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Variants of the caveolin-1 gene: a translational investigation linking insulin resistance and hypertension.

ABSTRACT: The co-occurrence of insulin resistance (IR) and hypertension is a heritable condition leading to cardiovascular complications. Caveolin-1 (CAV1), a gene previously associated with metabolic dysfunction in animal and cellular models, may be a marker for these conditions in humans.The objective of the study was to examine the relationship between CAV1 variants and IR in two hypertensive cohorts and to corroborate the findings in a CAV1 knockout mouse.A candidate gene association study was conducted in two hypertensive cohorts: 1) Caucasian and 2) Hispanic. Multivariate associations between individual variants and insulin-resistant phenotypes were analyzed, accounting for age, gender, body mass index, and sibling relatedness. Intraperitoneal glucose tolerance tests were conducted in wild-type and CAV1 knockout mice.In the Caucasian hypertensive cohort, minor allele carriers of two CAV1 single-nucleotide polymorphisms (rs926198, rs3807989) had significantly higher fasting insulin levels (P = 0.005, P = 0.007), increased homeostatic assessment model for insulin resistance (HOMA-IR) (P =0.005, P = 0.008), and decreased M value during hyperinsulinemic, euglycemic clamp procedure (P = 0.004, P = 0.05) than major allele homozygotes. Findings were replicated in the Hispanic hypertensive cohort cohort for fasting insulin levels (P = 0.005, P = 0.02) and HOMA-IR (P = 0.008 and P = 0.02). Meta-analysis demonstrated significant associations of both single-nucleotide polymorphisms with fasting insulin levels (P = 0.00008, P = 0.0004) and HOMA-IR (P = 0.0001, P = 0.0004). As compared with wild type, CAV1 knockout mice displayed higher blood pressure levels and higher fasting glucose, insulin, and HOMA-IR levels and an exaggerated glycemic response to a glucose challenge.Variations in the CAV1 gene are associated with IR and hypertension. CAV1 gene polymorphisms may be a biomarker for IR and hypertension, enabling earlier detection and improved treatment strategies.

SUBMITTER: Pojoga LH

PROVIDER: S-EPMC3146791 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Variants of the caveolin-1 gene: a translational investigation linking insulin resistance and hypertension.

Pojoga Luminita H LH Underwood Patricia C PC Goodarzi Mark O MO Williams Jonathan S JS Adler Gail K GK Jeunemaitre Xavier X Hopkins Paul N PN Raby Benjamin A BA Lasky-Su Jessica J Sun Bei B Cui Jinrui J Guo Xiuqing X Taylor Kent D KD Chen Yii-Der Ida YD Xiang Anny A Raffel Leslie J LJ Buchanan Thomas A TA Rotter Jerome I JI Williams Gordon H GH

The Journal of clinical endocrinology and metabolism 20110525 8

<h4>Context</h4>The co-occurrence of insulin resistance (IR) and hypertension is a heritable condition leading to cardiovascular complications. Caveolin-1 (CAV1), a gene previously associated with metabolic dysfunction in animal and cellular models, may be a marker for these conditions in humans.<h4>Objective</h4>The objective of the study was to examine the relationship between CAV1 variants and IR in two hypertensive cohorts and to corroborate the findings in a CAV1 knockout mouse.<h4>Design, ...[more]

PMID: 21613355

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Project description: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.

Dataset Information

Variants of the caveolin-1 gene: a translational investigation linking insulin resistance and hypertension.

Publications

Variants of the caveolin-1 gene: a translational investigation linking insulin resistance and hypertension.

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