Growth of Geographic Atrophy on Fundus Autofluorescence and Polymorphisms ofCFH,CFB,C3,FHR1-3, andARMS2in Age-Related Macular Degeneration

Abstract

for the Spanish Multicenter Group on AMD IMPORTANCE Identification of the genetic risk factors that contribute to geographic atrophy (GA) could lead to advancements in interventional trials and/or therapeutic approaches for combating vision loss.OBJECTIVE To investigate whether single-nucleotide polymorphisms (SNPs) are associated with the presence and progression of established GA in age-related macular degeneration (AMD). DESIGN, SETTING, AND PARTICIPANTS Prospective, controlled, multicenter study of 154 patients with GA/AMD and 141 age-matched control participants at 8 Spanish hospitals. MAIN OUTCOMES AND MEASURESSamples of DNA were collected to analyze SNPs within AMD-related genes (CFH, CFB, C3, FHR1-3, and ARMS2). Fundus autofluorescence imaging was used to evaluate GA progression during a 2-year period in 73 patients with GA/AMD. Finally, logistic regression was used to analyze the associations of SNPs, age, body mass index, and cigarette smoking with the rate of progression and relative growth of GA.RESULTS This case-control analysis revealed a significant (P < .05) association between the presence of GA and SNPs within CFH, ARMS2, and FHR1-3. Moreover, logistic regression analysis identified significant associations of the rate of progression with genetic polymorphisms (CFH-402His [P = .04] and CFH-62Ile [P = .04]) and demographic factors (sex [P = .02] and age [P = .02]), whereas relative growth was associated with 1 polymorphism (CFB-32Gln [P = .04]).CONCLUSIONS AND RELEVANCE Taken together, our findings confirm that genetic risk factors related to the presence of GA are not identical to those associated with GA progression. In fact, we demonstrate that gene variants of CFH and CFB, as well as demographic risk factors, confer significant risk for GA progression (both rate of progression and relative growth) within a Spanish population.

Growth of Geographic Atrophy in the Comparison of Age-related Macular Degeneration Treatments Trials

“…11 Monthly treatment may be associated with higher GA incidence but once the GA develops the growth rate is not significantly different from that observed in the PRN group. Two genetic studies that have recently shown that certain single nucleotide polymorphisms can affect the incidence of AMD pathologic features but not necessarily affect the progression of these features 23, 24 are consistent with our findings.…”

Progression Rate From Intermediate to Advanced Age-Related Macular Degeneration Is Correlated With the Number of Risk Alleles at the CFH Locus

“…18 However, CFH variants are usually more strongly associated with increased risk of GA, and ARMS2 variants with CNV, 17,18,53,54 whereas we found a stronger effect of CFH on progression to CNV. Nevertheless, growth rate of GA was correlated with genotype at the ARMS2 SNP in two studies, 55,56 but not at the CFH (Y402H) SNP, 55–57 although Caire et al 58 did not find evidence that GA growth rate was associated with variants in either locus. Overall, our results and previous work suggest that the CFH gene may be responsible for a slightly different AMD disease process than ARMS2, 2,18 and that different variants may have different effects on risk versus progression.…”

Potential role of lampalizumab for treatment of&nbsp;geographic atrophy

“…Given the significant prevalence of complement mutations in the AMD population, the complement cascade makes an intriguing clinical therapeutic target for non-neovascular AMD. Studies have already demonstrated that SNPs to the CFH and CFB genes contribute to the progression of GA 24. However, despite the promise that complement blockade shows for potential therapies, there have been several unsuccessful Phase I and Phase II trials of monoclonal antibodies, aptamers, receptor agonists, and a compstatin derivative which purported to modify the complement cascade.…”