Human Molecular Genetics Advance Access originally published online on June 1, 2005
Human Molecular Genetics 2005 14(14):1991-2002; doi:10.1093/hmg/ddi204
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Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy
1Department of Health Promotion and Development, School of Nursing, 2Department of Human Genetics, 3Department of Biostatistics, Graduate School of Public Health and 4Department of Ophthalmology, School of Medicine, University of Pittsburgh, Pittsburgh, USA
* To whom correspondence should be addressed at: Departments of Ophthalmology and Human Genetics, School of Medicine and Graduate School of Public Health, The Eye and Ear Institute Building, 203 Lothrop Street, University of Pittsburgh, Pittsburgh, PA 15213, USA. Tel: +1 4126477726; Fax: +1 4126475880; Email: gorinmb{at}upmc.edu
Received March 11, 2005; Revised May 12, 2005; Accepted May 23, 2005
Age-related maculopathy (ARM) is a leading cause of visual impairment in elderly Americans and is a complex genetic disorder. Hypothesized pathways for the etiology of ARM include cholesterol and lipoprotein metabolism and transport, extracellular matrix integrity, oxidative stress and inflammatory/immunologic processes. This study investigates 21 polymorphisms within 15 candidate genes whose products function within these pathways by performing family and case–control genetic association studies using clearly affected familial cases (n=338 families, 796 individuals), clearly affected, unrelated sporadic cases (n=196) and clearly unaffected, unrelated controls (n=120). Two genes demonstrated significant association with ARM status. A Met299Val variant in the elongation of very long chain fatty acids-like 4 (ELOVL4) gene was significantly associated with ARM in the case–control allele (P=0.001), case–control genotype (P=0.001) and case–control family (P<0.0001) tests. A Tyr402His variant in exon 9 in the complement factor H (CFH) gene was also significantly associated with ARM in the case–control allele (P<0.0001), case–control genotype (P<0.0001) and case–control family (P<0.0001) tests. All of these results remain significant after adjusting for false discovery rates to control for the impact of multiple testing. In addition, the CFH variant appears to play a role in exudative and atrophic disease, whereas the ELOVL4 variant may play a greater role in exudative disease in our population. These results support a potential role for multiple pathways in the etiology of ARM, including pathways involved with fatty acid biosynthesis and the complement system.
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