Genetic evidence for a normal-weight “metabolically obese” phenotype linking insulin resistance, hypertension, coronary artery disease and type 2 diabetes

  1. Timothy M. Frayling1
  1. 1Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
  2. 2MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK.
  3. 3Framingham Heart Study, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Framingham, Massachusetts, USA.
  4. 4Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
  5. 5Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
  6. 6Department of Internal Medicine, Division of Gastro enterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI
  7. 7Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
  8. 8Cardiology Center, Geneva University Hospital, Geneva, Switzerland.
  9. 9Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD.
  10. 10Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, Washington, USA.
  11. 11Center for Population Studies, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Framingham, Massachusetts, USA.
  12. 12Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  13. 13Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  14. 14Department of Genetics, Washington University School of Medicine, St Louis, MO.
  15. 15Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.
  16. 16University of Maryland School of Medicine, Division of Endocrinology, Baltimore, Maryland, USA.
  17. 17Center for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  18. 18Cardiovascular Science, National Heart & Lung Institute, Imperial College London, London, UK.
  19. 19Department of Epidemiology, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA.
  20. 20Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
  21. 21Department of Epidemiology and Public Health, University College London, London, UK.
  22. 22Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA, USA.
  23. 23General Medicine Division, Massachusetts General Hospital, Boston, MA, USA.
  24. 24Departments of Human Genetics and Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada.
  25. 25Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
  26. 26Department of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal, Canada.
  27. 27The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.
  28. 28The University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge, UK.
  1. Corresponding author: Timothy M. Frayling, E-mail: T.M.Frayling{at}


The mechanisms that predispose to hypertension, coronary artery disease (CAD) and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy – a reduction in subcutaneous adipose tissue – it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, coronary artery disease and type 2 diabetes. We aimed to test the hypothesis that common alleles associated with insulin resistance also influence the wider clinical and biochemical profile of monogenic insulin resistance. We selected 19 common genetic variants associated with fasting insulin based measures of insulin resistance. We used hierarchical clustering and results from genome wide association studies of 8 non-disease outcomes of monogenic insulin resistance, to group these variants. We analysed genetic risk scores against disease outcomes including 12,171 T2D cases, 40,365 CAD cases and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle, form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (ß=0.018; p=4x10-29), lower HDL cholesterol (ß=-0.020; p=7x10-37), greater hepatic steatosis (ß=0.021; p=3x10-4) higher alanine transaminase (ß=0.002; p=3x10-5), lower SHBG (ß=-0.010; p=9x10-13) and lower adiponectin (ß=-0.015; p=2x10-26). The same risk alleles were associated with lower BMI (per-allele ß=-0.008; p=7x10-8), and increased visceral-to-subcutaneous adipose tissue ratio (ß=-0.015; p=6x10-7). Individuals carrying >= 17 fasting insulin raising alleles (5.5% population) were slimmer (0.30 kgm-2) but at increased risk of T2D (odds ratio [OR] 1.46, per-allele p=5x10-13), CAD (OR 1.12, per-allele p=1x10-5), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg (per-allele p=2x10-5), and 0.67 mmHg (per-allele p=2x10-4), respectively, compared to individuals carrying <=9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the “metabolic syndrome” and point to reduced subcutaneous adiposity as a central mechanism.

  • Received February 24, 2014.
  • Accepted July 7, 2014.

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