Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Joanna M. M. Howson; Wei Zhao; Daniel R Barnes; Weang Kee Ho; Robin Young; Dirk S Paul; Lindsay Waite; Daniel F Freitag; Eric B Fauman; Elias L Salfati; Benjamin B Sun; John D Eicher; Andrew D Johnson; Wayne H-H Sheu; Sune F Nielsen; Wei-Yu Lin; Praveen Surendran; Anders Malarstig; Jemma B Wilk; Anne Tybjærg-Hansen; Katrine L Rasmussen; Pia R Kamstrup; Panos Deloukas; Jeanette Erdmann; Sekar Kathiresan; Nilesh J Samani; Heribert Schunkert; Hugh Watkins; CARDIoGRAMplusC4D; Ron Do; Daniel J Rader; Julie A Johnson; Stanley L Hazen; Arshed A Quyyumi; John A Spertus; Carl J Pepine; Nora Franceschini; Anne E Justice; Alex P Reiner; Steven Buyske; Lucia A Hindorff; Cara L Carty; Kari E North; Charles Kooperberg; Eric Boerwinkle; Kristin L Young; Mariaelisa Graff; Ulrike Peters; Devin Absher; Chao A Hsiung; EPIC-CVD Consortium; Børge G Nordestgaard; Themistocles L Assimes; J Danesh; Adam S Butterworth; D Saleheen

doi:10.1038/ng.3874

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Joanna M. M. Howson, Wei Zhao, Daniel R Barnes, Weang Kee Ho, Robin Young, Dirk S Paul, Lindsay Waite, Daniel F Freitag, Eric B Fauman, Elias L Salfati, Benjamin B Sun, John D Eicher, Andrew D Johnson, Wayne H-H Sheu, Sune F Nielsen, Wei-Yu Lin, Praveen Surendran, Anders Malarstig, Jemma B Wilk, Anne Tybjærg-HansenKatrine L Rasmussen, Pia R Kamstrup, Panos Deloukas, Jeanette Erdmann, Sekar Kathiresan, Nilesh J Samani, Heribert Schunkert, Hugh Watkins, CARDIoGRAMplusC4D, Ron Do, Daniel J Rader, Julie A Johnson, Stanley L Hazen, Arshed A Quyyumi, John A Spertus, Carl J Pepine, Nora Franceschini, Anne E Justice, Alex P Reiner, Steven Buyske, Lucia A Hindorff, Cara L Carty, Kari E North, Charles Kooperberg, Eric Boerwinkle, Kristin L Young, Mariaelisa Graff, Ulrike Peters, Devin Absher, Chao A Hsiung, EPIC-CVD Consortium, Børge G Nordestgaard, Themistocles L Assimes, J Danesh, Adam S Butterworth, D Saleheen

Institut for Klinisk Medicin

136 Citationer (Scopus)

Abstract

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	49
Sider (fra-til)	1113-1119
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.3874
Status	Udgivet - 1 jul. 2017

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Howson, J. M. M., Zhao, W., Barnes, D. R., Ho, W. K., Young, R., Paul, D. S., Waite, L., Freitag, D. F., Fauman, E. B., Salfati, E. L., Sun, B. B., Eicher, J. D., Johnson, A. D., Sheu, W. H-H., Nielsen, S. F., Lin, W-Y., Surendran, P., Malarstig, A., Wilk, J. B., ... Saleheen, D. (2017). Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms. Nature Genetics, 49, 1113-1119. https://doi.org/10.1038/ng.3874

Howson, JMM, Zhao, W, Barnes, DR, Ho, WK, Young, R, Paul, DS, Waite, L, Freitag, DF, Fauman, EB, Salfati, EL, Sun, BB, Eicher, JD, Johnson, AD, Sheu, WH-H, Nielsen, SF, Lin, W-Y, Surendran, P, Malarstig, A, Wilk, JB, Tybjærg-Hansen, A, Rasmussen, KL, Kamstrup, PR, Deloukas, P, Erdmann, J, Kathiresan, S, Samani, NJ, Schunkert, H, Watkins, H, CARDIoGRAMplusC4D, Do, R, Rader, DJ, Johnson, JA, Hazen, SL, Quyyumi, AA, Spertus, JA, Pepine, CJ, Franceschini, N, Justice, AE, Reiner, AP, Buyske, S, Hindorff, LA, Carty, CL, North, KE, Kooperberg, C, Boerwinkle, E, Young, KL, Graff, M, Peters, U, Absher, D, Hsiung, CA, EPIC-CVD Consortium, Nordestgaard, BG, Assimes, TL, Danesh, J, Butterworth, AS & Saleheen, D 2017, 'Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms', Nature Genetics, bind 49, s. 1113-1119. https://doi.org/10.1038/ng.3874

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abstract = "Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.",

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T1 - Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

AU - Howson, Joanna M. M.

AU - Zhao, Wei

AU - Barnes, Daniel R

AU - Ho, Weang Kee

AU - Young, Robin

AU - Paul, Dirk S

AU - Waite, Lindsay

AU - Freitag, Daniel F

AU - Fauman, Eric B

AU - Salfati, Elias L

AU - Sun, Benjamin B

AU - Eicher, John D

AU - Johnson, Andrew D

AU - Sheu, Wayne H-H

AU - Nielsen, Sune F

AU - Lin, Wei-Yu

AU - Surendran, Praveen

AU - Malarstig, Anders

AU - Wilk, Jemma B

AU - Tybjærg-Hansen, Anne

AU - Rasmussen, Katrine L

AU - Kamstrup, Pia R

AU - Deloukas, Panos

AU - Erdmann, Jeanette

AU - Kathiresan, Sekar

AU - Samani, Nilesh J

AU - Schunkert, Heribert

AU - Watkins, Hugh

AU - CARDIoGRAMplusC4D

AU - Do, Ron

AU - Rader, Daniel J

AU - Johnson, Julie A

AU - Hazen, Stanley L

AU - Quyyumi, Arshed A

AU - Spertus, John A

AU - Pepine, Carl J

AU - Franceschini, Nora

AU - Justice, Anne E

AU - Reiner, Alex P

AU - Buyske, Steven

AU - Hindorff, Lucia A

AU - Carty, Cara L

AU - North, Kari E

AU - Kooperberg, Charles

AU - Boerwinkle, Eric

AU - Young, Kristin L

AU - Graff, Mariaelisa

AU - Peters, Ulrike

AU - Absher, Devin

AU - Hsiung, Chao A

AU - EPIC-CVD Consortium

AU - Nordestgaard, Børge G

AU - Assimes, Themistocles L

AU - Danesh, J

AU - Butterworth, Adam S

AU - Saleheen, D

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

AB - Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

KW - Journal Article

U2 - 10.1038/ng.3874

DO - 10.1038/ng.3874

M3 - Letter

C2 - 28530674

SN - 1061-4036

VL - 49

SP - 1113

EP - 1119

JO - Nature: New biology

JF - Nature: New biology

ER -

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Abstract

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