Age-related Macular Degeneration

INTRODUCTION: Age-related macular degeneration is a major cause of blindness among people aged 50 and older in industrialized countries. Anti-VEGF therapy has been tremendously successful in the treatment of neovascular macular degeneration. Examining the pharmacogenetics of patients' response to the anti-VEGF molecules could allow for a tailored treatment strategy based on patients' underlying genetics rather than the "one-size fits all" approach currently used. METHODS: Review of the English literature for papers examining the pharmacogenetics of treatment response of neovascular macular degeneration to either ranibizumab or bevacizumab. Polymorphisms in CFH, ARMS2, HTRA1 and VEGF A were examined and reviewed. RESULTS: Patients with the high-risk CC genotype in complement factor H (CFH) had a worse response to therapy with ranibizumab and bevacizumab. No clear trends were found with ARMS2, HTRA1 and VEGF A. CONCLUSIONS: The goal of personalized medicine is to craft a treatment program that is ideally suited to an individual patient's disease and genetic make-up rather than simply what works for a large population who share similar disease characteristics. Continued research is needed to achieve this goal for the treatment of age-related macular degeneration.

Synonymous single nucleotide polymorphisms (SNPs) within a transcript's coding region produce no change in the amino acid sequence of the protein product and are therefore intuitively assumed to have a neutral effect on protein function. We report that two common variants of high-temperature requirement A1 (HTRA1) that increase the inherited risk of neovascular age-related macular degeneration (NvAMD) harbor synonymous SNPs within exon 1 of HTRA1 that convert common codons for Ala34 and Gly36 to less frequently used codons. The frequent-to-rare codon conversion reduced the mRNA translation rate and appeared to compromise HtrA1's conformation and function. The protein product generated from the SNP-containing cDNA displayed enhanced susceptibility to proteolysis and a reduced affinity for an anti-HtrA1 antibody. The NvAMD-associated synonymous polymorphisms lie within HtrA1's putative insulin-like growth factor 1 (IGF-1) binding domain. They reduced HtrA1's abilities to associate with IGF-1 and to ameliorate IGF-1-stimulated signaling events and cellular responses. These observations highlight the relevance of synonymous codon usage to protein function and implicate homeostatic protein quality control mechanisms that may go awry in NvAMD.

Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly. AMD progression is associated with alterations in inflammatory pathways and the immune system. A new study identifies a protective role for inflammasomes in AMD, suggesting that inflammasome activation might be manipulated as a potential therapeutic strategy for this condition (pages 791-798).

PURPOSE: To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes. DESIGN: Sibling correlation study and genome-wide association study (GWAS). PARTICIPANTS: For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls. METHODS: Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts. MAIN OUTCOME MEASURES: Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes. RESULTS: The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 × 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 × 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 × 10(-14) for combined discovery and replication analysis). CONCLUSIONS: Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies.