Variations in five genes and the severity of age-related macular degeneration: results from the Muenster aging and retina study

Abstract

Aims Little is known about the role of genetic variants in the early stages of age-related macular degeneration (AMD). We aimed to investigate how genetic variations within five well-defined genes relate to AMD severity. Methods We analysed SNPs in the genes for complement factor H (CFH), age-related maculopathy susceptibility (ARMS2), HtrA serine peptidase 1 (HtrA1), complement factor B (CFB), and complement component 2 (C2) in 183 controls and 730 patients with increasing severity of AMD from the Muenster aging and retina study (MARS). Severity scoring was based on the Rotterdam classification of fundus photographs. Results Compared with controls, patients with very early AMD showed a significantly increased minor allele frequency (MAF) only for CFH-rs1061170. With increasing severity of AMD, SNPs in CFH-rs1061170, as well as ARMS2-rs10490924, became consistently more common (Po0.001). Likewise, HtrA1-rs11200638 was less clearly associated with AMD severity, whereas C2-rs9332739 and CFB-rs641153 showed no relation. Multifactorial models confirmed CFH and ARMS2 as major determinants of AMD severity, whereas addition of HtrA1, C2 and CFB did not improve model prediction. In the models, age did not contribute to very early but to all more severe AMD stages, whereas smoking history had a significant impact only for late AMD. ConclusionOur findings indicate that the CFH gene is involved in the onset of AMD, whereas both, the CFH and ARMS2 genes, and more weakly, the HtrA1 gene, appear to account for the advancement of AMD. The results for SNPs in the C2 and CFB genes were inconclusive. Genetic factors dominated in their impact over age and smoking history.

Genetic Polymorphisms and the Phenotypic Characterization of Individuals with Early Age-Related Macular Degeneration

“…This could indicate a role of genetic risk factors for the development of drusen. Color imaging of the fundus showed a significant increase in late-stage AMD in partner eyes of carriers of the risk polymorphism in comparison to the non-carrier group, which confirms the results of earlier studies that showed a heightened risk of progression in persons homozygous for these SNPs [10][11][12] .…”

“…The selected patients had shown early AMD signs in at least 1 eye in MARS-III and were either homozygous for the risk SNP in the CFH gene (rs1061170) and/or homozygous for the risk SNP in the ARMS2 gene (rs10490924), or they were non-carriers (i.e., carried neither of these risk SNPs in both alleles). The procedure of genotyping was described in detail prior to this [10,11] .…”

“…In epidemiological genomewide association studies, single nucleotide polymorphisms (SNPs) in specific genes could be identified, and homozygous patients, carrying both risk alleles, were more strongly affected than their heterozygous counterparts or non-carriers [12,13] . Due to their population frequency and effect sizes, SNPs in the CFH and ARMS2 genes contribute most prominently to the incidence and progression of AMD [10,11,[14][15][16] .…”

“…Previous studies showed that the process of aging in combination with genetic risk factors, smoking, and obesity may lead to the occurrence of AMD and modify its progression [5][6][7][8] . More recently, genetic factors have been shown to be particularly important in disease progression [9][10][11] . In epidemiological genomewide association studies, single nucleotide polymorphisms (SNPs) in specific genes could be identified, and homozygous patients, carrying both risk alleles, were more strongly affected than their heterozygous counterparts or non-carriers [12,13] .…”

Re: "The Association Between Complement Component 2/Complement Factor B Polymorphisms and Age-Related Macular Degeneration: A Huge Review and Meta-analysis"

“…The data suggest some systematic genotyping problems. Farwick et al (5) reported minor allele frequencies of 2.8% for rs547154 and 10.9% for rs641153 in controls, though the frequencies should be approximately equal (1).…”