Independent Effects of CFH Genotype and Smoking History, but No Effect of APOE and ELOVL4 Genotype, on Risk for Neovascular Age–Related Macular Degeneration

Abstract

Purpose: : To examine if the T1277C (Tyr402His) allele in the complement factor H gene (CFH), the E2, E3 and E4 alleles of the apolipoprotein E gene (APOE) gene, and the A895G (Met299Val) allele in the elongation of very long chain fatty acids–like 4 gene (ELOVL4) confer risk independently and/or additively for neovascular age–related macular degeneration (AMD) when controlling for smoking exposure.

Methods: : We ascertained 140 sibpairs (103 families) where at least one member (index patient; mean age = 72.4) had neovascular AMD and another member (unaffected sibling; mean age = 74.3) had normal maculae and was past the age at which the affected sibling was diagnosed with neovasular AMD. Complete epidemiological information was collected for each sibship. Disease status for all participants was confirmed by grading of fundus photographs by two or more invesitigators or a home visit (n=6). CFH and ELOVL4 genotyping were performed by direct sequencing of exons 9 and 4 respectively. APOE genotyping was performed by separating HhaI digested fragments on an agarose gel and/or direct sequencing of exon 4. Conditional logistic regression was used to build a multivariate model that included risk factors from the univariate model associated with neovascular AMD at the p < 0.1 level of significance.

Results: : There was an association between the CFH T1277C polymorphism and neovascular AMD, but statistically significant elevation of disease risk was only in those individuals who were CC homozygotes compared to CT heterozygotes or TT homozygotes (p < 0.0001; odds ratio = 27.4). Significant deviation from Hardy–Weinberg equilibrium for the CC genotype (p < 0.001) was observed in affected siblings only. No significant association was observed between neovascular AMD and any of the APOE genotypes or the ELOVL4 (Met299Val) genotype. No significant interactions were found between CFH genotype and smoking, or between APOE genotype and smoking, nor were significant interactions found between CFH, ELOVL4, and/or APOE genotypes.

Conclusions: : Our results suggest that CFH CC genotype and smoking >10 pack years are independent risk factors for neovascular AMD. APOE and ELOVL4 genotypes do not modify risk. Heavy smokers (≥ 10 pack years) who also have the CFH CC genotype have a 69–fold increase in disease risk.

Keywords: age-related macular degeneration • neovascularization • genetics