1q32 and 10q26 Genotypes and Haplotypes Associated With Disease Severity in Age-Related Macular Degeneration

Abstract

Purpose: : To examine if variants in the complement factor H gene (CFH) (1q32) and the LOC387715/ARMS2/HTRA1 region on 10q26 in addition to smoking exposure can predict who is likely to develop neovascular AMD.

Methods: : We ascertained 46 unrelated patients with neovascular AMD who had at least one sibling with very early AMD (AREDS category 2) and was at least 65 years of age or older (92 total subjects). Significantly associated CFH AMD risk variants including CFH Y402H (rs1061170) along with 6 previously identified associated risk variants in the 10q26 region were examined. Genotyping was conducted by direct sequencing and the Sequenom iPLEX system. Analyses were done with family based association test (FBAT) and conditional logistic regression (CLR) to evaluate the effect of each SNP along with smoking on AMD risk. Haplotypes were inferred and tested for association using FBAT and CLR. CLR was used to determine the best fit for each genotypic model tested (Additive, Dominant, or Recessive).

Results: : Of the 16 variants examined, under an additive model, only CFH rs482934 (p= 0.002), CFH rs572515 (p= 0.007) and HTRA1 rs11200638 (p= 0.009) were significantly associated with risk in subjects who had neovascular AMD compared to their matched siblings with early AMD. More modest associations were found in CFH and included rs1061170 (p= 0.01) and rs1061147 (p= 0.02). Haplotype analysis demonstrated that the most significant haplotype blocks encompassed our significantly associated AMD risk SNPs within CFH. In CFH, the first block had one haplotype, G-AATGCG, found to be protective for risk of developing neovascular AMD (corrected p= 0.004). The second block had two haplotypes that were significantly associated with risk of neovascular AMD: GC (protective) and TT (increasing risk), (both corrected p= 0.002). For LOC387715/HTRA1, there was one block spanning all 6 SNPs tested. This block contained one significant haplotype, T-ACTC/T, that was associated with increased risk of developing neovascular AMD (corrected p= 0.006) under an additive model. A smoking history of 10 or more pack years was also associated with development of neovascular AMD (p= 0.01).

Conclusions: : Preliminary analysis suggests that specific variants within the 1q25 and 10q26 region along with smoking may indicate which individuals are more likely to develop advanced disease. Analysis is ongoing in a much larger cohort.

Keywords: age-related macular degeneration • protective mechanisms • gene screening