Assessment of Genetic Risk at CC3 and Mitochondrial DNA Polymorphism A4917G After Adjustment for CFH, ARMS2, CFB and Smoking in an Irish AMD Cohort

Abstract

Purpose: : Polymorphic variation within complement component 3 and the mitochondrial SNP A4917G have been reported to be associated with AMD. We assess the impact of these variants within an Irish AMD sample after adjusting for other known risk factors.

Methods: : Patient samples with documented end-stage neovascular AMD (n=511) and an age and sex-matched controls (n=446) underwent full ophthalmic examination and participated in a short questionnaire to detail history of smoking, micro and macro angiopathic disease, drug history, refractive status, eye colour, body mass index and family history. Genotype analysis was undertaken for the CC3 SNP rs2230199 and the mitochondrial SNP A4917G. Genotyping was performed by SNaPshot (ABI). Data was combined with that reported previously for CFH, ARMS2, CFB and smoking¹.

Results: : CC3 SNP rs2230199 was significantly associated with AMD with increased Odds Ratio (OR) of 1.49 (P<0.001; Confidence Intervals (CI): 1.21-1.83) in a univariate analysis. Inclusion of risk data for CFH, ARMS2, CFB and smoking within logistic regression increased the OR to 1.57 (P<0.001; CI: 1.20-2.05). Univariate analysis of the mitochondrial SNP A4917G showed marginal significance (P=0.04; OR=1.26; CI: 1.01-1.58) which was no longer significant when other covariates were assessed within the model.

Conclusions: : Our results show the effect exerted by CC3 is similar in magnitude to that of CFB. Indeed both variants have similar minor allele frequencies and population attributable risk (PAR). Both ARMS2 and CFH exert an effect of greater magnitude and are at a higher frequency in the population and as such, are likely to have a higher PAR. While the mitochondrial SNP A4917G was marginally significant when assessed alone, it failed to do so in a multivariate analysis. Previous reports identified the need to adjust for age when measuring the effect of this SNP² which is ongoing in this sample. Evidence suggests increased mitochondrial germline mutation accumulation with time, particularly in males and certain mitochondrial haplogroups have been implicated in other age-related disorders. As such, the effect of age or sex bias will be assessed.1. McKay et al. Invest Ophthalmol Vis Sci 2008; (eprint ahead of publication).2. Canter et al. PLoS Genet 2008; 3 (e2091).

Keywords: age-related macular degeneration • genetics • clinical (human) or epidemiologic studies: risk factor assessment