title: Variants of the caveolin-1 gene: a translational investigation linking insulin resistance and hypertension.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors: Luminita H
authors: LH
authors: Pojoga
authors: Patricia C
authors: PC
authors: Underwood
authors: Mark O
authors: MO
authors: Goodarzi
authors: Jonathan S
authors: JS
authors: Williams
authors: Gail K
authors: GK
authors: Adler
authors: Xavier
authors: X
authors: Jeunemaitre
authors: Paul N
authors: PN
authors: Hopkins
authors: Benjamin A
authors: BA
authors: Raby
authors: Jessica
authors: J
authors: Lasky-Su
authors: Bei
authors: B
authors: Sun
authors: Jinrui
authors: J
authors: Cui
authors: Xiuqing
authors: X
authors: Guo
authors: Kent D
authors: KD
authors: Taylor
authors: Yii-Der Ida
authors: YD
authors: Chen
authors: Anny
authors: A
authors: Xiang
authors: Leslie J
authors: LJ
authors: Raffel
authors: Thomas A
authors: TA
authors: Buchanan
authors: Jerome I
authors: JI
authors: Rotter
authors: Gordon H
authors: GH
authors: Williams
references: Endocrinology. 2010 Mar;151(3):1236-46
references: 20097717
references: Proc Natl Acad Sci U S A. 2007 Aug 21;104(34):13678-83
references: 17699617
references: Am J Physiol Endocrinol Metab. 2003 Dec;285(6):E1151-60
references: 14607781
references: Clin Endocrinol (Oxf). 2008 Feb;68(2):213-9
references: 17803693
references: Bioinformatics. 2010 Sep 1;26(17):2190-1
references: 20616382
references: J Clin Endocrinol Metab. 2010 Sep;95(9):E75-9
references: 20631015
references: Am J Physiol Cell Physiol. 2003 Jul;285(1):C222-35
references: 12660144
references: Am J Physiol Heart Circ Physiol. 2008 Mar;294(3):H1258-65
references: 18178722
references: Biometrics. 1986 Mar;42(1):121-30
references: 3719049
references: J Cell Biochem. 2006 Oct 15;99(3):747-58
references: 16676355
references: Ann Med. 2004;36(8):584-95
references: 15768830
references: Nat Rev Genet. 2008 Nov;9(11):819-30
references: 18852695
references: FASEB J. 2002 Feb;16(2):249-51
references: 11744627
references: Mol Interv. 2003 Dec;3(8):445-64
references: 14993453
references: Lipids Health Dis. 2008 Jan 31;7:3
references: 18237401
references: Hypertension. 2002 Jul;40(1):1-6
references: 12105129
references: Am J Physiol Heart Circ Physiol. 2010 Jun;298(6):H1776-88
references: 20363891
references: Diabetologia. 1993 May;36(5):414-22
references: 8390949
references: J Hypertens. 2001 Jan;19(1):99-105
references: 11204310
references: Circulation. 2001 Jan 2;103(1):78-83
references: 11136689