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CLINICAL RESEARCH: ACUTE MYOCARDIAL INFARCTION

A Common Polymorphism in the Complement Factor H Gene Is Associated With Increased Risk of Myocardial Infarction

The Rotterdam Study

Isabella Kardys, MD^_*, Caroline C.W. Klaver, MD, PhD^_*,, Dominiek D.G. Despriet, MD^_*,, Arthur A.B. Bergen, PhD^¶,||, André G. Uitterlinden, PhD, Albert Hofman, MD, PhD^_*, Ben A. Oostra, PhD, Cornelia M. Van Duijn, PhD^_*, Paulus T.V.M. de Jong, MD, PhD^_*,¶,# and Jacqueline C.M. Witteman, PhD^_*,_*

^_* Department of Epidemiology & Biostatistics, Erasmus Medical Center, Rotterdam, the Netherlands
Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands
^¶ Department of Ophthalmogenetics, Netherlands Ophthalmic Research Institute, Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands
^|| Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands
^# Department of Ophthalmology, Academic Medical Center, Amsterdam, the Netherlands

Manuscript received September 15, 2005; revised manuscript received November 17, 2005, accepted November 28, 2005.

^_* Reprint requests and correspondence: Dr. Jacqueline C. M. Witteman, Erasmus Medical Center, Department of Epidemiology & Biostatistics, P.O. Box 1738, 3000 DR Rotterdam, the Netherlands (Email: j.witteman{at}erasmusmc.nl).

OBJECTIVES: This study was designed to investigate the association between a common polymorphism (Tyr402His, rs1061170) in the complement factor H (CFH) gene and risk of coronary heart disease.

BACKGROUND: The evidence that inflammation is an important mechanism in atherogenesis is growing. C-reactive protein (CRP), complement factors, and complement regulatory factors have all been linked to coronary heart disease. The CFH gene is an important regulator of the alternative complement cascade. We investigated its association with coronary heart disease.

METHODS: The study was embedded in the Rotterdam Study, a prospective population-based study among men and women aged 55 years and over. A total of 5,520 participants without history of coronary heart disease was genotyped for the Tyr402His polymorphism of the CFH gene. Cox proportional hazards analysis was used to determine risk of myocardial infarction for Tyr402His genotypes.

RESULTS: Mean age among participants was 69.5 years (SD 9.1 years). The overall frequency of the His allele was 36%; genotype frequencies were 41%, 45%, and 14% for TyrTyr, TyrHis, and HisHis, respectively. During a mean follow-up period of 8.4 years, 226 myocardial infarctions occurred. After adjustment for age, gender, established cardiovascular risk factors, and CRP level, HisHis homozygotes had a hazard ratio of 1.77 (95% confidence interval 1.23 to 2.55) for myocardial infarction. Total cholesterol level, diabetes mellitus, and smoking modified the effect. The Tyr402His polymorphism was not associated with established cardiovascular risk factors or CRP level.

CONCLUSIONS: Our data suggest that the CFH gene determines susceptibility to myocardial infarction. This finding underscores the importance of the alternative complement system in cardiovascular disease.

Abbreviations and Acronyms   CABG = coronary artery bypass grafting   CFH = complement inhibitor factor H   CI = confidence interval   CRP = C-reactive protein   GP = general practitioner   HDL = high-density lipoprotein   PTCA = percutaneous transluminal coronary angioplasty

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