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Pirro G Hysi, Mark James Simcoe, Anthony P Khawaja, Christopher J Hammond; Gene-drug interactions alter response to prostaglandin analogue treatment of high intraocular pressure and glaucoma. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5223.
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Prostaglandin analogues (PGA) are the most commonly drugs used to treat high intraocular pressure (IOP) and glaucoma. However, one in five patients fails to satisfactorily respond to PGA treatment. It is currently unclear how much of the non-response rate is due to molecular mechanisms under pharmacogenetic control. The purpose of this work was to conduct a genome-wide exploration of genetic factors that modify response to PGA.
The work was conducted in two stages. In the first, we studied the post-treatment IOP measurements as a function of their genotypes in subjects treated with PGA, other classes of IOP-lowering drugs using a gene-by-environment interaction model in UK Biobank participants. In the second stage, significant genetic variants identified in the first stage we evaluated for association for with response to PGA in a small cohort (N=180) of British patients with primary open angle glaucoma, for whom both pre- and post-treatment IOP measurements were available. In both stages we grouped together patients treated by any PGA medication, removed subjects who had received surgery or laser interventions and adjusted analyses for age, sex and main principal components.
The genome-wide association analysis, identified a statistically significant gene by drug association for several common genetic variants located on the same genomic region, between the DAG1 and BSN genes. The rs73074830.T allele was associated with a lower post-treatment IOP (β=1.58mmHg, p=3.21x10-08) among PGA-treated patients, but not among patients receiving beta-blockers or untreated participants. The same variant was also significantly associated with the difference between pre- and post-treatment IOP levels in the smaller replication cohort (β=1.48mmHg, p=0.036). DAG1 participates in laminin and basal membrane asembly, and may be involved in maintaining tissue permeability, while the wider genomic region has previously been associated with muscular dystrophy, autoimmune, hematopoietic, cognitive, serum protein levels, etc.
This study is the first GWAS of pharmacogenomics of IOP-lowering drugs efficacy. Despite limitations, such as relatively small sample sizes, potential efficacy heterogeneity among different preparations, and imperfect study design for the discovery stage, this study identified a candidate region that may alter individual patients’ response to PGA.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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