Aims/hypothesis Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study... Show moreAims/hypothesis Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes.Methods One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and primary endpoints of drug response. In a more focused analysis, we evaluated the influence of 804 unique type 2 diabetes- and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalisation analyses to identify shared genetic signals.Results Five genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency [MAF(Afr)]=0.0283) at rs149403252 and lower fasting glucose at Visit 2 following metformin (p=1.9x10(-9)); carriers were found to have a 0.94 mmol/l larger decrease in fasting glucose. rs111770298, another African ancestry-specific variant (MAF(Afr)=0.0536), was associated with a reduced response to metformin (p=2.4x10(-8)), where carriers had a 0.29 mmol/l increase in fasting glucose compared with non-carriers, who experienced a 0.15 mmol/l decrease. This finding was validated in the Diabetes Prevention Program, where rs111770298 was associated with a worse glycaemic response to metformin: heterozygous carriers had an increase in HbA(1c) of 0.08% and non-carriers had an HbA(1c) increase of 0.01% after 1 year of treatment (p=3.3x10(-3)). We also identified associations between type 2 diabetes-associated variants and glycaemic response, including the type 2 diabetes-protective C allele of rs703972 near ZMIZ1 and increased levels of active glucagon-like peptide 1 (GLP-1) (p=1.6x10(-5)), supporting the role of alterations in incretin levels in type 2 diabetes pathophysiology.Conclusions/interpretation We present a well-phenotyped, densely genotyped, multi-ancestry resource to study gene-drug interactions, uncover novel variation associated with response to common glucose-lowering medications and provide insight into mechanisms of action of type 2 diabetes-related variation. Show less
In many patients drugs do not show the expected efficacy, whereas in other patients they cause toxic effects, sometimes even at low dose. Response rates to major classes of drugs range from 25 to... Show moreIn many patients drugs do not show the expected efficacy, whereas in other patients they cause toxic effects, sometimes even at low dose. Response rates to major classes of drugs range from 25 to 60 percent. For some patients, the reason for this variability may be explained by genetic variation. Pharmacogenetics is the study of variations in DNA sequence as related to drug response. The ultimate goal of pharmacogenetics is to predict and thereby improve drug response in the individual patient. The concept of interindividual differences in drug response was proposed as early as 1909. With the completion of the Human Genome Project in 2003 hope was raised that pharmacogenetics could be implemented in clinical practice in the near future. However, the clinical use of pharmacogenetic testing remained limited. Yet, the body of evidence supporting its usefulness is growing continuously. The research presented in this thesis aims to identify the reasons for the slow clinical translation of pharmacogenetics and to explore and expand possible solutions to address these obstacles. The thesis is divided into four parts. First, obstacles and possible solutions for the clinical implementation of pharmacogenetics are identified. In the second part, issues related to the quality control of pharmacogenetic testing are discussed. In the third part, the influence of genetic variation on the response to sulfonylureas is used as a case model to investigate the possibilities for pharmacogenetics in primary care. The fourth part contains the general discussion and a future outlook. Show less
