Expression of Phosphofructokinase in Skeletal Muscle Is Influenced by Genetic Variation and Associated With Insulin Sensitivity

  1. Ola Hansson2
  1. 1Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
  2. 2Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Skåne University Hospital Malmö, Lund University, Malmö, Sweden
  3. 3Department of Twin Research and Genetic Epidemiology, King’s College London, London, U.K.
  4. 4Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, U.K.
  5. 5Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
  6. 6Department of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
  7. 7Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Oxford, U.K.
  8. 8Swedish Winter Sports Research Centre, Department of Health Sciences, Mid Sweden University, Östersund, Sweden
  9. 9Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
  10. 10European Molecular Biology Laboratory–European Bioinformatics Institute, Cambridge, U.K.
  11. 11Department of Clinical Sciences, Genetic and Molecular Epidemiology, Lund University Diabetes Centre, Skåne University Hospital Malmö, Lund University, Malmö, Sweden
  12. 12Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA
  1. Corresponding author: Ola Hansson, ola.hansson{at}
  1. S.K., J.F., C.M.L., and O.H. contributed equally to this work.


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 × 10−5) and 49 expression–insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment–insulin resistance, and BMI) (FDR <5%; P = 1.34 × 10−4). 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 × 10−6) 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; r2 = 0.75) was nominally associated with T2D (DIAGRAM P = 2.7 × 10−3). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity.


  • Received August 26, 2013.
  • Accepted November 29, 2013.

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