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

Adam S. Butterworth; Peter S. Braund; groep; Martin Farrall; Robert J. Hardwick; Danish Saleheen; John F. Peden; Nicole Soranzo; John C. Chambers; Suthesh Sivapalaratnam; Marcus E. Kleber; Brendan Keating; Atif Qasim; Norman Klopp; Jeanette Erdmann; Themistocles L. Assimes; Stephen G. Ball; Anthony J. Balmforth; Timothy A. Barnes; Hanneke Basart; Jens Baumert; Connie R. Bezzina; Eric Boerwinkle; Bernhard O. Boehm; Jessy Brocheton; Peter Bugert; Francois Cambien; Robert Clarke; Veryan Codd; Rory Collins; David Couper; L. Adrienne Cupples; Jonas S. de Jong; Patrick Diemert; Kenechi Ejebe; Clara C. Elbers; Paul Elliott; Myriam Fornage; Maria Grazia Franzosi; Philippe Frossard; Stephen Garner; Anuj Goel; Alison H. Goodall; Christian Hengstenberg; Sarah E. Hunt; Nienke Bruinsma; Marco Alings; S. Shah; Abbas Dehghan; Albert Hofman; Andre G. Uitterlinden

doi:10.1371/journal.pgen.1002260

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

Adam S. Butterworth, Peter S. Braund, groep, Martin Farrall, Robert J. Hardwick, Danish Saleheen, John F. Peden, Nicole Soranzo, John C. Chambers, Suthesh Sivapalaratnam, Marcus E. Kleber, Brendan Keating, Atif Qasim, Norman Klopp, Jeanette Erdmann, Themistocles L. Assimes, Stephen G. Ball, Anthony J. Balmforth, Timothy A. Barnes, Hanneke BasartJens Baumert, Connie R. Bezzina, Eric Boerwinkle, Bernhard O. Boehm, Jessy Brocheton, Peter Bugert, Francois Cambien, Robert Clarke, Veryan Codd, Rory Collins, David Couper, L. Adrienne Cupples, Jonas S. de Jong, Patrick Diemert, Kenechi Ejebe, Clara C. Elbers, Paul Elliott, Myriam Fornage, Maria Grazia Franzosi, Philippe Frossard, Stephen Garner, Anuj Goel, Alison H. Goodall, Christian Hengstenberg, Sarah E. Hunt, Nienke Bruinsma, Marco Alings, S. Shah, Abbas Dehghan, Albert Hofman, Andre G. Uitterlinden

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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^-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.

Original language	English
Article number	e1002260
Journal	PLoS Genetics
Volume	7
Issue number	9
DOIs	https://doi.org/10.1371/journal.pgen.1002260
Publication status	Published - 1 Sept 2011

Bibliographical note

Funding Information:
Muredach P Reilly and Daniel J Rader have a research grant from GlaxoSmithKline. The division of Pharmacoepidemiology and Clinical Pharmacology employing Bas Peters, Olaf Klungel, Anthonius de Boer, and Anke-Hilse Maitland-van der Zee has received unrestricted funding for pharmacoepidemiological research from GlaxoSmithKline, Novo Nordisk, the private-public funded Top Institute Pharma ( www.tipharma.nl , includes co-funding from universities, government, and industry), the Dutch Medicines Evaluation Board, and the Dutch Ministry of Health. Arthur AM Wilde is a consultant for Transgenomics (Familion test) and Sorin. No other disclosures were reported.

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Butterworth, A. S., Braund, P. S., groep, 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., ... Uitterlinden, A. G. (2011). Large-scale gene-centric analysis identifies novel variants for coronary artery disease. PLoS Genetics, 7(9), Article e1002260. https://doi.org/10.1371/journal.pgen.1002260

@article{3b17b71d52984e579e86ff3ed61b2904,

title = "Large-scale gene-centric analysis identifies novel variants for coronary artery disease",

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.",

author = "Butterworth, {Adam S.} and Braund, {Peter S.} and groep and Martin Farrall and Hardwick, {Robert J.} and Danish Saleheen and Peden, {John F.} and Nicole Soranzo and Chambers, {John C.} and Suthesh Sivapalaratnam and Kleber, {Marcus E.} and Brendan Keating and Atif Qasim and Norman Klopp and Jeanette Erdmann and Assimes, {Themistocles L.} and Ball, {Stephen G.} and Balmforth, {Anthony J.} and Barnes, {Timothy A.} and Hanneke Basart and Jens Baumert and Bezzina, {Connie R.} and Eric Boerwinkle and Boehm, {Bernhard O.} and Jessy Brocheton and Peter Bugert and Francois Cambien and Robert Clarke and Veryan Codd and Rory Collins and David Couper and {Adrienne Cupples}, L. and {de Jong}, {Jonas S.} and Patrick Diemert and Kenechi Ejebe and Elbers, {Clara C.} and Paul Elliott and Myriam Fornage and Franzosi, {Maria Grazia} and Philippe Frossard and Stephen Garner and Anuj Goel and Goodall, {Alison H.} and Christian Hengstenberg and Hunt, {Sarah E.} and Nienke Bruinsma and Marco Alings and S. Shah and Abbas Dehghan and Albert Hofman and Uitterlinden, {Andre G.}",

note = "Funding Information: Muredach P Reilly and Daniel J Rader have a research grant from GlaxoSmithKline. The division of Pharmacoepidemiology and Clinical Pharmacology employing Bas Peters, Olaf Klungel, Anthonius de Boer, and Anke-Hilse Maitland-van der Zee has received unrestricted funding for pharmacoepidemiological research from GlaxoSmithKline, Novo Nordisk, the private-public funded Top Institute Pharma ( www.tipharma.nl , includes co-funding from universities, government, and industry), the Dutch Medicines Evaluation Board, and the Dutch Ministry of Health. Arthur AM Wilde is a consultant for Transgenomics (Familion test) and Sorin. No other disclosures were reported. ",

year = "2011",

month = sep,

day = "1",

doi = "10.1371/journal.pgen.1002260",

language = "English",

volume = "7",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "9",

}

Butterworth, AS, Braund, PS, groep, 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, Adrienne Cupples, L, 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, Bruinsma, N, Alings, M, Shah, S, Dehghan, A, Hofman, A & Uitterlinden, AG 2011, 'Large-scale gene-centric analysis identifies novel variants for coronary artery disease', PLoS Genetics, vol. 7, no. 9, e1002260. https://doi.org/10.1371/journal.pgen.1002260

TY - JOUR

T1 - Large-scale gene-centric analysis identifies novel variants for coronary artery disease

AU - Butterworth, Adam S.

AU - Braund, Peter S.

AU - groep

AU - Farrall, Martin

AU - Hardwick, Robert J.

AU - Saleheen, Danish

AU - Peden, John F.

AU - Soranzo, Nicole

AU - Chambers, John C.

AU - Sivapalaratnam, Suthesh

AU - Kleber, Marcus E.

AU - Keating, Brendan

AU - Qasim, Atif

AU - Klopp, Norman

AU - Erdmann, Jeanette

AU - Assimes, Themistocles L.

AU - Ball, Stephen G.

AU - Balmforth, Anthony J.

AU - Barnes, Timothy A.

AU - Basart, Hanneke

AU - Baumert, Jens

AU - Bezzina, Connie R.

AU - Boerwinkle, Eric

AU - Boehm, Bernhard O.

AU - Brocheton, Jessy

AU - Bugert, Peter

AU - Cambien, Francois

AU - Clarke, Robert

AU - Codd, Veryan

AU - Collins, Rory

AU - Couper, David

AU - Adrienne Cupples, L.

AU - de Jong, Jonas S.

AU - Diemert, Patrick

AU - Ejebe, Kenechi

AU - Elbers, Clara C.

AU - Elliott, Paul

AU - Fornage, Myriam

AU - Franzosi, Maria Grazia

AU - Frossard, Philippe

AU - Garner, Stephen

AU - Goel, Anuj

AU - Goodall, Alison H.

AU - Hengstenberg, Christian

AU - Hunt, Sarah E.

AU - Bruinsma, Nienke

AU - Alings, Marco

AU - Shah, S.

AU - Dehghan, Abbas

AU - Hofman, Albert

AU - Uitterlinden, Andre G.

N1 - Funding Information: Muredach P Reilly and Daniel J Rader have a research grant from GlaxoSmithKline. The division of Pharmacoepidemiology and Clinical Pharmacology employing Bas Peters, Olaf Klungel, Anthonius de Boer, and Anke-Hilse Maitland-van der Zee has received unrestricted funding for pharmacoepidemiological research from GlaxoSmithKline, Novo Nordisk, the private-public funded Top Institute Pharma ( www.tipharma.nl , includes co-funding from universities, government, and industry), the Dutch Medicines Evaluation Board, and the Dutch Ministry of Health. Arthur AM Wilde is a consultant for Transgenomics (Familion test) and Sorin. No other disclosures were reported.

PY - 2011/9/1

Y1 - 2011/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=80053452394&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1002260

DO - 10.1371/journal.pgen.1002260

M3 - Article

C2 - 21966275

AN - SCOPUS:80053452394

SN - 1553-7390

VL - 7

JO - PLoS Genetics

JF - PLoS Genetics

IS - 9

M1 - e1002260

ER -

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

Abstract

Bibliographical note

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