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.
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| Johnson, Julie A; Lima, John J (2003) Drug receptor/effector polymorphisms and pharmacogenetics: current status and challenges. Pharmacogenetics 13:525-34 |
