Purpose-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.Participants-Eight hundred and five AMD cases and 921 controls from The Eye Clinic of National Eye Institute, Age-Related Eye Diseases Study (AREDS), Blue Mountain Eye Study Cohort, and Minnesota Lions Eye Bank.Methods-DNA Samples were genotyped for polymorphisms of rs11200638 in HtrA1 promotor 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. †Corresponding to Chi-Chao Chan: Bldg. 10, Rm. 10N103, 10 Center Dr., NIH/NEI, Bethesda, MD 20892−1857, Phone: (301) 496 −0417, Fax: (301) 402−8664, Email: chanc@nei.nih.gov.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Précis:The genetic variant of HtrA1 confers increased risk for developing age-related macular degeneration (AMD). AMD risk increases further when the risk alleles from HtrA1 are combined with either CFH risk alleles or history of smoking.
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Materials and Methods
Patient PopulationEach participant provided written informed consent according to protocols approved by the Institutional Review/Ethics Boards of NEI Institutional Review Board, AREDS clinical site, University of Minnesota, or University of Sydney, respectively. This research followed the tenets of the Helsinki Declaration.The clinic-based NEI case-control study included diagnosed advanced AMD cases and controls from the greater Washington, D.C. area, who had been evaluated by AREDS ophthalmologists at the NEI. Venous whole blood (10 mL) was collected from NEI study subjects. Genomic DNA was extracted and isolated using a QIAamp DNA Blood Maxi kit (Qiagen, Valencia, CA). 7,14 In addition, DNA samples from the AREDS Genetic Repository were obtained and...
