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.
- © 2014 by the American Diabetes Association.
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 http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.