Cigarette Smoking Strongly Modifies the Effect of LOC387715 on yhe Risk of Age–Related Macular Degeneration

Abstract

Purpose: : We used iterative association mapping to identify a susceptibility gene for age–related macular degeneration (AMD) on chromosome 10q26, which is one of the most consistently implicated linkage regions for this disorder.

Methods: : We employed linkage analysis methods, followed by family–based and case–control association analysis using two independent datasets. Additional analyses were performed to incorporate the two most important known AMD risk factors, smoking and the Y402H variant of the complement factor H (CFH) gene.

Results: : Our results strongly implicate a coding change (Ala69Ser) in the LOC387715 gene as the second major AMD susceptibility allele, confirming earlier suggestions. Its effect on AMD is statistically independent of CFH and of similar magnitude to Y402H. We estimate that LOC387715 and CFH together account for 65% of the population–attributable risk (PAR) of AMD. Interestingly, the overall effect of the LOC387715 coding variant is driven primarily by a strong association in smokers, as we observed significant evidence for a statistical interaction of the LOC387715 variant with a history of cigarette smoking. This gene–environment interaction is supported by statistically independent family–based and case–control analysis methods. We estimate that LOC287715 and smoking together explain 34% of the PAR of AMD.

Conclusions: : For the first time, we demonstrate that a genetic susceptibility coupled with a modifiable lifestyle factor such as cigarette smoking confers a significantly higher risk of AMD than either factor alone.

Keywords: age-related macular degeneration • gene mapping • gene modifiers