POLYMORPHISMS OF B1 AND B2 RECEPTOR GENES AND OBESITY

B1 和 B2 受体基因多态性与肥胖

• 批准号: 6500177
• 负责人: JOHN J LIMA
• 金额: $ 2.62万
• 依托单位: NEMOURS CHILDREN'S CLINIC
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-15 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6500177
• 关键词: alleles; beta adrenergic receptor; catecholamines; clinical research; gene frequency; genetic polymorphism; genotype; human subject; lipolysis; obesity; polymerase chain reaction

Obesity has been associated with insulin resistance, hyperinsulinemia, non-insulin-dependent diabetes mellitus, hypertension and a higher risk of cardiovascular disease and death. Genetic, metabolic and environmental factors are known to contribute to obesity. Genes that are involved in the regulation of catecholamine function may be important because of the role catecholamines play in energy expenditure and lipolysis. Ninety percent of fat in the body is stored in white adipose tissue as triglycerides, which are broken to free fatty acids and glycerol through the action of hormone-sensitive lipase. Lipolysis is stimulated by beta1, beta2 and beta3 adrenergic receptors in human adipocytes, with the beta1 and beta2 adrenergic receptors (beta1 and beta2 AR) being the most dominant subtypes. Catecholamine-stimulated lipolysis is reduced in obesity, which is thought to be due to defects in the beta2 AR-signaling pathway. Mis-sense mutations in the beta1 AR gene results in polymorphisms at nucleic acid 145 (A->G), which results in a substitution of Ser for Gly at position 49, and at nucleic acid 1165 (G- >C, which results in a substitution of Gly for Arg and position 389. Beta1 AR polymorphisms have functional significance; whether or not they associate with obesity is unknown. Mutations in the 5' leader and coding regions of the human beta2 AR gene give rise to several polymorphisms, which can after receptor density and function. The working hypotheses of this submission are that polymorphisms at position 389 and haplotypes of beta2 AR polymorphisms in the 5' leader and coding regions associate with obesity. Specific Aim #1: to compare the beta1 AR allele frequencies and genotypes in healthy obese and non- obese subjects. The hypothesis driving this specific aim is that obesity associates with the Gly 389 beta1 AR allele. Specific Aims #2: to compare the distribution of beta2 AR haplotypes in healthy obese (Body Mass Indexes > 30) and non-obese (BMI < 25) subjects. Beta2 AR haplotypes will be determined by PCR and direct sequencing. The thesis driving this specific aim is that obesity associates with the Arg19-Gly16- Glu27 beta2 AR haplotype. The distribution of beta2 AR haplotypes in 118 non-obese and 118 otherwise healthy obese subjects will be compared. The results of this study will determine whether polymorphisms in beta1 and beta2 AR allels associate with obesity. The information obtained from our studies are important in designing clinical trials of interventions designed to reduce body weight.

肥胖与胰岛素抵抗、高胰岛素血症、非胰岛素依赖型糖尿病、高血压以及心血管疾病和死亡的较高风险有关。已知遗传、代谢和环境因素会导致肥胖。由于儿茶酚胺在能量消耗和脂肪分解中发挥的作用，参与儿茶酚胺功能调节的基因可能很重要。体内百分之九十的脂肪以甘油三酯的形式储存在白色脂肪组织中，通过激素敏感性脂肪酶的作用分解成游离脂肪酸和甘油。脂肪分解是由人类脂肪细胞中的 β1、β2 和 β3 肾上腺素能受体刺激的，其中 β1 和 β2 肾上腺素能受体（β1 和 β2 AR）是最主要的亚型。儿茶酚胺刺激的脂肪分解在肥胖症中减少，这被认为是由于 β2 AR 信号通路的缺陷所致。 beta1 AR 基因中的错义突变会导致核酸 145 (A->G) 处的多态性，从而导致第 49 位上的 Ser 取代 Gly，以及核酸 1165 处的多态性 (G->C，从而导致甘氨酸取代精氨酸和第 389 位。β1 AR 多态性具有功能意义；它们是否与人类肥胖相关尚不清楚。 beta2 AR 基因会产生多种多态性，这些多态性可能会影响受体密度和功能。本次提交的工作假设是 389 位的多态性和 5' 前导区和编码区的 beta2 AR 多态性单倍型与肥胖相关。图 1：比较健康肥胖和非肥胖受试者的 beta1 AR 等位基因频率和基因型 推动这一特定目标的假设是肥胖与 Gly 389 相关。具体目标#2：比较健康肥胖（体重指数 > 30）和非肥胖（BMI < 25）受试者中 beta2 AR 单倍型的分布。 Beta2 AR 单倍型将通过 PCR 和直接测序来确定。推动这一具体目标的论文是肥胖与 Arg19-Gly16-Glu27 beta2 AR 单倍型相关。将比较 118 名非肥胖受试者和 118 名健康肥胖受试者中 beta2 AR 单倍型的分布。这项研究的结果将确定 beta1 和 beta2 AR 等位基因的多态性是否与肥胖相关。从我们的研究中获得的信息对于设计旨在减轻体重的干预措施的临床试验非常重要。