The Genes of the Alternate Complement Cascade and Risk for Age-related Macular Degeneration in the French-Canadian Population

Abstract

Purpose: : Variations in the genes of the alternate complement cascade have been shown to represent major risk factors for age-related macular degeneration (AMD). However, this contribution still remains to be established in the French-Canadian (F-C) founder population. To assess if these variations altered susceptibility to AMD and to detect potential founder haplotypes in this population, we performed association studies between the disorder and single nucleotide polymorphisms (SNP) located in the genes encoding complement factor H (CFH), ARMS2/LOC387715, complement C3 (C3), C-reactive protein pentraxin-related (CRP) and complement factor B (CFB)/complement component 2 (C2).

Methods: : 166 unrelated F-C patients and 103 controls matched for age and sex were genotyped using DNA sequencing or Sequenom mass array. AMD diagnoses were made according to criteria of the International Age-Related Maculopathy Epidemiological Study. We used PLINK to reconstruct haplotypes and Armitage test to estimate associations.

Results: : Within CFH, 2 SNPs in strong linkage disequilibrium showed extreme association with AMD. In the heterozygotic state, these 2 SNPs decreased by 5 fold the risk for AMD. Five CFH haplotypes encompassing 17 SNPs were reconstructed over the CFH locus. Two of them were strongly associated with AMD. The QC1AMD haplotype, which encompassed the Y402H risk allele, was associated with an increased risk for the disorder, whereas, the QC2AMD haplotype, which harbored H402H, decreased such risk. Interestingly, a 3rd haplotype, which encompassed a unique G allele at a specific SNP in the middle of the CFH gene, showed prevalences similar between patients and controls although it contained the well-characterized Y402H risk allele. Within C3, only one haplotype (9 SNPs) increased risk for AMD. This haplotype harbored three previously reported risk variations. Among ARMS2 haplotypes (3 SNPs), only the one harboring A69S increased risk for AMD. Variations in CRP and CFB/C2 were not associated with the disorder.

Keywords: age-related macular degeneration • candidate gene analysis • gene mapping