Variants in the 10q26 Gene Cluster (LOC387715 and HTRA1) Exhibit Enhanced Risk of Age-Related Macular Degeneration Along With CFH in Indian Patients

Abstract

Purpose: : Single nucleotide polymorphisms (SNPs) in the LOC387715 (rs10490924), HTRA1 (rs11200638) and CFH (rs1061170) have been implicated in age-related macular degeneration (AMD). Earlier we demonstrated the association of rs1061170 in a cohort from India. The present study was undertaken to understand the involvement of LOC387715 and HTRA1 in that cohort.

Methods: : The coding region of LOC387715 and the promoter of HTRA1 were resequenced in cases (n=250) and controls (n=250). Odds ratios were calculated to assess the risk of individual genotypes. Linkage disequilibrium (LD) and haplotype frequencies were estimated with Haploview software. Population attributable risk (PAR%) were calculated for the additive effect of these SNPs. Meta analysis was performed to discern the statistical evidence of these associations.

Results: : AMD cases exhibited a higher frequency of "risk" alleles of LOC387715 [rs10490924 (p=5.34x10^-12)] and HTRA1 [rs11200638 (p=4.32x10^-12) and rs2672598 (p=3.39x10^-11)] and higher disease odds in the corresponding "risk" genotypes. The rs10490924 and rs11200638 SNPs were in tight LD (D’=0.90, 95%CI, 0.84-0.93). The "G-C-T-A-C" was the risk haplotype (p=8.04x10-15), while the "G-C-G-G-T" haplotype was protective (p=2.01x10^-4). The additive effect of CFH and LOC387715 risk genotypes exhibited a PAR of 69.8% (OR=8.34, 95%CI, 5.22-13.31). Genotype, haplotype and Meta analysis data suggested that the rs10490924 could be the most AMD-susceptible SNP in the present cohort.

Conclusions: : The present data provides an independent validation of the association of LOC387715 and HTRA1 SNPs along with their risk estimates among AMD patients. These associations underscore their significant involvement in AMD susceptibility, which may be useful for predictive testing.

Keywords: age-related macular degeneration • genetics • gene screening