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An Investigation of the Developmental Glaucoma Genes as Genetic Risk Factors in Ocular Hypertension and Primary Open Angle Glaucoma

¹Developmental Biology Unit, UCL Institute of Child Health, London, United Kingdom
²Division of Clinical Developmental Sciences, St George’s Hospital Medical School, London, United Kingdom
³Ophthalmology, The Newcastle upon Tyne Hospitals NHS Trust, Newcastle, United Kingdom
⁴Ophthalmology, Sunderland Eye Infirmary, Sunderland, United Kingdom

Commercial Relationships: S. Park, None; Y. Jamshidi, None; D. Vaideanu, None; S. Fraser, None; J.C. Sowden, None.

Support: The Royal College of Surgeons of Edinburgh, Alcon Laboratories

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, ²= 9.4, fisher's p = 0.002, odds ratio= 1.5 (95% confidence interval = 1.16-2.00)] and genotype frequency (² = 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 [²= 10.9, fisher's p = 0.001, odds ratio= 1.51 (95% confidence interval = 1.19-2.00)] and genotype frequency (² = 11.1, fisher's p = 0.004). OHT cases by themselves showed an association with the intronic tSNP (² = 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

© 2008, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Permission to republish any abstract or part of an abstract in any form must be obtained in writing from the ARVO Office prior to publication.