED
de Boer, AUNSPECIFIEDUNSPECIFIED
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Attwood, TUNSPECIFIEDUNSPECIFIED
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Braund, PUNSPECIFIEDUNSPECIFIED
Cooper, JUNSPECIFIEDUNSPECIFIED
Crisp-Hihn, AUNSPECIFIEDUNSPECIFIED
Foad, NUNSPECIFIEDUNSPECIFIED
Gracey, JUNSPECIFIEDUNSPECIFIED
Gray, EUNSPECIFIEDUNSPECIFIED
Gwilliams, RUNSPECIFIEDUNSPECIFIED
Heimerl, SUNSPECIFIEDUNSPECIFIED
Jolley, JUNSPECIFIEDUNSPECIFIED
Krishnan, UUNSPECIFIEDUNSPECIFIED
Lloyd-Jones, HUNSPECIFIEDUNSPECIFIED
Lugauer, IUNSPECIFIEDUNSPECIFIED
Lundmark, PUNSPECIFIEDUNSPECIFIED
Moore, JSUNSPECIFIEDUNSPECIFIED
Muir, DUNSPECIFIEDUNSPECIFIED
Murray, EUNSPECIFIEDUNSPECIFIED
Neudert, JUNSPECIFIEDUNSPECIFIED
Niblett, DUNSPECIFIEDUNSPECIFIED
Date : September 2011
Identification Number : 10.1371/journal.pgen.1002260
Additional Information : Copyright: 2011 Butterworth et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Depositing User : Symplectic Elements
Date Deposited : 04 Nov 2014 11:06
Last Modified : 03 Dec 2014 14:33
URI: http://epubs.surrey.ac.uk/id/eprint/806383

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