Skeletal Muscle Expression of Phosphofructokinase is Influenced by Genetic Variation and Associated with Insulin Sensitivity

  1. Ola Hansson2,*
  1. 1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, United Kingdom
  2. 2 Lund University Diabetes Center, Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital Malmö, Lund University, Malmö 20502, Sweden
  3. 3 Department of Twin Research and Genetic Epidemiology, King’s College London, London, SE1 7EH, United Kingdom
  4. 4 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, United Kingdom
  5. 5 Department of Genetic Medicine and Development, University of Geneva, Medical School, 1211 Geneva 4, Switzerland
  6. 6 Department of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, H3T 1E2, Canada
  7. 7 Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom
  8. 8 Swedish Winter Sports Research Centre, Department of Health Sciences, Mid Sweden University, SE-83125 Östersund, Sweden
  9. 9 EMBL-EBI, European Molecular Biology Laboratory-European Bioinformatics Institute, Cambridge, CB10 1SD, United Kingdom
  10. 10 Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, OX3 7LE, United Kingdom
  11. 11 Lund University Diabetes Center, Department of Clinical Sciences, Genetic and Molecular Epidemiology, Skåne University Hospital Malmö, Lund University, Malmö 20502, Sweden
  12. 12 Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  1. Corresponding Author: Dr. Ola Hansson, E-mail: ola.hansson{at}


Using an integrative approach where genetic variation, gene expression and clinical phenotypes are assessed in relevant tissues may help functionally characterize the genetic contribution to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (eQTL), as well as expression associated with measures of insulin sensitivity. We investigated associations of 3799401 genetic variants with gene expression from >7000 genes from three cohorts (n=104). We identified 287 genes with cis-acting eQTLs (FDR<5%; P<1.96x10-5) and 49 expression-insulin sensitivity phenotype associations (i.e. fasting insulin, HOMA-IR and BMI) (FDR<5%; P=1.34x10-4). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Further, 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 over-expressed (PBF-corrected=0.03) in skeletal muscle in T2D patients (n=102) compared with normoglycemic controls (n=87). The PFKM eQTL (rs4547172; PeQTL=7.69x10-6) 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 GWAS data (from DIAGRAM and MAGIC) and a proxy for the PFKM eQTL (rs11168327, r2=0.75), was nominally associated with T2D (PDIAGRAM=2.7x10-3). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity.


  • * These authors contributed equally to this work

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

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See for details.