Functional candidate genes in age-related macular degeneration: Significant association with VEGF, VLDLR, and LRP6

PURPOSE. Age-related macular degeneration (AMD) is a retinal degenerative disease that is the leading cause of blindness worldwide for individuals over the age of 60. Although the etiology of AMD remains largely unknown, numerous studies have suggested that both genes and environmental risk factors significantly influence the risk of developing AMD. Identification of the underlying genes has been difficult, with both genomic screen (locational) and candidate gene (functional) approaches being used. The present study tested candidate genes for association with AMD. METHODS. Eight genes (alpha-2-macroglobulin [A2M], creatine kinase [CKB], angiotensin-converting enzyme [DCP1], interleukin-1 alpha [IL1A], low-density lipoprotein receptor-related protein 6 [LRP6], microsomal glutathione-S-transferase 1 [MGST1], vascular entothelial growth factor [VEGF], and very low density lipoprotein receptor [VLDLR]) were tested for genetic linkage and allelic association, using two independent datasets: a family-based association dataset including 162 families and an independent case-control dataset with 399 cases and 159 fully evaluated controls. RESULTS. Test results suggested that genetic variation in five of these genes (IL1A, CKB, A2M, MGST1, and DCP1) is unlikely to explain a significant fraction of the risk of developing AMD in this population. LRP6 showed evidence both for linkage (heterogeneity lod [HLOD] = 1.14) in the family-based dataset and for association (P = 0.004) in the case-control dataset. VEGF showed evidence of linkage (HLOD = 1.32) and demonstrated significant independent allelic association in both the family-based (P = 0.001) and case-control (P = 0.02) datasets. VLDLR showed evidence of association in both the family based (P = 0.03) and case-control (P = 0.01) datasets. CONCLUSIONS. These data suggest that LRP6, VEGF, and VLDLR may play a role in the risk of developing AMD.