Association of the Complement Factor H Y402H Polymorphism With Cardiovascular Disease Is Dependent Upon Hypertension Status: The ARIC Study

Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA.
American Journal of Hypertension (Impact Factor: 2.85). 06/2008; 21(5):533-8. DOI: 10.1038/ajh.2007.81
Source: PubMed


Complement factor H (CFH) is a plasma protein that is essential in the regulation of the alternative complement pathway and has been implicated as taking part in complement inhibition in atherogenesis. We evaluated the association of the Y402H polymorphism with incident coronary heart disease (CHD), incident ischemic stroke, and carotid artery wall thickness (intima-media thickness (IMT)) in the Atherosclerosis Risk in Communities (ARIC) cohort.
Incident ischemic stroke and CHD were identified through annual telephone calls and hospital and death certificate surveillance. Carotid IMT was measured by means of high-resolution B-mode ultrasound. Four hundred eighty-three validated ischemic stroke and 1,544 CHD events were identified. Because of allele frequency differences between whites and African Americans, analyses were performed separately according to the racial group.
The 402HH homozygous genotype was a significant predictor of incident ischemic stroke in whites (hazard rate ratio (HRR) 1.47, 95% confidence interval (CI) 1.05-2.05). Significant interaction effects between genotype and hypertension were observed for CHD in whites and for cIMT in whites and African Americans. In further analyses of incident CHD, genotypes carrying the 402H allele were a significant predictor of incident CHD in whites who had hypertension (402YH: HRR 1.19, 95% CI 1.01-1.40; 402HH: HRR 1.28, 95% CI 1.04-1.57). The 402H allele was also associated with higher cIMT measures for whites in the overall cohort, and for whites with hypertension.
The CFH 402H allele was associated with an increased risk for incident CHD and ischemic stroke in whites, with the strength and significance of the association dependent upon hypertension status.

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    • "Boiocchi et al. [54] demonstrated that complement receptor I (CR1) gene polymorphisms may be involved in the predisposition to the development of the disease. More interestingly, the same CFH Y402H polymorphism that is associated with the risk of AMD, is found to be associated with increased incidence of atherosclerosis in hypertensive white individuals [55]. "
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    Inflammation & Allergy - Drug Targets (Formerly ?Current Drug Targets - Inflammation & Allergy) 07/2014; 13(3). DOI:10.2174/1871528113666140522112003
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    • "Some studies have also shown an association between the rs1061170 (Y402H) polymorphism and the incidence of myocardial infarction and coronary artery disease [26], [27]. Indeed several clinical trials using complement inhibitors in both AMD and atherosclerosis are currently under way [24]. "
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    ABSTRACT: A common polymorphism in the complement factor H gene (rs1061170, Y402H) is associated with a high risk of age-related macular degeneration (AMD). In the present study we hypothesized that healthy young subjects homozygous for the high-risk haplotype (CC) show abnormal choroidal blood flow (ChBF) regulation decades before potentially developing the disease. A total of 100 healthy young subjects were included in the present study, of which 4 subjects were excluded due to problems with genotyping or blood flow measurements. ChBF was measured continuously using laser Doppler flowmetry while the subjects performed isometric exercise (squatting) for 6 minutes. The increase in ChBF was less pronounced than the response in ocular perfusion pressure (OPP), indicating for some degree of choroidal blood flow regulation. Eighteen subjects were homozygous for C, 47 subjects were homozygous for T and 31 subjects were heterozygous (CT). The increase in OPP during isometric exercise was not different between groups. By contrast the increase in ChBF was more pronounced in subjects homozygous for the high risk C allele (p = 0.041). This was also evident from the pressure/flow relationship, where the increase in ChBF in homozygous C carriers started at lower OPPs as compared to the other groups. Our data indicate that the regulation of ChBF is abnormal in rs1061170 CC carriers. So far this polymorphism has been linked to age related macular degeneration (AMD) mainly via inflammatory pathways associated with the complement system dysfunction. Our results indicate that it could also be related to vascular factors that have been implicated in AMD pathogenesis.
    PLoS ONE 04/2013; 8(4):e60424. DOI:10.1371/journal.pone.0060424 · 3.23 Impact Factor
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    • "According to the initial report of Kardys et al. (2006) a positive association between Y402H and the incidence of myocardial infarction in the Rotterdam Study was observed. Following this report, data from the large population-based study of Volcik et al. (2008) showed a direct link between the Y402H polymorphism and the incidence of coronary artery disease, particularly in white hypertensive individuals . In addition, a strong positive correlation between the unfavourable CFH variant and higher carotid artery wall thickness in white patients was observed. "
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    ABSTRACT: Age-related macular degeneration (AMD) shares several pathological and epidemiological similarities with systemic atherosclerosis (AS). First, an association between AS and AMD is apparent from the analyses of the histological and biochemical structure of atherosclerotic plaques in the vascular walls and retinal drusen, the hallmark of AMD. Second, there is considerable evidence implicating endothelial dysfunction in the pathogenesis of both disorders, and cellular oxidative stress appears to be a common denominator underlying this process. Moreover, there are observations that the complement system (CS) triggering inflammatory response contributes to the onset and advancement of both diseases. The CS plays a role in the generation of drusen and neovascularization in AMD as well as in vascular endothelium activation, cell damage and ultimately atherosclerotic plaque formation in the course of systemic arteriosclerosis. It is widely recognized that both AMD and AS are not only related to local stimulation of the CS, but also result in its systemic activation. In addition, a specific Y402H polymorphism of the complement inhibitor factor H has been found to be associated with the incidence of both AMD and AS. Here, we propose a linking hypothesis between CS activation, endothelial dysfunction and the pathogenesis of two common and age-related pathological processes, AS and AMD. We also discuss the potential therapeutic value of pharmacological modulation of CS activation in these disorders.
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