Common Variants Near CAV1 And CAV2 Are Associated With POAG In A US Caucasian Population

Abstract

Primary Open Angle Glaucoma (POAG) is an etiologically heterogeneous disorder characterized by progressive optic nerve degeneration resulting in irreversible blindness. A recent large, multi-ethnic genome wide association study identified two SNPs between two members of the caveolin family of genes (CAV1/CAV2) associated with POAG (Thorleifsson et al., 2010). We examined the association between SNPs in the CAV1/CAV2 genomic interval and POAG in the GLAUGEN (Glaucoma Gene and Environment Initiative) case-control dataset. We included 1000 cases and 1183 controls from three different studies: the Genetic Etiologies of POAG (GEP), Nurses Health Study (NHS) and the Health Professionals Follow-up study (HPFS). POAG was defined as VF loss consistent with NFL loss in the context of slit lamp exam which shows no secondary cause elevated IOP, open angles on gonioscopy and no secondary cause of VF loss on fundus exam. Multivariable models were constructed controlling for age, gender, study site, DNA extraction method and DNA source. We found both SNPs significantly associated with POAG risk in our study population, with effect sizes comparable to those found in the Thorleifsson study: rs4236601, p= 0.0010, OR1.29 (95% CI: 1.11-1.50); rs1052990, p=0.0002, OR 1.31 (95% CI: 1.14-1.51). We broadened our investigation to include 60 additional SNPs in the greater CAV1/CAV2 genomic region. We found 14 SNPs nominally associated with risk of POAG in the CAV1/CAV2 region at chr7q31.2. Sliding window haplotype analysis in the region identified two haplotypes as significantly associated with POAG risk after multiple testing correction via permutation testing: Haplotype 1: rs10256914 G, rs3807986 A, rs959173 A, rs10270569 A (p=0.0273); Haplotype 2: rs6975771 G, rs6976316 G, rs12530912 C, rs17138756 A, (p=0.0285). Furthermore, we also present data suggesting that the CAV1/CAV2 SNPs and haplotypes are mostly positively associated with disease in women. We have replicated the association between intergenic SNPs and POAG in a US Caucasian population.

Keywords: Genetics Clinical (Human) Or Epidemiologic Studies, Biostatistics/Epidemiology Methodology