Variations in Complement Factor H (CFH) and LOC387715/ARMS2 Are Associated With Increased Risk of Age-Related Macular Degeneration in the French-Canadian Population

Abstract

Purpose: : During the past 3 years, major progress has been made in our understanding of the genetic factors involved in age-related macular degeneration (AMD). Until recently, the French-Canadian population has maintained a demographic growth without immigration and a high birth rate. To assess if founder haplotypes account for changes in the risk for AMD in this population, we tested for associations between the disorder and single-nucleotide polymorphisms (SNP) spanning complement factor H (H1/CFH) at 1q31-32, LOC387715/ARMS2, C-reactive protein pentraxin-related (CRP) and complement factor B (CFB)/complement component 2 (C2).

Methods: : We conducted a case/control study in 112 AMD patients and 123 control individuals, matched for age and sex, selected from the Quebec Eye Hereditary Diseases Database. AMD patients adhered to the International Age-Related Maculopathy Epidemiological Study criteria. SNPs were genotyped by direct DNA sequencing or by the Mass Array technology from Sequenom. Fisher exact tests were performed to evaluate associations. Haplotypes were constructed using Unphased.

Results: : Two (2) SNPs, rs10465586 and rs1410996, at CFH showed highly significant associations with AMD. Their p-values were estimated at <10^-6. Twelve other SNPs, including the Y402H variant at CFH and A69S at LOC387715, displayed p-values between 10^-3 and 10^-6. SNPs at CRP and CFB/C2 did not show any evidence of association. At CFH, haplotypes were grouped in two distinct blocks. Two of these haplotypes were clearly associated with an increased risk for AMD. On the other hand, one characteristic haplotype at LOC387715/ARMS2 was associated with a lower risk for AMD.

Conclusions: : In the French-Canadian population, rs10465586 and rs1410996 at CFH represent major susceptibility variants for AMD. At this locus, two CFH haplotypes were associated with an increased risk for the disorder whereas, at LOC387715, one protective haplotype accounted for a lesser risk of becoming affected. Risk-associated haplotypes for the disorder support the presence of founder effects for susceptibility for, or protection against, AMD in this population.

Keywords: age-related macular degeneration • genetics • gene screening