Diabetologia, 2014, Vol.57(3), pp.485-490
Byline: Paul W. Franks (1,2,3,4), Costas A. Christophi (4), Kathleen A. Jablonski (4), Liana K. Billings (5,6), Linda M. Delahanty (5,6), Edward S. Horton (6,7), William C. Knowler (8), Jose C. Florez (5,6,9) Keywords: Cholesterol; Dyslipidaemia; Gene x environment interaction; Gene x lifestyle interaction; Genetics; Lifestyle intervention; Metformin; Pharmacogenetics; PPARGC1A; PPARGC1B; Randomised controlled trial; Triacylglycerol Abstract: Aims/hypothesis PPARGC1A and PPARGCB encode transcriptional coactivators that regulate numerous metabolic processes. We tested associations and treatment (i.e. metformin or lifestyle modification) interactions with metabolic traits in the Diabetes Prevention Program, a randomised controlled trial in persons at high risk of type 2 diabetes. Methods We used Tagger software to select 75 PPARGCA1 and 94 PPARGC1B tag single-nucleotide polymorphisms (SNPs) for analysis. These SNPs were tested for associations with relevant cardiometabolic quantitative traits using generalised linear models. Aggregate genetic effects were tested using the sequence kernel association test. Results In aggregate, PPARGC1A variation was strongly associated with baseline triacylglycerol concentrations (p=2.9x10.sup.-30), BMI (p=2.0x10.sup.-5) and visceral adiposity (p=1.9x10.sup.-4), as well as with changes in triacylglycerol concentrations (p=1.7x10.sup.-5) and BMI (p=9.9x10.sup.-5) from baseline to 1 year. PPARGC1B variation was only associated with baseline subcutaneous adiposity (p=0.01). In individual SNP analyses, Gly482Ser (rs8192678, PPARGC1A) was associated with accumulation of subcutaneous adiposity and worsening insulin resistance at 1 year (both p〈0.05), while rs2970852 (PPARGC1A) modified the effects of metformin on triacylglycerol levels (p .sub.interaction=0.04). Conclusions/interpretation These findings provide several novel and other confirmatory insights into the role of PPARGC1A variation with respect to diabetes-related metabolic traits. Trial registration ClinicalTrials.gov NCT00004992 Author Affiliation: (1) Department of Clinical Science, Genetic and Molecular Epidemiology Unit, Lund University, Malmo, Sweden (2) Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden (3) Department of Nutrition, Harvard School of Public Health, Boston, MA, USA (4) Diabetes Prevention Program Coordinating Center, The Biostatistics Center, George Washington University, 6110 Executive Blvd, Suite 750, Rockville, MD, 20852, USA (5) Department of Medicine, Harvard Medical School, Boston, MA, USA (6) Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA, USA (7) Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA (8) Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, USA (9) Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA Article History: Registration Date: 26/11/2013 Received Date: 23/09/2013 Accepted Date: 19/11/2013 Online Date: 07/12/2013 Article note: A full list of Diabetes Prevention Program investigators is shown in the electronic supplementary material (ESM) Disclosure A previous version of this paper (doi 10.1007/s00125-013-2911-3) was retracted because of an inadvertent overlap with an earlier broader study (Jablonski et al, Diabetes, 2010 doi: 10.2337/db10-0543). In the retracted article one of the key findings had been reported in the supplementary materials of Jablonski et al. The article was retracted at the request of the authors before it was published in print form. The retracted paper has now been completely replaced by this version. Electronic supplementary material The online version of this article (doi: 10.1007/s00125-013-3133-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Cholesterol ; Dyslipidaemia ; Gene × environment interaction ; Gene × lifestyle interaction ; Genetics ; Lifestyle intervention ; Metformin ; Pharmacogenetics ; PPARGC1A ; PPARGC1B ; Randomised controlled trial ; Triacylglycerol
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