William Cade

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 = 7.51×10−30), ARMS2 (P = 1.94×10−23), and RDBP/CFB/C2 (P = 4.37×10−10), while joint effects analysis revealed three genomic regions with P < 10−5. 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 × 10−5), 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.

The ARMS2 A69S variant and bilateral advanced age-related macular degeneration.

Purpose: To identify genetic associations between specific risk genes and bilateral advanced age-related macular degeneration (AMD) in a retrospective, observational case series of 1,003 patients: 173 patients with geographic atrophy in at least 1 eye and 830 patients with choroidal neovascularization in at least 1 eye. Methods: Patients underwent clinical examination and fundus photography. The images were subsequently graded using a modified grading system adapted from the Age-Related Eye Disease Study. Genetic analysis was performed to identify genotypes at 4 AMD-associated variants (ARMS2 A69S, CFH Y402H, C3 R102G, and CFB R32Q) in these patients. Results: There were no statistically significant relationships between clinical findings and genotypes at CFH, C3, and CFB. The genotype at ARMS2 correlated with bilateral advanced AMD using a variety of comparisons: unilateral geographic atrophy versus bilateral geographic atrophy (P = 0.08), unilateral choroidal neovascularization versus bilateral choroidal neovascularization (P = 9.0 × 10−8), and unilateral late AMD versus bilateral late AMD (P = 5.9 × 10−8). Conclusion: In this series, in patients with geographic atrophy or choroidal neovascularization in at least 1 eye, the ARMS2 A69S substitution strongly associated with geographic atrophy or choroidal neovascularization in the fellow eye. The ARMS2 A69S substitution may serve as a marker for bilateral advanced AMD.

Set-Based Joint Test of Interaction Between SNPs in the VEGF Pathway and Exogenous Estrogen Finds Association With Age-Related Macular Degeneration

Purpose:Age-Related Macular Degeneration (AMD) is the leading cause of irreversible visual loss in developed countries. Its etiology includes genetic and environmental factors. Although VEGFA variants are associated with AMD, the joint action of variants within the VEGF pathway and their interaction with non-genetic factors has not been investigated. Methods:Affymetrix 6.0 chipsets were used to genotype 668,238 SNPs in 1,207 AMD cases and 686 controls. Environmental exposures were collected by questionnaire. A set-based test was conducted using the chi-square statistic at each SNP derived from Krafts 2df joint test. Pathway and gene-based test statistics were calculated as the mean of all independent SNP statistics. Phenotype labels were permuted 10,000 times to generate an empirical p-value. Results: While a main effect of the VEGF pathway was not identified, the pathway was associated with neovascular AMD in women when accounting for birth control pill (BCP) use (P= 0.017). Analysis of VEGFs subpathways found that SNPs in the Proliferation subpathway were associated with neovascular AMD (P=0.029) when accounting for BCP use. Nominally significant genes within this subpathway were also observed. Stratification by BCP use revealed novel significant genetic effects in women who had taken BCPs. Conclusions: These results illustrate that some AMD genetic risk factors may only be revealed when considering complex relationships among risk factors. This shows the utility of exploring pathways of previously associated genes to find novel effects. It also demonstrates the importance of incorporating environmental exposures in tests of genetic association at the SNP, gene, or pathway level.