Interaction Between SNPs in the NOS2A Gene and Smoking in Age-Related Macular Degeneration

Abstract

Purpose: : SNPs in the NOS2A gene have been previously associated with a modified smoking effect in neurodegenerative diseases. The protective smoking effect in Parkinson disease (PD) is attenuated by the rs1060826 synonymous SNP. Cigarette smoking is a strong risk factor for age-related macular degeneration (AMD), with a demonstrated synergistic interaction with genotypes of the ARMS2 locus. We hypothesized that SNPs in the NOS2A gene might modulate the smoking effect on AMD.

Methods: : We enrolled 998 subjects for the study (712 AMD cases and 286 unrelated controls with no macular changes). Using a TaqMan assay, we genotype 17 SNPs within the NOS2A region in our Caucasian non-Hispanic population. Data was analyzed using chi-square and logistic regression model with genotypes (dominant and recessive coding), age, sex, and smoking status (ever/never), along with a two-way interaction between genotype and smoking.

Results: : When controls (grade 1) and neovascular AMD cases (grade 5) were evaluated an interaction was detected under the recessive model for the rs1060826 (p=0.36) and under the recessive and additive model for the rs2248814 (p=0.039 and p=0.037, respectively). Due to high LD (r2 = 0.95 in cases and 0.96 in controls) between the significant SNPs, and the exonic location of rs1060826, we proceeded to stratify the data set by rs1060826 genotype and examine the modification of the effect of smoking by allele carrier status.The stratified analysis demonstrated that the strength of the association between smoking and AMD was stronger in carriers of the rs1060826 AG or AA genotypes (OR 4.1, 95% CI [1.9, 8.6 than in carriers of the GG genotype (OR 2.1, 95% CI [0.94, 4.9])

Keywords: genetics • gene modifiers • candidate gene analysis