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Luminita H. Pojoga, Patricia C. Underwood, Mark O. Goodarzi, Jonathan S. Williams, Gail K. Adler, Xavier Jeunemaitre, Paul N. Hopkins, Benjamin A. Raby, Jessica Lasky-Su, Bei Sun, Jinrui Cui, Xiuqing Guo, Kent D. Taylor, Yii-Der Ida Chen, Anny Xiang, Leslie J. Raffel, Thomas A. Buchanan, Jerome I. Rotter, Gordon H. Williams, Variants of the Caveolin-1 Gene: A Translational Investigation Linking Insulin Resistance and Hypertension, The Journal of Clinical Endocrinology & Metabolism, Volume 96, Issue 8, 1 August 2011, Pages E1288–E1292, https://doi.org/10.1210/jc.2010-2738
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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.
