The HtrA1 Promoter Polymorphism, Smoking, and Age-related Macular Degeneration in Multiple Case-control Samples
Received 23 January 2008; received in revised form 7 May 2008; accepted 13 May 2008. published online 21 August 2008.
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.
Financial Disclosure(s)
The authors have no proprietary or commercial interest in any materials discussed in this article.
Available online: August 21, 2008.
1Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland
2Division of Epidemiology and Clinical Research, National Eye Institute, National Institutes of Health, Bethesda, Maryland
3Center for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, Westmead, Australia
4Department of Ophthalmology, University of Minnesota, Minneapolis, Minnesota
Correspondence: Chi-Chao Chan, MD, Building 10, Room 10N103, 10 Center Drive, NIH/NEI, Bethesda, MD 20892-1857
Manuscript no. 2008-117.
Financial Disclosure(s): No conflicting relationship exists for any author.
The sponsor or funding organization had no role in the design or conduct of this research.
Research funded by National Eye Institute Intramural Research Program, Australian National Health and Medical Research Council, National Institutes of Health/National Institute of Aging AG025392 (TWO), an unrestricted grant from Research to Prevent Blindness (TWO), and Minnesota Lions Eye Bank.
ABSTRACT