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.

Figure 1

Cluster analysis of fasting insulin variants using eight traits known to be nondisease metabolic traits of monogenic IR, including those representing dyslipidemia (HDL and triglyceride), adiposity (BMI and visceral-to-subcutaneous adipose tissue ratio), fatty liver (CT-measured hepatic steatosis and the liver enzyme ALT), and adiponectin and SHBG levels. The dendrogram (A) shows that 11 variants and 5 variants are grouped in two significant clusters (the approximate unbiased values = 96% [P = 0.04] and 98% [P = 0.02], respectively). The heatmap (B) shows this cluster is consistent with monogenic lipodystrophic IR; the stronger the green color, the stronger the effect of the insulin-raising allele with reduced trait levels; the stronger the pink color, the stronger the effect of the insulin-raising allele with higher trait levels. VATSAT, visceral-to-subcutaneous adipose tissue ratio; NAFLD, nonalcoholic fatty liver disease.

Figure 2

Forest plots of the effect of the 11 “lipodystrophy-like” variants on six metabolic disease outcomes. The x-axis is the effect size per fasting insulin–increasing alleles on each trait. The dashed line is the null effect. For cIMT, actual effects ranged from −0.003 to 0.003 but here are shown rounded to two decimal places. FE, fixed effect.