Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma

Abstract

We conducted a genome-wide association study for primary open-angle glaucoma (POAG) in 1,263 affected individuals (cases) and 34,877 controls from Iceland. We identified a common sequence variant at 7q31 (rs4236601[A], odds ratio (OR) = 1.36, P = 5.0 × 10-10). We then replicated the association in sample sets of 2,175 POAG cases and 2,064 controls from Sweden, the UK and Australia (combined OR = 1.18, P = 0.0015) and in 299 POAG cases and 580 unaffected controls from Hong Kong and Shantou, China (combined OR = 5.42, P = 0.0021). The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG.

Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma

“…[62][63][64][65][66][67] Although not all studies have found associations with variants in the NOS3 gene that codes for eNOS, 68,69 variants or haplotypes of SNPs in NOS3 have been reported to be associated with POAG overall, 62,65 POAG with migraines, 66 POAG or high tension POAG among women only, 63,64 and familial POAG. 67 Furthermore, the CAV1/CAV2 gene region, which codes for caveolins that control eNOS activity, contain variants associated with POAG in one GWAS, 24 and this finding was replicated in another large candidate gene study. 23 The caveolin/eNOS interaction is critical to prevent inadequate NO production under basal conditions and to the translation of extracellular stimuli to intracellular NO signals.…”

“…Recent large POAG genome-wide association studies (GWAS) have identified significant associations for single-nucleotide polymorphism (SNP) in the genomic region containing CAV1, [23][24][25] which codes for caveolins that are involved in vascular regulation, thereby supporting the role of vascular dysregulation in POAG. Because biologic pathway analyses (where SNP sets from functionally related genes are collectively evaluated in relation to a disease of interest) can enhance the power to discover aetiologically relevant pathways and networks, we tested the hypothesis of whether a collection of SNPs in genes functionally involved in vascular tone regulation and identified as significant hits in GWAS of blood pressure are possibly associated with POAG.…”

Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1

“…Linkage and candidate gene studies have identified several genes likely to be involved in OAG including myocilin 3 and NTF4 4 , although for the latter, findings have varied in different populations 5 . A recent GWAS using Icelandic OAG cases of unselected severity identified association with variants near CAV1 6 . To identify genes predisposing individuals to OAG blindness, we performed a GWAS in Australian Caucasians with advanced OAG (individuals with OAG who have progressed to severe visual field loss or blindness).…”

“…Although the CAV1 SNP (rs4236601) did not reach statistical significance in this GWAS (p=0.17 for a 1 sided test), the observed odds ratio of 1.07 is consistent with that previously reported in larger European cohorts, as are the allele frequencies (cases; 0.290, controls; 0.276 for A allele). It should be noted that many of the cases in the current study are included in the previously reported Australian replication cohort 6 . Genes at the 9p21 locus are known to play a role in aberrant cell division, and we propose that the 9p21 OAG risk variants may predispose RGCs to gradual apoptosis.…”

Genome-wide association studies: applications and insights gained in Ophthalmology

“…First, they validated the efficacy of using extreme phenotypes in GWAS; the variants found in their discovery cohort of severe OAG were replicated in cases with less severe disease. Second, many of the cases in this study were used as a replication in the GWAS of Thorleifsson et al 27 Interestingly, although in the latter paper the analysis confirmed a role for CAV1 & CAV2, this was not found to be so in this full GWAS with the same cases. This is not a novel situation and highlights some of the challenges of interpreting GWAS and replication data.…”