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William K. Scott, Adam C. Naj, William H. Cade, Monique D. Courtenay, Stephen G. Schwartz, Jaclyn L. Kovach, Anita Agarwal, Gaofeng Wang, Jonathan L. Haines, Margaret A. Pericak-Vance; Genetic Factors In Non-smokers With Age-related Macular Degeneration Revealed Through Genome-wide Gene-environment Interaction Analysis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):83.
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Age-related macular degeneration (AMD) has a complex etiology comprising several genetic and environmental risk factors. This study aimed to identify novel factors associated with AMD via genome-wide gene-environment interaction analysis.
A genome-wide association study of 894 white AMD cases and 525 white controls was conducted using the Affymetrix 6.0 array. History of smoking at least 100 cigarettes was determined by a self-administered questionnaire. After quality control, 671,524 SNPs were analyzed. Logistic regression tested the association of SNP minor alleles (coded additively) with AMD, adjusting for age, sex, and smoking. Joint effects of SNPs and smoking were tested by including an interaction term in the model and conducting a likelihood ratio test against a model containing only age, sex, and smoking.
Genome-wide significant main effects were detected at three known loci: CFH(p=1.5x10-24), ARMS2(p=2.9x10-18), and CFB/C2(p=8.5x10-9). Joint effects analysis revealed no novel genome-wide significant loci. However, five novel joint effects generated p<1x10-4. Analysis stratified by smoking found effects largely restricted to non-smokers. Variation in LOC100130954 was positively associated with AMD in non-smokers (odds ratio (OR)=1.87, p=7.5x10-6) but not in smokers. Three loci were inversely associated with AMD in non-smokers (intergenic SNP rs4619440, between RGS9 and AXIN2: OR=0.29, p=8.1x10-6; EYS1: OR=0.52, p=1.26x10-5; DGKI: OR=0.54, p=1.34x10-5) but not in smokers. Intergenic SNP rs17073641 (between SERPINB8 and CDH7) was inversely associated in non-smokers (OR=0.56, p=9.8x10-6) and positively associated in smokers (OR=1.42, p=2.3x10-4).
These results suggest that smoking modifies the effect of some genetic polymorphisms on risk of AMD. The genes inversely associated with AMD in non-smokers are biologically plausible and important in retinal cell function; mutations in RGS9 and EYS1 cause bradyopsia and retinitis pigmentosa, respectively, and DGKI might be important in regulating phosphatidic acid production in retina. Additional studies to replicate and extend these findings are needed to establish the biological mechanisms underlying the interactions.
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