Your browser has javascript turned off or blocked. This will lead to some parts of our website to not work properly or at all. Turn on javascript for best performance.

The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Paul Franks

Paul Franks

Principal investigator

Paul Franks

Common variation in PPARGC1A/B and progression to diabetes or change in metabolic traits following preventive interventions: the Diabetes Prevention Program.

Author

  • Paul Franks
  • C A Christophi
  • K A Jablonski
  • L M Delahanty
  • E S Horton
  • W C Knowler
  • J C Florez

Summary, in English

AIMS/HYPOTHESIS: PPARGC1A and PPARGC1B encode transcriptional coactivators that regulate numerous type 2 diabetes-related metabolic processes. Common genetic variation across PPARGC1A/B was characterised by genotyping tagging variants. We then tested associations of these variants with diabetes incidence or change in quantifiable metabolic traits directly or via interactions (with metformin treatment or intensive lifestyle modification) in the Diabetes Prevention Program (DPP), a randomised controlled trial in persons at high risk of type 2 diabetes. METHODS: We used Tagger software to select 75 PPARGC1A and 94 PPARGC1B tag single nucleotide polymorphisms (SNPs) for analysis. These SNPs were tested for association with diabetes incidence using Cox proportional hazards regression models, and a range of relevant metabolic quantifiable traits, using generalised linear models. RESULTS: Eight PPARGC1A variants were nominally (p < 0.05) associated with diabetes incidence, of which one (rs3736265/Thr612Met) was associated with diabetes in the DPP (HR 1.31, 95% CI 1.05, 1.63 per copy of the 612Met allele) and in the DIAGRAM database (OR 1.11, 95% CI 1.01, 1.21). Consistent with earlier reports, the Gly482Ser (rs8192678) variant showed nominally significant effects on 1 year accumulation of adiposity and worsening insulin resistance (both p < 0.05). A third PPARGC1A variant (rs2970852) modified the effects of metformin on triacylglycerol levels (p interaction = 0.04; p = 0.0001 for association of SNP with triacylglycerol concentrations in metformin-treated participants). A number of other PPARGC1A/B variants were nominally directly associated with diabetes incidence or modified treatment effects on diabetes incidence. CONCLUSIONS/INTERPRETATION: These findings provide some novel and confirmatory insights into the roles of PPARGC1A/B variation in type 2 diabetes and related metabolic traits. TRIAL REGISTRATION: ClinicalTrials.gov NCT00004992.

Department/s

  • Genetic and Molecular Epidemiology
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • EpiHealth: Epidemiology for Health

Publishing year

2013-04-25

Language

English

Publication/Series

Diabetologia

Document type

Journal article

Publisher

Springer

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Genetic and Molecular Epidemiology

ISBN/ISSN/Other

  • ISSN: 1432-0428