Genetic Examination of Functional Candidate Genes In Age Related Macular Degeneration

Abstract

Abstract: : Purpose: Age–Related Macular Degeneration (AMD) is one of the most significant causes of vision loss in the elderly. There is substantial evidence that both genes and environment play a critical role in its etiology. As part of our ongoing genetic epidemiological studies of AMD, we are collecting a large series of rigorously diagnosed multiplex and simplex families with AMD, along with rigorously defined normal aged controls. Methods: Our current sample consists of two independent datasets. The first consists of 93 multiplex families and the second consists of 222 cases and 70 normal controls. We identified eight candidate genes based their potential functional role in the etiology of AMD. Two genes (IL1A and CKB) were chosen since cDNA microarray experiments demonstrated that their expression was significantly altered in AMD retinal tissue. Three genes (VLDLR, A2M, LRP6) were chosen because of their known relationship to APOE, which has been consistently demonstrated to modify the risk for AMD. Two other genes (MGST1, ACE) were chosen because of their roles in oxidative stress, and a previously published association, respectively. We performed both family–based (Pedigree Disequilibrium Test) and case–control (Chi–square) analyses on multiple SNPs within each gene. Results: Three genes (A2M, MGST1, CKB) did not demonstrate any association. Two genes (IL1A, p=0.005; ACE, p=0.05) had one SNP each with nominally significant results. Of most interest were the results for VLDLR, which had significant results for the same SNP in both the familial and case–control datasets (p=0.01, p=0.01) and LRP6, which had significant results for 4 SNPs in the case–control dataset (p=0.004, 0.02, 0.02, 0.01). Conclusions: While studies of additional SNPs in A2M, MGST1, CKB, IL1A, and ACE will be necessary to definitively exclude these genes as candidates, our data suggests the tested polymorphisms are not major contributors to AMD risk. Additional analyses in a larger dataset and with more SNPs are currently underway for VLDLR and LRP6, which are strong candidates for risk factors in AMD.

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