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The HtrA1 promoter polymorphism, smoking, and age-related macular degeneration in multiple case-control samples.

ABSTRACT: OBJECTIVE:To assess the association and combined effect on the risk of age-related macular degeneration (AMD) by the HtrA1 and complement factor H (CFH) polymorphisms, smoking, and serum cholesterol. DESIGN:Clinic-based and population-based case control study. PARTICIPANTS:A total of 805 AMD cases and 921 controls from The Eye Clinic of National Eye Institute, Age-Related Eye Diseases Study, Blue Mountain Eye Study Cohort, and Minnesota Lions Eye Bank. METHODS:DNA samples were genotyped for polymorphisms of rs11200638 in HtrA1 promoter and rs380390 in CFH. HtrA1 protein in ocular tissue was measured. Interactions of the HtrA1 risk allele with the CFH risk variant, smoking status, and cholesterol were assessed. MAIN OUTCOME MEASURES:AMD was evaluated by retinal specialists, and AMD subtypes (geographic atrophy and neovascularization) were determined. RESULTS:Strong associations of the HtrA1 risk allele (A) with AMD were present in all sample sets. A similar magnitude of association was observed for central geographic atrophy and neovascular AMD. The combination of the HtrA1 and CFH risk alleles increased AMD susceptibility, as did the combination of the HtrA1 risk allele with smoking. No combined effect of HtrA1 risk allele and cholesterol level was found. Enhanced expression of HtrA1 protein was detected in retina with AMD. CONCLUSIONS:Findings from multiple samples support an AMD genetic variant harbored within HtrA1. The risk of advanced AMD increased when the presence of risk alleles from HtrA1 was combined with either CFH risk alleles or history of smoking.

SUBMITTER: Tuo J

PROVIDER: S-EPMC2610681 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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The HtrA1 promoter polymorphism, smoking, and age-related macular degeneration in multiple case-control samples.

Tuo Jingsheng J Ross Robert J RJ Reed George F GF Yan Qing Q Wang Jie Jin JJ Bojanowski Christine M CM Chew Emily Y EY Feng Xiao X Olsen Timothy W TW Ferris Frederick L FL Mitchell Paul P Chan Chi-Chao CC

Ophthalmology 20080821 11

<h4>Objective</h4>To assess the association and combined effect on the risk of age-related macular degeneration (AMD) by the HtrA1 and complement factor H (CFH) polymorphisms, smoking, and serum cholesterol.<h4>Design</h4>Clinic-based and population-based case control study.<h4>Participants</h4>A total of 805 AMD cases and 921 controls from The Eye Clinic of National Eye Institute, Age-Related Eye Diseases Study, Blue Mountain Eye Study Cohort, and Minnesota Lions Eye Bank.<h4>Methods</h4>DNA sa ...[more]

PMID: 18718667

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Project description:BACKGROUND: Age-related macular degeneration (AMD) is the major cause of blindness in the elderly. Those with the neovascular end-stage of disease have irreversible loss of central vision. AMD is a complex disorder in which genetic and environmental factors play a role. Polymorphisms in the complement factor H (CFH) gene, LOC387715, and the HTRA1 promoter are strongly associated with AMD. Smoking also contributes to the etiology. We aimed to provide a model of disease risk based on these factors. METHODS AND FINDINGS: We genotyped polymorphisms in CFH and LOC387715/HTRA1 in a case-control study of 401 patients with neovascular AMD and 266 controls without signs of disease, and used the data to produce genetic risk scores for the European-descent population based on haplotypes at these loci and smoking history. CFH and LOC387715/HTRA1 haplotypes and smoking status exerted large effects on AMD susceptibility, enabling risk scores to be generated with appropriate weighting of these three factors. Five common haplotypes of CFH conferred a range of odds ratios (ORs) per copy from 1 to 4.17. Most of the effect of LOC387715/HTRA1 was mediated through one detrimental haplotype (carriage of one copy: OR 2.83; 95% confidence interval [CI] 1.91-4.20), with homozygotes being at particularly high risk (OR 32.83; 95% CI 12.53-86.07). Patients with neovascular macular degeneration had considerably higher scores than those without disease, and risk of blinding AMD rose to 15.5% in the tenth of the population with highest predicted risk. CONCLUSIONS: An individual's risk of developing AMD in old age can be predicted by combining haplotype data with smoking status. Until there is effective treatment for AMD, encouragement to avoid smoking in those at high genetic risk may be the best option. We estimate that total absence of smoking would have reduced the prevalence of severe AMD by 33%. Unless smoking habits change or preventative treatment becomes available, the prevalence of AMD will rise as a consequence of the increasing longevity of the population.

Dataset Information

The HtrA1 promoter polymorphism, smoking, and age-related macular degeneration in multiple case-control samples.

Publications

The HtrA1 promoter polymorphism, smoking, and age-related macular degeneration in multiple case-control samples.

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