Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10(-75)), ARMS2 (P < 10(-59)), C2/CFB (P < 10(-20)), C3 (P < 10(-9)), and CFI (P < 10(-6)). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10(-11)), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10(-7); CETP, P = 7.4 x 10(-7)) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 x 10(-3)) and ABCA1 (P = 5.6 x 10(-4)). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.

Association between high-risk disease loci and response to anti-vascular endothelial growth factor treatment for wet age-related macular degeneration.

PURPOSE: To investigate whether there is an association between known age-related macular degeneration genetic risk variants in the CFH, ARMS2, and HTRA1 genes and response to anti-vascular endothelial growth factor (VEGF) (ranibizumab or bevacizumab) treatment for wet age-related macular degeneration. METHODS: A retrospective review of 150 patients with documented wet age-related macular degeneration based on clinical examination and fluorescein angiogram was performed. Patients received anti-VEGF therapy with ranibizumab and/or bevacizumab. Patients were genotyped for the single-nucleotide polymorphism rs1061170, rs10490924, rs3750848, rs3793917, rs11200638, and rs932275 and for the indel del443ins54 spanning the CFH, ARMS2, and HTRA1 genes. RESULTS: There were 57 patients who were characterized as negative responders to anti-VEGF therapy, and 93 patients who were characterized as positive responders. There was no significant difference in mean baseline visual acuity between the groups. Negative responders were followed for a mean duration of 24.0 months, while positive responders were followed for a mean duration of 22.0 months. Although the frequency of the at-risk alleles was higher in the positive responders when compared with the negative responder, this did not reach statistical significance. Additionally, there was no significant association between genotype and the number of injections or absolute change in visual acuity in both groups of responders. CONCLUSION: In our patient cohort, there was no statistically significant association between response to anti-VEGF therapy and the genotype in both positive-responder and negative-responder groups. Larger studies with more power are necessary to further determine whether a pharmacogenetic association exists between wet age-related macular degeneration and anti-VEGF therapy.

Analysis of six genetic risk factors highly associated with AMD in the region surrounding ARMS2 and HTRA1 on chromosome 10, region q26.

Purpose. To determine the relationship of six genetic variants (rs10490924, rs3750848, del443ins54, rs3793917, rs11200638, and rs932275) localized to the ARMS2-HTRA1 region of chromosome 10, region q26, as risk factors for age-related macular degeneration (AMD), to define the haplotype structure of these six loci, and to confirm their genetic association with the disease. Methods. Caucasian patients (n = 482) were stratified into categories based on AREDS (Age-Related Eye Disease Study) grading criteria (groups 0 and 1 served as the control, groups 3 and 4 contained subjects with AMD, and group 2 was excluded from the analysis). The six genetic variants in the ARMS2-HTRA1 region were genotyped and analyzed both independently and as a joint haplotype for association in subjects with disease (n = 291) compared with the control (n = 191). Results. The six high-risk alleles all showed a statistically significant association with AMD (the most significant SNP was rs10490924 [P < or = 3.31 x 10(-5), OR = 1.86]; the least significant SNP was rs932275 [P < or = 9.15 x 10(-5), OR = 1.78]). Multimarker analysis revealed that all six markers were in strong linkage disequilibrium with each other, and the two major haplotypes that captured >98% of the genetic variation in the region were both significantly associated with the disease: One increased the risk of AMD and contained only risk alleles (P < or = 2.20 x 10(-5)), and the other haplotype decreased the risk of AMD and contained only wild-type alleles (P < or = 6.81 x 10(-5)). Furthermore, 36 individuals comprising both cases and controls were identified outside of these two major haplotypes, with at least one discordant marker. Conclusions. The results replicate the previously reported association between the high-risk alleles and AMD and independently confirm, for the first time, an association with AMD and the indel (del443ins54) polymorphism in a Caucasian population. Two major haplotypes that are associated with AMD and many minor novel haplotypes were identified. The novel haplotypes, identified from 36 cases and controls with discordant alleles spanning the ARMS2-HTRA1 region provide unique opportunities to gauge the relative phenotypic contributions of each of these genetic risk factors. With the identification of more discordant patients in the future, it may be possible to resolve the ongoing controversy as to which of the risk alleles and genes (ARMS2 vs. HTRA1) has the greatest impact on disease susceptibility. Future work should include the analysis of larger and more diverse populations, to further define the linkage structure of the region with a focus on phenotypic effects on AMD of the various haplotypes involving 10q26, as well as a functional analysis of the normal ARMS2 protein.