title: Genetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes.
abstract: 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, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin-based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed 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 (β = 0.018; P = 4 × 10(-29)), lower HDL cholesterol (β = -0.020; P = 7 × 10(-37)), greater hepatic steatosis (β = 0.021; P = 3 × 10(-4)), higher alanine transaminase (β = 0.002; P = 3 × 10(-5)), lower sex-hormone-binding globulin (β = -0.010; P = 9 × 10(-13)), and lower adiponectin (β = -0.015; P = 2 × 10(-26)). The same risk alleles were associated with lower BMI (per-allele β = -0.008; P = 7 × 10(-8)) and increased visceral-to-subcutaneous adipose tissue ratio (β = -0.015; P = 6 × 10(-7)). Individuals carrying ≥17 fasting insulin-raising alleles (5.5% population) were slimmer (0.30 kg/m(2)) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5 × 10(-13)), CAD (OR 1.12; per-allele P = 1 × 10(-5)), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg [per-allele P = 2 × 10(-5)] and 0.67 mmHg [per-allele P = 2 × 10(-4)], respectively) compared with 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.
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
authors.forename: Hanieh
authors.initials: H
authors.lastname: Yaghootkar
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, U.K.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Scott
authors.affiliation: Framingham Heart Study, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, MA Department of Biostatistics, Boston University School of Public Health, Boston, MA.
authors.forename: Charles C
authors.initials: CC
authors.lastname: White
authors.affiliation: Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, U.K.
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Speliotes
authors.affiliation: Clinical 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, U.K.
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Munroe
authors.affiliation: Cardiology Center, Geneva University Hospital, Geneva, Switzerland Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD.
authors.forename: Georg B
authors.initials: GB
authors.lastname: Ehret
authors.affiliation: Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.affiliation: Framingham Heart Study, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, MA Center for Population Studies, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, MA Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K.
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, MO.
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.affiliation: Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Knowles
authors.affiliation: University of Maryland School of Medicine, Division of Endocrinology, Baltimore, MA.
authors.forename: Laura
authors.initials: L
authors.lastname: Yerges-Armstrong
authors.affiliation: Center for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, U.K.
authors.forename: John R B
authors.initials: JR
authors.lastname: Perry
authors.affiliation: Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, U.K.
authors.forename: John C
authors.initials: JC
authors.lastname: Chambers
authors.affiliation: Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, U.K.
authors.forename: Jaspal S
authors.initials: JS
authors.lastname: Kooner
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, U.K. Department of Epidemiology and Public Health, University College London, London, U.K.
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.affiliation: Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA General Medicine Division, Massachusetts General Hospital, Boston, MA.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Hivert
authors.affiliation: Departments of Human Genetics and Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada.
authors.forename: Zari
authors.initials: Z
authors.lastname: Dastani
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, U.K. Department of Medicine, Human Genetics, Epidemiology, and Biostatistics, McGill University, Montreal, Quebec, Canada.
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
authors.affiliation: The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, U.K. The University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge, U.K.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Semple
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K. t.m.frayling@ex.ac.uk.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
mesh_terms: D015992:Body Mass Index; D003324:Coronary Artery Disease / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics*; D050152:Intra-Abdominal Fat; D008060:Lipodystrophy / Q000235:genetics*; D024821:Metabolic Syndrome / Q000235:genetics*; D009765:Obesity / Q000235:genetics; D016017:Odds Ratio; D010641:Phenotype; D050151:Subcutaneous Fat