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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

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