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Title: Pharmacogenetics of glaucoma : the role of beta2 adrenoreceptor and prostanoid (FP) receptor polymorphisms in the response to topical timolol and latanoprost in Malaysian population
Author: Ahmad Tajudin, L. B.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2012
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Personalised medicine has been area of interest for decades especially in treatment of chronic diseases, such as glaucoma. Topical pressure lowering medication is an effective mode of treatment. Variation in responsiveness to these medications is well recognised. In this thesis, the possible role of genetics in governing the responsiveness to topical Timolol XE 0.5% and latanoprost 0.005% was studied. The possible role of beta2 adrenoreceptor gene (ADRB2) and prostaglandin FP receptor gene (PTGFR) as susceptibility genes for glaucoma was also explored. A prospective observational cohort study of 97 and 86 glaucoma patients (POAG and NTG) treated with topical timolol monotherapy and topical latanoprost respectively was conducted. Intraocular pressure (IOP) was measured at baseline, 1, 3, 6 and 12 months post-treatment. Venesection was conducted on glaucoma patients and 190 unrelated age/ethnicity-matched controls. High purity genomic DNA was extracted and subjected for multiplex PCR to detect polymorphism at specific codons within ADRB2. Direct sequencing was used to screen the PTGFR covering 3000bp upstream from 5‟UTR and 1000bp downstream from 3‟UTR. Topical timolol and latanoprost provided good pressure lowering effect with mean IOP reduction from baseline of 5.4(5.1) mmHg and 7.1(4.2) mmHg respectively. Higher baseline IOP was found in patients with -47CC and 79CC of ADRB2. There was no significant association between ADRB2 and responsiveness to topical timolol. 79G and -20T were found to increase the susceptibility to glaucoma 1.9-fold (95%CI 1.0, 3.6) and 1.7-fold (95% CI 1.1, 2.7) respectively. Certain PTGFR polymorphisms appeared to confer protective effects against glaucoma. The minor alleles of rs11162505, rs554185 and rs551253 reduced the susceptibility to glaucoma significantly. rs686262GG was associated with 6.3-fold (95%CI 1.3, 31.0) risk of poor response to topical latanoprost. Therefore, ADRB2 and PTGFR are potential pharmacodynamic genes for the responsiveness to topical timolol and latanoprost. ADRB2 and PTGFR may also act as susceptibility genes for glaucoma.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available