Replication of Association of CFH, Plekha1/LOC387715 and Elovl4 Genes With ARM in the AREDS Cohort

Abstract

Purpose: : We have sought to replicate the associations of variants in CFH, PLEKHA1/LOC38775 and ELOVL4 genes with ARM in an independent, well–characterized cohort.

Methods: : We have conducted linkage and candidate gene association studies utilizing our family based cohort as well as our case control subjects. Association analysis allowing for related cases strongly supported two tightly linked genes PLEKHA1 and LOC387715 (LOC) on 10q26, CFH on 1q31 and ELOVL4 on 6q14. Due to high linkage disequilibrium between PLEKHA1 and LOC in our dataset, distinguishing between these genes is very challenging. We used the Decay of Haplotype Sharing Mapping (DHSMAP) method on a set of unrelated cases and controls.

Results: : The two most significantly–associated SNPs (p–value < 0.00001) in PLEKHA1 and LOC were both within the 95% confidence interval for the most likely position of the disease–causing variant. All three of these genes are biologically relevant candidates, although very little is known about the function of LOC. We have conducted further analyses of the Y402H variant in the CFH gene, the A69S variant in LOC and the M299V variant in ELOVL4 utilizing the NEI–Age–Related Eye Disease Study (AREDS) cohort. We have replicated strong association of ARM with both CFH and LOC (p–value < 0.00001) and the association of ELOVL4 with exudative disease (genotype test: P=0.047; allele test: P=0.032).

Conclusions: : These data continue to support a role for these three genes in susceptibility to ARM using an independent cohort. Samples from the NEI–Age–Related Eye Disease Study (AREDS) Genetic Repository were used for this research.

Keywords: age-related macular degeneration • genetics • clinical (human) or epidemiologic studies: risk factor assessment