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Brian Yaspan, Zhengrong Li, Amy Dressen, Menno van Lookeren Campagne, Robert R Graham, Kha Le, Tushar Bhangale, Phillip Lai, Carole Ho, Eric C Strauss, ; A Common SNP at the CFI Locus is Associated with Rapid Progression of Geographic Atrophy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2234.
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Geographic atrophy (GA) is a progressive advanced form of age-related macular degeneration (AMD). Single nucleotide polymorphisms (SNPs) in genes coding for alternative complement pathway (ACP) proteins are strongly associated with risk for onset of both GA and neovascular subtypes of AMD. The association of these SNPs to the progression of GA area is not well understood. The MAHALO Phase 2 study data were analyzed to evaluate the relationship between published common risk SNPs in the ACP and the progression of GA area.
The MAHALO Phase 2 study (NCT01229215) collected whole blood samples for genotyping (Illumina 2.5M Omni SNP array) on 94 patients. From the 94 patients with DNA, 29 received sham injections and completed the study. The relationship between carriers vs. non-carriers of risk SNPs for complement factor H (CFH), complement factor I (CFI), C3, and one SNP tagging both C2 and complement factor B (C2/CFB) was investigated. Tag SNPs for each locus were selected according to a recent genetic meta-analysis containing >17,000 cases and >60,000 controls, and the progression of GA area was evaluated for patients with sham injections.
Due to small sample size, heterozygotes and homozygotes for the risk alleles were pooled for analysis (n=29). Of the 29 patients, 27, 28, 15 and 12 were risk allele carriers for CFH, C2/CFB, C3 and CFI, respectively. The CFH and C2/CFB SNPs were not informative for analysis due to the high prevalence in the study population. The C3 risk allele did not show a difference in progression of GA between carriers of the C3 risk allele vs. non-carriers of the C3 allele. The CFI risk allele carriers had a change from baseline in GA area at month 18 of 4.169 mm2 compared with 2.792 mm2 in the non-carriers of the CFI risk allele. This corresponds to a 49% increase in GA area growth over 18 months in CFI risk allele carriers compared with non-carriers of the CFI risk allele.
In the MAHALO study, patients who were carriers of the risk allele for CFI were found to have a faster progression of GA area compared with non-carriers of the CFI risk allele. These results suggest that this common genome-wide association study (GWAS)-associated CFI SNP is prognostic for rapid GA progression. Further studies are needed to confirm the association of CFI with GA progression as well as to elucidate the function of the risk haplotype.
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