Genetic and non-genetic determinants of drug response in type 2 diabetes

• Main Author: Dawed, Adem Yesuf
• Other Authors: Pearson, Ewan
• Published: University of Dundee 2017
• Subjects: 616.4
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.725761

<b>Background</b>: Approximately 415 million people live with diabetes worldwide. Type 2 diabetes (T2D) accounts for 85%–95% of the cases. Despite the availability of several drugs, considerable interindividual variation in response to medications results in unnecessary treatment failure. In addition to non-genetic factors, genetic factors are thought to contribute to such variability. <b>Aim</b>: This thesis attempts to investigate genetic and non-genetic factors underlying the variability in response to commonly used drugs in T2D. <b>Methods</b>: We assessed drug response as efficacy and/or adverse effect following treatment using data gathered from medical records mainly from the Diabetes Research for Patient Stratification (DIRECT) consortium and the Genetics of Diabetes Audit and Research Tayside Study (GoDARTS). Genetic data was obtained using chip-based arrays followed by imputation and TaqMan genotyping. Subsequent candidate gene and genome wide association (GWAS) analyses were conducted using linear and logistic regressions followed by meta-analyses. In addition, downstream rare variant burden test and pathway analyses were performed. <b>Results</b>: We showed robust association of metformin use with fasting glucagon like peptide-1 (GLP-1) levels in diabetic and non-diabetic subjects. Gastrointestinal (GI) irritation is the most common side effect of metformin. Concomitant administration of metformin with gut metformin transporter inhibiting drugs such as tricyclic antidepressants, proton pump inhibitors and codeine increased the odds of GI intolerance. Moreover we showed association of the G allele at rs3889348-<i>SLC29A4</i> (PMAT) with increased odds of intolerance.  In the GoDARTS study performed on subjects who have been taking sulphonylureas (SUs) as an add-on therapy to metformin, carriers of the K allele at E23K-<i>KCNJ11</i> had greater HbA1c reduction and this was replicated in another study using data from the Diabetes Care System West-Friesland (DCS) study. We also identified a novel locus, rs11535279-<i>LHFPL3</i>, associated with glycaemic response to SUs. Further analysis revealed enrichment of the insulin/IGF pathway-mitogen activated protein kinase/MAPK cascade in glycaemic response to SU treatment suggesting the role of the post insulin secretion pathway in glycaemic response to SUs. In a study investigating joint effect of variants in transporter (<i>SLCO1B1</i> 521T>C) and metabolizing (CYP2C8*<i>3</i>) proteins with HbA1c reduction and weight gain to thiazolidinediones (TZDs), we showed a large clinical impact on the therapeutic response to rosiglitazone.  Lastly, in a meta-analysis consisting of 1,235 T2D subjects treated with GLP-1RAs, carriers of two or more variant alleles derived from <i>GLP-1R</i> variants (Gly168Ser and Pro7Leu) had significantly reduced efficacy compared to homozygous carriers of the parent alleles. In addition, rare variant analysis revealed suggestive evidence of association of the mutational load of variants in genes previously implicated in GLP-1/glucose stimulated insulin secretion with glycaemic response to GLP-1RAs. Conclusions</b>: In this thesis, we have identified clinical and novel genetic factors underlying treatment efficacy and adverse effects related to drugs used to treat in T2D.