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- Title
Variants of the caveolin-1 gene: a translational investigation linking insulin resistance and hypertension.
- Authors
Pojoga, Luminita H; Underwood, Patricia C; Goodarzi, Mark O; Williams, Jonathan S; Adler, Gail K; Jeunemaitre, Xavier; Hopkins, Paul N; Raby, Benjamin A; Lasky-Su, Jessica; Sun, Bei; Cui, Jinrui; Guo, Xiuqing; Taylor, Kent D; Chen, Yii-Der Ida; Xiang, Anny; Raffel, Leslie J; Buchanan, Thomas A; Rotter, Jerome I; Williams, Gordon H
- Abstract
<bold>Context: </bold>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.<bold>Objective: </bold>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.<bold>Design, Setting, and Participants: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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.
- Publication
Journal of Clinical Endocrinology & Metabolism, 2011, Vol 96, Issue 8, pE1288
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/jc.2010-2738