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European Heart Journal Advance Access originally published online on April 14, 2008
European Heart Journal 2008 29(11):1370-1376; doi:10.1093/eurheartj/ehn154
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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

Gene-load score of the renin–angiotensin–aldosterone system is associated with coronary heart disease in familial hypercholesterolaemia

Jeroen B. van der Net1,2, Jeroen van Etten1,2, Mojgan Yazdanpanah1, Geesje M. Dallinga-Thie3, John J.P. Kastelein3, Joep C. Defesche3, Richard P. Koopmans4, Ewout W. Steyerberg2 and Eric J.G. Sijbrands1,*

1 Department of Internal Medicine—D435, Erasmus MC, University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands
2 Department of Public Health, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
3 Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
4 Department of Internal Medicine, Academic Hospital Maastricht, Maastricht, The Netherlands

Received 3 October 2007; revised 18 March 2008; accepted 20 March 2008; online publish-ahead-of-print 14 April 2008.

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

Aims: Familial hypercholesterolaemia (FH) is characterized by premature coronary heart disease (CHD). However, the incidence of CHD varies considerably among FH patients. Genetic variation in the renin–angiotensin–aldosterone system (RAAS) and the adrenalin/noradrenalin system may be of importance in determining the CHD risk in FH, because of their involvement in CHD. We investigated the association between CHD risk and combined genetic variation in the RAAS and adrenalin/noradrenalin system.

Methods and results: In 2190 FH patients, we genotyped six RAAS polymorphisms and five adrenalin/noradrenalin polymorphisms. For each patient, we calculated two gene-load scores by counting the number of risk genotypes within each pathway. Four of the six RAAS polymorphisms and none of the polymorphisms in the adrenalin/noradrenalin system were significantly associated with CHD (P < 0.05). The RAAS gene-load score was significantly associated with CHD (Plinear trend < 0.001): in patients with a gene-load score of 5 or 6, the CHD risk was 2.3 times as high as in patients with a score of 0 or 1. The gene-load score of the adrenalin/noradrenalin system was not associated with CHD.

Conclusion: Genetic variation in the RAAS contributes gene-dose dependently to CHD risk in patients with FH, whereas genetic variation in the adrenalin/noradrenalin system is not associated with CHD.

Key Words: Coronary heart disease • Familial hypercholesterolaemia • Genetics • Polymorphism • Renin–angiotensin–aldosterone system • Adrenalin/noradrenalin system


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