CFH, C3 and ARMS2 Are Significant Risk Loci for Susceptibility but Not for Disease Progression of Geographic Atrophy Due to AMD

Abstract

BackgroundAge-related macular degeneration (AMD) is a prevalent cause of blindness in Western societies. Variants in the genes encoding complement factor H (CFH), complement component 3 (C3) and age-related maculopathy susceptibility 2 (ARMS2) have repeatedly been shown to confer significant risks for AMD; however, their role in disease progression and thus their potential relevance for interventional therapeutic approaches remains unknown.Methodology/Principal FindingsHere, we analyzed association between variants in CFH, C3 and ARMS2 and disease progression of geographic atrophy (GA) due to AMD. A quantitative phenotype of disease progression was computed based on longitudinal observations by fundus autofluorescence imaging. In a subset of 99 cases with pure bilateral GA, variants in CFH (Y402H), C3 (R102G), and ARMS2 (A69S) are associated with disease (P = 1.6×10−9, 3.2×10−3, and P = 2.6×10−12, respectively) when compared to 612 unrelated healthy control individuals. In cases, median progression rate of GA over a mean follow-up period of 3.0 years was 1.61 mm2/year with high concordance between fellow eyes. No association between the progression rate and any of the genetic risk variants at the three loci was observed (P>0.13).Conclusions/SignificanceThis study confirms that variants at CFH, C3, and ARMS2 confer significant risks for GA due to AMD. In contrast, our data indicate no association of these variants with disease progression which may have important implications for future treatment strategies. Other, as yet unknown susceptibilities may influence disease progression.

Genetic Factors Associated with Age-Related Macular Degeneration

“…Moreover, this study demonstrated that these risk alleles in LD are independent of the major risk alleles of CFH and LOC387715; they are also independent of smoking, with a population-attributable risk of 14.6% [83]. This independent effect from other known genetic factors has been confirmed in other studies [84,85,86,87]. …”

Genetic analysis of simultaneous geographic atrophy and choroidal neovascularization

“…Six single-nucleotide polymorphisms (SNPs), in four genes associated with AMD, were selected according to the literature. They were rs2274700 and rs1061170 in CFH, 6,7 rs10490924 and rs1120638 in HTRA1/LOC387715, 6,8,9 rs2230199 in C3 14,15 and rs9332739 in C2. 14,15 These specific SNPs were selected because the most convincing evidence for a genetic contribution to AMD was the identification of major disease susceptibility alleles on chromosome 1q32, which includes the gene for CFH and HTRA1/LOC387715.…”

“…The literature has also shown C3 and C2 to be candidate genes. 14,15 All SNPs were genotyped using the SNaPshot method according to the manufacturer's recommendations. In brief, a SNP was amplified by PCR, the PCR product purified by Exo I and shrimp alkaline phosphatase (SAP) (New England Biolabs, Ipswich, MA, USA).…”

Distinct Genetic Risk Profile of the Rapidly Progressing Diffuse-Trickling Subtype of Geographic Atrophy in Age-Related Macular Degeneration (AMD)

“…Both have been described in detail elsewhere. 16,17,29 Briefly, patients needed to be above 50 years of age (55 years for DSGA) at the time of inclusion and had to exhibit GA in at least one eye. Clear ocular media that allowed for good-quality imaging had to be present.…”

“…Furthermore, 311 patients with GA but without the dt-GA subtype were recruited in Würzburg 11,30 and Bonn, equally as part of the FAM study. 16,29 Blood samples were taken from each patient after informed consent was given. 31 …”