Genetic Factors in Nonsmokers with Age-Related Macular Degeneration Revealed Through Genome-Wide Gene-Environment Interaction Analysis

Relatively little is known about the interaction between genes and environment in the complex etiology of age-related macular degeneration (AMD). This study aimed to identify novel factors associated with AMD by analyzing gene-smoking interactions in a genome-wide association study of 1207 AMD cases and 686 controls of Caucasian background with genotype data on 668,238 single nucleotide polymorphisms (SNPs) after quality control. Participants' history of smoking at least 100 cigarettes lifetime was determined by a self-administered questionnaire. SNP associations modeled the effect of the minor allele additively on AMD using logistic regression, with adjustment for age, sex, and ever/never smoking. Joint effects of SNPs and smoking were examined comparing a null model containing only age, sex, and smoking against an extended model including genotypic and interaction terms. Genome-wide significant main effects were detected at three known AMD loci: CFH (P= 7.51x1030), ARMS2 (P= 1.94x1023), and RDBP/CFB/C2 (P= 4.37x1010), while joint effects analysis revealed three genomic regions with P< 105. Analyses stratified by smoking found genetic associations largely restricted to nonsmokers, with one notable exception: the chromosome 18q22.1 intergenic SNP rs17073641 (between SERPINB8 and CDH7), more strongly associated in nonsmokers (OR= 0.57, P= 2.73 x 105), with an inverse association among smokers (OR= 1.42, P= 0.00228), suggesting that smoking modifies the effect of some genetic polymorphisms on AMD risk.