Variants In CDKN2B, SIX1, and BCAS3 Are Associated With Risk Of POAG

Abstract

Purpose: : Primary open angle glaucoma has a complex genetic architecture, and risk of disease is influenced by a variety of factors. Optic nerve head dimensions are highly heritable and the vertical cup-disc ratio (VCDR) is commonly used to document the extent of glaucomatous optic neuropathy. A recent study (Ramdas et al., PLoS Genetics. 6:e1000978) used a genome-wide quantitative trait locus (QTL) analysis to identify genetic variants that influence optic head morphology. Variants near ATOH7 and CDC7 are associated with optic disc area, while variants near CDKN2B and SIX1 are associated with VCDR. Meta-analysis with additional datasets also identified associations with variants in genes BCAS3, DCLK1, SALL1. The purpose of the present study is to evaluate the role that these variants play in the risk of POAG in both Caucasians and individuals of African ancestry.

Methods: : Nine single nucleotide polymorphisms were genotyped with the Taqman allelic discrimination assay in three independent POAG case/control datasets: a Duke Caucasian cohort of 492 cases and 440 controls; a combined Duke and consortium African American cohort of 950 cases and 931 controls; and a Ghanaian cohort of 479 cases and 590 controls. Genotype associations with disease were evaluated using a logistic regression model corrected for age and gender.

Results: : Rs1063192 near CDKN2B is strongly associated with POAG risk in Caucasians [p=0.004, OR=1.32, (95%CI 1.09-1.60)], as is rs10483727m near SIX1 [( p=0.0009, OR=1.38, (95%CI 1.14-1.67)]. Rs8068952, located near gene BCAS3, was associated with POAG risk in African Americans (p=0.014, OR=1.25, 95%CI 1.05-1.49). No variants were significantly associated in the Ghanaian dataset.

Conclusions: : Variants near CDKN2B and SIX1 can influence vertical cup disc ratio, and are also strongly associated with POAG risk in Caucasians. Intriguingly, CDKN2B has also been strongly associated with cardiovascular disease risk. The odds ratios associated with variants in these two genes are comparable to those associated with variants in CAV1/2, recently identified through a genome wide association analysis of POAG.The POAG African American Study Group includes Janey Wiggs, Douglas Gaasterland, Paul Lichter, Leon Herndon, Pratap Challa, Robert Ritch, and Donald Budenz.

Keywords: genetics • optic disc