Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
J Clin Endocrinol Metab. 2011 Aug;96(8):E1288-92. doi: 10.1210/jc.2010-2738. Epub 2011 May 25.
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.
DESIGN, SETTING, AND PARTICIPANTS: 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.
胰岛素抵抗（IR）和高血压的同时发生是一种遗传状况，会导致心血管并发症。窖蛋白-1（CAV1）是一种先前与动物和细胞模型中的代谢功能障碍相关的基因，它可能是人类出现这些情况的标志物。
本研究的目的是在两个高血压队列中研究 CAV1 变体与 IR 之间的关系，并在 CAV1 基因敲除小鼠中验证这些发现。
设计、地点和参与者：对两个高血压队列（1）白人和 2）西班牙裔进行了候选基因关联研究。分析了个体变体与胰岛素抵抗表型之间的多变量关联，考虑了年龄、性别、体重指数和兄弟姐妹关系。在野生型和 CAV1 基因敲除小鼠中进行了腹腔内葡萄糖耐量试验。
在白人高血压队列中，两个 CAV1 单核苷酸多态性（rs926198、rs3807989）的次要等位基因携带者空腹胰岛素水平显著升高（P=0.005，P=0.007），稳态模型评估的胰岛素抵抗（HOMA-IR）（P=0.005，P=0.008）和高胰岛素-正葡萄糖钳夹过程中的 M 值降低（P=0.004，P=0.05）高于主要等位基因纯合子。在西班牙裔高血压队列中，空腹胰岛素水平（P=0.005，P=0.02）和 HOMA-IR（P=0.008，P=0.02）也得到了复制。荟萃分析表明，这两个单核苷酸多态性与空腹胰岛素水平（P=0.00008，P=0.0004）和 HOMA-IR（P=0.0001，P=0.0004）均存在显著关联。与野生型相比，CAV1 基因敲除小鼠的血压水平更高，空腹血糖、胰岛素和 HOMA-IR 水平更高，对葡萄糖挑战的血糖反应更明显。
CAV1 基因的变异与 IR 和高血压有关。CAV1 基因多态性可能是 IR 和高血压的生物标志物，能够更早地发现并改善治疗策略。
