Association of CAV1/CAV2 Genomic Variants with Primary Open-Angle Glaucoma Overall and by Gender and Pattern of Visual Field Loss

Purpose The CAV1/CAV2 ( caveolin 1and caveolin 2) genomic region previously was associated with primary open-angle glaucoma (POAG), although replication among independent studieshas been variable. The aim of this study was to assess the association between CAV1/CAV2 single nucleotide polymorphisms ( SNPs) and POAG in a large case-control dataset and to explore associations by gender and pattern of visual field (VF) loss further. Design Case-control study. Participants We analyzed 2 large POAG data sets: the Glaucoma Genes and Environment (GLAUGEN) study (976 cases, 1140 controls) and the National Eye Institute Glaucoma Human GeneticsCollaboration (NEIGHBOR) consortium (2132 cases, 2290 controls). Methods We studied the association between 70 SNPslocated within the CAV1/CAV2 genomic region in the GLAUGEN and NEIGHBOR studies, both genotyped on the Illumina Human 660WQuadv1C BeadChip array and imputed with the Markov Chain Haplotyping algorithm using the HapMap 3 reference panel. We used logistic regression models of POAG in the overall population and separated by gender, as well as by POAG subtypes defined by type of VF defect (peripheral or paracentral). Results from GLAUGEN and NEIGHBOR were meta-analyzed, and a Bonferroni-correctedsignificance level of 7.7×10 −4 was used to account for multiple comparisons. Main Outcome Measures Overall POAG, overall POAG by gender, and POAG subtypes defined by pattern of early VF loss. Results We found significant associations between 10 CAV1/CAV2 SNPsand POAG (top SNP, rs4236601; pooled P = 2.61×10 −7 ). Of these, 9 were significant only in women (top SNP, rs4236601; pooled P = 1.59×10 −5 ). Five of the 10 CAV1/CAV2 SNPswere associated with POAG with early paracentral VF (top SNP, rs17588172; pooled P = 1.07×10 −4 ), and none of the 10 were associated with POAG with peripheral VF loss only or POAG among men. Conclusions CAV1/CAV2 SNPswere associated significantly with POAG overall, particularly among women. Furthermore, we found an association between CAV1/CAV2 SNPsand POAG with paracentral VF defects. These data support a role for caveolin 1, caveolin 2, or both in POAG and suggest that the caveolinsparticularly may affect POAG pathogenesis in women and in patients with early paracentral VF defects.