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

TitleGenetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes.
Publication TypeJournal Article
Year of Publication2014
AuthorsYaghootkar H, Scott RA, White CC, Zhang W, 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 M-F, Dastani Z, J Richards B, Semple RK
Secondary AuthorsFrayling TM
JournalDiabetes
Volume63
Issue12
Pagination4369-77
Date Published2014 Dec
ISSN1939-327X
KeywordsBody Mass Index, Coronary Artery Disease, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Humans, Hypertension, Insulin Resistance, Intra-Abdominal Fat, Lipodystrophy, Metabolic Syndrome, Obesity, Odds Ratio, Phenotype, Subcutaneous Fat
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.

DOI10.2337/db14-0318
Alternate JournalDiabetes
PubMed ID25048195
PubMed Central IDPMC4392920
Grant ListG0500070 / / Medical Research Council / United Kingdom
12/0004470 / / Diabetes UK / United Kingdom
MC_UU_12015/1 / / Medical Research Council / United Kingdom
MC_UU_12015/2 / / Medical Research Council / United Kingdom
098498 / / Wellcome Trust / United Kingdom
G0600717 / / Medical Research Council / United Kingdom
100574 / / Wellcome Trust / United Kingdom