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European Heart Journal Advance Access published online on December 19, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn568
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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

Complement factor H Y402H decreases cardiovascular disease risk in patients with familial hypercholesterolaemia

Kristel C.M.C. Koeijvoets1, Simon P. Mooijaart2, Geesje M. Dallinga-Thie3, Joep C. Defesche3, Ewout W. Steyerberg4, Rudi G.J. Westendorp2, John J.P. Kastelein3, P. Martin van Hagen1 and Eric J.G. Sijbrands1,*

1 Department of Internal Medicine, Erasmus Medical Center, PO Box 2040, 3000 AC Rotterdam, The Netherlands
2 Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
3 Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
4 Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands

Received 28 April 2008; revised 19 September 2008; accepted 27 November 2008.

* Corresponding author. Tel: +31 107033283, Fax: +31 107033639, Email: e.sijbrands{at}erasmusmc.nl

Aims: Activation of the complement system seems an important link between inflammation and atherogenesis. The Y402H polymorphism of complement factor H (CFH) has been associated with cardiovascular events, but results are conflicting and possibly modified by age of onset of cardiovascular disease (CVD).

Methods and results: We determined whether or not the Y402H polymorphism influenced CVD risk in a multicentre cohort study involving 2016 unrelated patients with familial hypercholesterolaemia (FH), who have an extremely increased susceptibility to premature CVD. We identified 261 individuals who were homozygous for the polymorphism (CC genotype; 12.9%), 929 individuals who were heterozygous (TC genotype; 46.1%), and 826 individuals carried the wild-type (TT genotype; 41.0%). During 95 115 person years, 644 patients had a cardiovascular event. Carriers of the CC genotype had a decreased risk of CVD (hazard ratio 0.67, 95% confidence interval 0.51–0.87; P = 0.003) relative to the other genotype groups. This association was unaltered after adjustment for clinically relevant cardiovascular risk factors or age effects.

Conclusion: Among patients with severely increased risk of early onset CVD, the Y402H CFH variant was inversely associated with susceptibility to CVD. This suggests that CFH is a modifier gene of CVD.

Key Words: Complement factor H • Cardiovascular disease • Familial hypercholesterolemia • Polymorphism


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