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

Abstract

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide1,2. Although 58 genomic regions have been associated with CAD thus far3,4,5,6,7,8,9, most of the heritability is unexplained9, 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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Figure 1: Schematic of the study design.
Figure 2: Plot showing the association of 79,000 variants with CAD (−log10P) in up to 88,192 cases and 162,544 controls from the all-ancestry fixed-effects meta-analysis.

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Acknowledgements

J.D. is a British Heart Foundation Professor, European Research Council Senior Investigator and NIHR Senior Investigator. J.D.E. and A.D.J. were supported by NHLBI Intramural Research Program funds. N.F. is supported by R21HL123677-01 and R56 DK104806-01A1. N.S. is supported by the British Heart Foundation and is an NIHR Senior Investigator. T.L.A. is supported by NIH career development award K23DK088942. This work was funded by the UK Medical Research Council (G0800270), the British Heart Foundation (SP/09/002), the UK National Institute for Health Research Cambridge Biomedical Research Centre, the European Research Council (268834), European Commission Framework Programme 7 (HEALTH-F2-2012-279233) and Pfizer. The eQTL database construction was supported by NHLBI intramural funds. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the US Department of Health and Human Services.

A full list of acknowledgments for the studies contributing to this work is provided in the Supplementary Note.

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Contributions

Central analysis group: J.M.M.H., W.Z., D.R.B., T.L.A., A.S.B., D.S. Writing group: J.M.M.H., W.Z., D.R.B., D.S.P., T.L.A., A.S.B., J.D. Study analysts: J.M.M.H., W.-K.H., R.Y., L.L.W., E.L.S., S.F.N., W.-Y.L., R.D., N.F., A.J., A.P.R., C.L.C., K.Y., M.G., D.A., C.A.H., Y.-H.C., X.G., T.L.A. Study PIs and co-PIs: W.H.-H.S., P.D., J.E., S.K., N.J.S., H.S., H.W., D.J.R., J.A.J., S.L.H., A.A.Q., J.S., C.J.P., K.E.N., C.K., U.P., C.A.H., W.-J.L., I.-T.L., R.-H.C., Y.-J.H., J.I.R., J.-M.J.J., T.Q., T.-D.W., D.S.A., A.a.S.M., E.D.A., R.C., Y.-D.I.C., B.G.N., T.L.A., J.D., A.S.B., D.S., A.R., P.F. Bioinformatics, eQTL, pQTL and pathway analyses: D.S.P., W.Z., D.R.B., D.F.F., T.L.A., E.B.F., A.M., J.B.W., E.L.S., B.B.S., A.S.B., J.D.E., A.D.J., P.S., T.L.A., J.M.M.H. Genotyping: S.B., L.A.H., C.K., E.B., U.P., D.A., K.D.T., T.Q., T.L.A. Phenotyping: W.H.H.S., A.T.-H., K.L.R., P.R.K., K.E.N., C.K., C.A.H., W.-J.L., I.-T.L., R.-H.C., Y.-J.H., J.-M.J.J., T.Q., Y.-D.I.C.

Corresponding author

Correspondence to Joanna M M Howson.

Ethics declarations

Competing interests

A.M., E.B.F. and J.B.W. are full-time employees of Pfizer. D.F.F. is now a full-time employee of Bayer AG, Germany. J.D. reports personal fees and non-financial support from Merck Sharp & Dohme UK Atherosclerosis, the Novartis Cardiovascular & Metabolic Advisory Board, the Pfizer Population Research Advisory Panel and the Sanofi Advisory Board.

Additional information

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8, Supplementary Tables 1–4, 6 and 7, and Supplementary Note (PDF 7944 kb)

Supplementary Table 5

Results of meta-analyses across the studies (including all samples) with de novo genotyping at the new CAD-associated SNPs reported in Supplementary Table 4. (XLSX 17 kb)

Supplementary Table 8

Ingenuity Pathway Analysis results. (XLSX 19 kb)

Supplementary Table 9

Coordinates for the genomics regions used for each new CAD locus. (XLSX 9 kb)

Supplementary Table 10

eQTL lookups of the 15 new CAD-associated regions. (XLSX 16 kb)

Supplementary Table 11

HaploReg enrichment analyses of H3K27ac enhancer marks. (XLSX 9 kb)

Supplementary Table 12

Association results for established CAD loci. (XLSX 30 kb)

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Howson, J., Zhao, W., Barnes, D. et al. Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms. Nat Genet 49, 1113–1119 (2017). https://doi.org/10.1038/ng.3874

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