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European Heart Journal Advance Access published online on July 3, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn303
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Replication study of 10 genetic polymorphisms associated with coronary heart disease in a specific high-risk population with familial hypercholesterolemia

Jeroen B. van der Net1,2, Daniëlla M. Oosterveer1, Jorie Versmissen1, Joep C. Defesche3, Mojgan Yazdanpanah1, Bradley E. Aouizerat4,5, Ewout W. Steyerberg2, Mary J. Malloy6,7,8, Clive R. Pullinger4,6, John J.P. Kastelein3, John P. Kane6,7,9 and Eric J.G. Sijbrands1,*

1 Department of Internal Medicine, Erasmus MC—University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, The Netherlands
2 Department of Public Health, Erasmus MC—University Medical Center Rotterdam, Rotterdam, The Netherlands
3 Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
4 Department of Physiological Nursing, University of California, San Francisco, CA, USA
5 Institute for Human Genetics, University of California, San Francisco, CA, USA
6 Cardiovascular Research Institute, University of California, San Francisco, CA, USA
7 Department of Medicine, University of California, San Francisco, CA, USA
8 Department of Pediatrics, University of California, San Francisco, CA, USA
9 Department Biochemistry and Biophysics, University of California, San Francisco, CA, USA

Received 14 April 2008; revised 9 June 2008; accepted 12 June 2008.

* Corresponding author. Tel: +31 10 7033283, Fax: +31 10 7033639, Email: e.sijbrands{at}erasmusmc.nl

Aims: Recent large association studies have revealed associations between genetic polymorphisms and myocardial infarction and coronary heart disease (CHD). We performed a replication study of 10 polymorphisms and CHD in a population with familial hypercholesterolemia (FH), individuals at extreme risk of CHD.

Methods and results: We genotyped 10 polymorphisms in 2145 FH patients and studied the association between these polymorphisms and CHD in Cox proportional hazards models. We confirmed the associations between four polymorphisms and CHD, the rs1151640 polymorphism in the olfactory receptor family 13 subfamily G member 1 (OR13G1) gene (HR 1.14, 95% CI 1.01–1.28, P = 0.03), the rs11881940 polymorphism in the heterogeneous nuclear ribonucleoprotein U-like 1 (HNRPUL1) gene (HR 1.27, 95% CI 1.07–1.51, P = 0.007), the rs3746731 polymorphism in the complement component 1 q subcomponent receptor 1 (CD93) gene (HR 1.26, 95% CI 1.06–1.49, P = 0.01), and the rs10757274 polymorphism near the cyclin-dependent kinase N2A and N2B (CDKN2A and CDKN2B) genes (HR 1.39, 95% CI 1.15–1.69, P < 0.001).

Conclusion: We confirmed previously found associations between four polymorphisms and CHD, but refuted associations for six other polymorphisms in our large FH population. These findings stress the importance of replication before genetic information can be implemented in the prediction of CHD.

Key Words: Coronary heart disease • Familial hypercholesterolemia • Genetics • Polymorphism • Replication


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