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Genetic Evidence for a Normal-Weight "Metabolically Obese" Phenotype Linking Insulin Resistance, Hypertension, Coronary Artery Disease, and Type 2 Diabetes

Lookup NU author(s): Professor Mark Walker


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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 (beta = 0.018; P = 4 x 10(-29)), lower HDL cholesterol (beta = -0.020; P = 7 x 10(-37)), greater hepatic steatosis (beta = 0.021; P = 3 x 10(-4)), higher alanine transaminase (beta = 0.002; P = 3 x 10(-5)), lower sex-hormone-binding globulin (beta = -0.010; P = 9 x 10(-13)), and lower adiponectin (beta = -0.015; P = 2 x 10(-26)). The same risk alleles were associated with lower BMI (per-allele beta = -0.008; P = 7 x 10(-8)) and increased visceral-to-subcutaneous adipose tissue ratio (beta = -0.015; P = 6 x 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 x 10(-13)), CAD (OR 1.12; per-allele P = 1 x 10(-5)), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg [per-allele P = 2 x 10(-5)] and 0.67 mmHg [per-allele P = 2 x 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.

Publication metadata

Author(s): Yaghootkar H, Scott RA, White CC, Zhang WH, Speliotes E, Munroe PB, Ehret GB, Bis JC, Fox CS, Walker M, Borecki IB, Knowles JW, Yerges-Armstrong L, Ohlsson C, Perry JRB, Chambers JC, Kooner JS, Franceschini N, Langenberg C, Hivert MF, Dastani Z, Richards JB, Semple RK, Frayling TM

Publication type: Article

Publication status: Published

Journal: Diabetes

Year: 2014

Volume: 63

Issue: 12

Pages: 4369-4377

Print publication date: 01/12/2014

Acceptance date: 15/07/2014

ISSN (print): 0012-1797

ISSN (electronic): 1939-327X

Publisher: American Diabetes Association


DOI: 10.2337/db14-0318


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Funder referenceFunder name
National Institute for Health Research Barts Cardiovascular Biomedical Research Unit
University of Exeter Medical School
Wellcome Trust
ERS: 323195European Research Council