Park, S.; (2009) An investigation of genetic risk factors in primary open-angle glaucoma. Doctoral thesis , UCL (University College London).

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Abstract

Primary open-angle glaucoma (POAG) is a multifactorial disease with a strong genetic component. Notably however, few genes have been robustly associated with POAG in the general population. Genes in which mutation causes anterior segment angle anomalies, including LMX1B and FOXC1 are associated with a high incidence of glaucoma to about 33-75% and are strong candidates for glaucoma susceptibility. In addition, growth factors including TGFβ2 and BMP4 act in concert to maintain a balance between extracellular matrix (ECM) deposition and degradation and may play a role in glaucoma pathogenesis through misregulation of ECM synthesis of the trabecular meshwork (TM). Furthermore, OPTN E50K mutation, a known genetic locus for POAG, has been shown to account for a high percentage of 13.5% of familial normal-tension glaucoma (NTG) in individuals of white British origin. In this study, the contribution of variation at the LMX1B, FOXC1, TGFβ2 and BMP4 loci to risk of glaucoma was investigated in a case-control genetic association study in a cohort of white British descent recruited in the North-East of England comprised of 272 patients with high-tension glaucoma (HTG), 37 patients with NTG, 58 patients with ocular hypertension (OHT), and 276 normal controls. The role of OPTN E50K mutation in these unrelated white British individuals with POAG was also examined. No significant associations were identified for FOXC1, TGFβ2 and BMP4. The OPTN E50K mutation was also absent in this cohort. The study identified a significant under representation of two LMX1B haplotypes [ATG; P = 5.0E-4 (permutation P = 0.01), GCAGAC; P = 5.0E-4 (permutation P = 0.0150)] among the POAG individuals compared to the control population, consistent with a 0.3 fold decreased risk of developing POAG. A replication study involving a second cohort of 222 NTGs and 108 HTGs recruited in London showed a similar distribution of the ATG haplotype (P = 0.0047) but did not withstand permutation testing. In conclusion, LMX1B haplotypes may influence susceptibility to develop POAG in the white British population, suggesting altered LMX1B function predisposes to glaucomatous damage.

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