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Y. Yu, R. Reynolds, J. Seddon; Assessment of Non-Complement-Related Genes Including Novel HDL Loci and Drusen Phenotypes in Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1280.
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Large, confluent or soft drusen usually precede advanced stages of age-related macular degeneration (AMD). In addition to genetic variants in the complement pathway, variants in other pathways are associated with AMD. Investigation of the roles of these genes in drusen accumulation may lead to prevention and treatments of this disease in its early stages.
Phenotypes for 3,762 subjects in the Age-Related Eye Disease Study were evaluated. Subjects were recategorized into 5 grades based on the latest ocular examination and fundus photography of the worst eye as 1-no drusen or small drusen (<63nm, n=269); 2-intermediate drusen (63-124nm, n=981); 3- large, soft drusen(>=125nm, n=1205); 4- central and non-central geographic atrophy (n=305); 5-neovascular disease (n=1002). DNA samples of 3,189 participants were obtained and genotyped for SNPs in the CFH, C2, C3, CFB, CFI, APOE, LOC387715, and novel LIPC, CETP, ABCA1 genes/regions. Associations between genetic variants and AMD or drusen phenotypes were tested using logistic regression.
Known genes in the complement pathway were confirmed to be associated with AMD (advanced grades 4, 5), but were not as strongly associated with drusen phenotypes (grade 2, 3) compared to controls (grade 1). After adjusting for age, gender, education, smoking, BMI, antioxidant treatment and known genetic factors, the minor allele T of both LIPC (p=0.011) and ABCA1 (p=0.0002) were significantly associated with a reduced risk of AMD, and with a reduced risk of drusen phenotypes (LIPC [p=0.012], ABCA1 [p=0.0037]). Compared with the respective CC genotypes, the TT genotype of LIPC (odds ratio [OR] =0.53 [0.33, 0.87]) and the TT genotype of ABCA1 (OR=0.5 [0.29, 0.86]) significantly reduced risk of drusen phenotypes (grades 2, 3). The protective effect was significant for both intermediate (grade 2) and large drusen (grade 3). The T allele of LOC387715 increased risk of large drusen (OR=1.8[1.3, 2.4]), but was not significant for intermediate size drusen.
Two genes in the lipid pathway, LIPC and ABCA1, were associated with drusen phenotypes, independent of other genetic and environmental factors. Results suggest that these lipid genes may play important roles in drusen accumulation in early or intermediate stages of AMD.
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