بيانات النشر: Mittuniversitetet, Avdelningen för hälsovetenskap
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Lund University, Malmö, Sweden
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom
Department of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Jewish General Hospital, Montreal, QC, Canada
European Molecular Biology Laboratory-European Bioinformatics Institute, Cambridge, United Kingdom
Department of Clinical Sciences, Genetic and Molecular Epidemiology, Lund University Diabetes Centre, Lund University, Malmö, Sweden
Broad Institute of Massachusetts Institute of Technology, Harvard University, Cambridge, MA, USA
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom
نبذة مختصرة : Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of >7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] <5%; P < 1.96×1025) and 49 expression-insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment-insulin resistance, and BMI) (FDR <5%; P = 1.34×1024). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Furthermore, the expression of PFKM, a rate-limiting enzyme in glycolysis, was nominally associated with glucose uptake in skeletal muscle (P = 0.026; n = 42) and overexpressed (Bonferroni-corrected P = 0.03) in skeletal muscle of patients with T2D (n = 102) compared with normoglycemic controls (n = 87). The PFKM eQTL (rs4547172; P = 7.69 × 1026) was nominally associated with glucose uptake, glucose oxidation rate, intramuscular triglyceride content, and metabolic flexibility (P = 0.016-0.048; n = 178). We explored eQTL results using published data from genome-wide association studies (DIAGRAM and MAGIC), and a proxy for the PFKM eQTL (rs11168327; r 2 = 0.75) was nominally associated with T2D (DIAGRAM P = 2.7×1023). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity. © 2014 by the American Diabetes Association. ; Language of Original Document: English
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