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.