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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 :
NameEmailORCID
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
Niblett, D
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 : 31 Oct 2017 17:03
URI: http://epubs.surrey.ac.uk/id/eprint/806383

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