Dataset Information

WTCCC2 Pharmacogenomic Response to Statins study

ABSTRACT: A WTCCC2 project genome-wide study for pharmacogenomic response to statins (PR) in individuals from Scotland.

PROVIDER: EGAS00000000121 | EGA |

REPOSITORIES: EGA

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Publications

Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes.

Zhou Kaixin K Bellenguez Celine C Spencer Chris C A CC Bennett Amanda J AJ Coleman Ruth L RL Tavendale Roger R Hawley Simon A SA Donnelly Louise A LA Schofield Chris C Groves Christopher J CJ Burch Lindsay L Carr Fiona F Strange Amy A Freeman Colin C Blackwell Jenefer M JM Bramon Elvira E Brown Matthew A MA Casas Juan P JP Corvin Aiden A Craddock Nicholas N Deloukas Panos P Dronov Serge S Duncanson Audrey A Edkins Sarah S Gray Emma E Hunt Sarah S Jankowski Janusz J Langford Cordelia C Markus Hugh S HS Mathew Christopher G CG Plomin Robert R Rautanen Anna A Sawcer Stephen J SJ Samani Nilesh J NJ Trembath Richard R Viswanathan Ananth C AC Wood Nicholas W NW Harries Lorna W LW Hattersley Andrew T AT Doney Alex S F AS Colhoun Helen H Morris Andrew D AD Sutherland Calum C Hardie D Grahame DG Peltonen Leena L McCarthy Mark I MI Holman Rury R RR Palmer Colin N A CN Donnelly Peter P Pearson Ewan R ER

Nature genetics 20101226 2

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.4 ...[more]

PMID: 21186350

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Project description:Methadone maintenance treatment (MMT) is commonly used for controlling opioid dependence, preventing withdrawal symptoms, and improving the quality of life of heroin-dependent patients. A steady-state plasma concentration of methadone enantiomers, a measure of methadone metabolism, is an index of treatment response and efficacy of MMT. Although the methadone metabolism pathway has been partially revealed, no genome-wide pharmacogenomic study has been performed to identify genetic determinants and characterize genetic mechanisms for the plasma concentrations of methadone R- and S-enantiomers. This study was the first genome-wide pharmacogenomic study to identify genes associated with the plasma concentrations of methadone R- and S-enantiomers and their respective metabolites in a methadone maintenance cohort. After data quality control was ensured, a dataset of 344 heroin-dependent patients in the Han Chinese population of Taiwan who underwent MMT was analyzed. Genome-wide single-locus and haplotype-based association tests were performed to analyze four quantitative traits: the plasma concentrations of methadone R- and S-enantiomers and their respective metabolites. A significant single nucleotide polymorphism (SNP), rs17180299 (raw p = 2.24 × 10-8), was identified, accounting for 9.541% of the variation in the plasma concentration of the methadone R-enantiomer. In addition, 17 haplotypes were identified on SPON1, GSG1L, and CYP450 genes associated with the plasma concentration of methadone S-enantiomer. These haplotypes accounted for approximately one-fourth of the variation of the overall S-methadone plasma concentration. The association between the S-methadone plasma concentration and CYP2B6, SPON1, and GSG1L were replicated in another independent study. A gene expression experiment revealed that CYP2B6, SPON1, and GSG1L can be activated concomitantly through a constitutive androstane receptor (CAR) activation pathway. In conclusion, this study revealed new genes associated with the plasma concentration of methadone, providing insight into the genetic foundation of methadone metabolism. The results can be applied to predict treatment responses and methadone-related deaths for individualized MMTs.

Dataset Information

WTCCC2 Pharmacogenomic Response to Statins study

Publications

Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes.

Similar Datasets

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