Abstract
Purpose: :
This study aims to ascertain whether alleles of FOXC1, LMX1B, TGFβ2 and BMP4 predispose to ocular hypertension (OHT) and primary open angle glaucoma (POAG) in white British subjects.
Methods: :
Two independent cohorts comprised of 332 cases affected with either OHT (n= 57) or POAG (n=275) and 276 matched controls of white British descent were recruited in this study. The candidate genes were screened using 4 tagging single nucleotide polymorphisms (tSNPs) for FOXC1, 5 tSNPs forBMP4, 21 tSNPs forTGFβ2 and 25 tSNPs for LMX1B.
Results: :
A significant association was found between a non-coding tSNP situated within intron 2 of LMX1B and POAG cases, for both allele frequency [76.6% of cases vs 68.2% of controls, Χ2= 9.4, fisher's p = 0.002, odds ratio= 1.5 (95% confidence interval = 1.16-2.00)] and genotype frequency (Χ2 = 9.3, fisher's p = 0.009). This association became marginally stronger when combining OHT subjects with POAG cases (OHT-POAG), for both allele frequency [Χ2= 10.9, fisher's p = 0.001, odds ratio= 1.51 (95% confidence interval = 1.19-2.00)] and genotype frequency (Χ2 = 11.1, fisher's p = 0.004). OHT cases by themselves showed an association with the intronic tSNP (Χ2 = 3.9, p =0.0482). More importantly, a 3-tSNP haplotype (ATG) was significantly associated with POAG cases (p = 0.0017, permutation p value = 0.0445), and more so with the combined OHT-POAG cases (p = 0.0007, permutation p value = 0.0206). Variants of FOXC1, TGFβ2 and BMP4 were not associated with either OHT or POAG cases.
Conclusions: :
This is the first study to show an association between sequence variants of LMX1B and OHT/POAG. These data suggest that anterior segment dysfunction and/or developmental abnormalities in anterior segment structures caused by altered LMX1B function may predispose to glaucoma in the general adult population. This study provides a platform for further investigation of LMX1B as a genetic risk factor for adult-onset glaucoma.
Keywords: genetics • anterior segment • intraocular pressure