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ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure.

Hum. Mol. Genet. 2015, vol. 24, issue 9

Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7, and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG. We performed a genome-wide association study of IOP in the population-based Rotterdam Study I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n=8,105) we identified a new locus associated with IOP. The most significantly associated SNP was rs58073046 (β=0.44, p-value=1.87x10(-8), minor allele frequency=0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n=7,471) resulted in an effect size in the same direction that was significantly associated (β=0.16, p-value=0.04). The SNP was also significantly associated with POAG in two independent case-control studies (n=1,225 cases and n=4,117 controls; OR=1.53, p-value=1.99x10(-8)), especially with high-tension glaucoma (OR=1.66, p-value=2.81x10(-9); for normal-tension glaucoma OR=1.29, p-value=4.23x10(-2)). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2, and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12.

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