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Circ Cardiovasc Genet. 2011 Dec;4(6):647-54. doi: 10.1161/CIRCGENETICS.111.960583. Epub 2011 Oct 9.

Post-genomic update on a classical candidate gene for coronary artery disease: ESR1.

Collaborators (186)

Kathiresan S, Reilly MP, Samani NJ, Schunkert H, Erdmann J, Assimes TL, Boerwinkle E, Erdmann J, Hall A, Hengstenberg C, Kathiresan S, Konig IR, Laaksonen R, McPherson R, Reilly MP, Samani NJ, Schunkert H, Thompson JR, Thorsteinsdottir U, Ziegler A, Absher D, Assimes TL, Fortmann S, Go A, Hlatky M, Iribarren C, Knowles J, Myers R, Quertermous T, Sidney S, Risch N, Tang H, Blankenberg S, Zeller T, Schillert A, Wild P, Ziegler A, Schnabel R, Sinning C, Lackner K, Tiret L, Nicaud V, Cambien F, Bickel C, Rupprecht HJ, Perret C, Proust C, Munzel T, Barbalic M, Bis J, Boerwinkle E, Der IY, Cupples LA, Dehghan A, Demissie-Banjaw S, Folsom A, Glazer N, Gudnason V, Harris T, Heckbert S, Levy D, Lumley T, Marciante K, Morrison A, O'Donnell CJ, Psaty BM, Rice K, Rotter JI, Siscovick DS, Smith N, Smith A, Taylor KD, van Duijn C, Volcik K, Whitteman J, Ramachandran V, Hofman A, Uitterlinden A, Gretarsdottir S, Gulcher JR, Holm H, Kong A, Stefansson K, Thorgeirsson G, Andersen K, Thorleifsson G, Thorsteinsdottir U, Erdmann J, Fischer M, Grosshennig A, Hengstenberg C, Konig IR, Lieb W, Linsel Nitschke P, Preuss M, Stark K, Schreiber S, Wichmann HE, Ziegler A, Schunkert H, Aherrahrou Z, Bruse P, Doering A, Erdmann J, Hengstenberg C, Illig T, Klopp N, Konig IR, Linsel-Nitschke P, Loley C, Medack A, Meisinger C, Meitinger T, Nahrstedt J, Peters A, Preuss M, Stark K, Wagner AK, Wichmann HE, Willenborg C, Ziegler A, Schunkert H, Bohm BO, Dobnig H, Grammer TB, Halperin E, Hoffmann MM, Kleber M, Laaksonen R, Marz W, Meinitzer A, Winkelmann BR, Pilz S, Renner W, Scharnagl H, Stojakovic T, Tomaschitz A, Winkler K, Voight BF, Musunuru K, Guiducci C, Burtt N, Gabriel SB, Siscovick DS, O'Donnell CJ, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Melander O, Altshuler D, Kathiresan S, Stewart AF, Chen L, Dandona S, Wells GA, Jarinova O, McPherson R, Roberts R, Reilly MP, Li M, Qu L, Wilensky R, Matthai W, Hakonarson HH, Devaney J, Burnett MS, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Knouff CW, Waterworth DM, Walker MC, Mooser V, Epstein SE, Rader DJ, Samani NJ, Thompson JR, Braund PS, Nelson CP, Wright BJ, Balmforth AJ, Ball SG, Hall AS.

Author information

Cardiovascular Epidemiology and Genetics Group, Institut Municipal d'Investigació Mèdica, Barcelona, Spain.



After age, sex is the most important risk factor for coronary artery disease (CAD). The mechanism through which women are protected from CAD is still largely unknown, but the observed sex difference suggests the involvement of the reproductive steroid hormone signaling system. Genetic association studies of the gene-encoding Estrogen Receptor α (ESR1) have shown conflicting results, although only a limited range of variation in the gene has been investigated.


We exploited information made available by advanced new methods and resources in complex disease genetics to revisit the question of ESR1's role in risk of CAD. We performed a meta-analysis of 14 genome-wide association studies (CARDIoGRAM discovery analysis, N=≈87,000) to search for population-wide and sex-specific associations between CAD risk and common genetic variants throughout the coding, noncoding, and flanking regions of ESR1. In addition to samples from the MIGen (N=≈6000), WTCCC (N=≈7400), and Framingham (N=≈3700) studies, we extended this search to a larger number of common and uncommon variants by imputation into a panel of haplotypes constructed using data from the 1000 Genomes Project. Despite the widespread expression of ERα in vascular tissues, we found no evidence for involvement of common or low-frequency genetic variation throughout the ESR1 gene in modifying risk of CAD, either in the general population or as a function of sex.


We suggest that future research on the genetic basis of sex-related differences in CAD risk should initially prioritize other genes in the reproductive steroid hormone biosynthesis system.

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