Association analyses of adrenergic receptor polymorphisms with obesity and metabolic alterations

Abstract

Genes involved in the regulation of catecholamine function may be important in obesity because of the role catecholamines play in energy expenditure and lipolysis. To determine if common single nucleotide polymorphisms (SNPs) in β₁-adrenergic receptor (ADRB1), β₂-adrenergic receptor (ADRB2), β₃-adrenergic receptor (ADRB3), and α₂-adrenergic receptor (ADRA2A) genes associate with obesity and metabolic alterations, we recruited 74 healthy African American and 161 white men and women (age, 18-49 years) to participate in this case-control genetic association study. Genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism. Associations between genotype and body mass index (BMI), percentage of body fat (by measuring skinfold thickness in 7 different sites), fasting (12-hour) plasma glucose, insulin, potassium concentrations, glycated hemoglobin, and insulin resistance (homeostasis model assessment [HOMA_IR] score) were performed. Among whites, the ADRB1 Arg389→Gly variant associated with insulin concentrations and HOMA_IR: mean ± SD values for insulin and HOMA_IR in Arg389 homozygotes and carriers of the Gly were 10 ± 7.0 and 12 ± 9.4 μIU/mL (P = .02) and 2.1 ± 1.7 and 2.6 ± 2.2 (P = .057), respectively. Systolic blood pressure was higher in whites for carriers of the ADBR1 Ser49 compared to Gly49 homozygotes (124 ± 12.6 vs 119 ± 11.3 mm Hg, respectively; P = .02). Subsequent analysis revealed that these associations were attributable to a higher BMI among obese participants. The ADRA2A G1780A SNP associated with BMI and percentage of body fat in African Americans (P = .05). Interactions were detected between ADRA2A C-1291G and ADRB2 Gln27→Glu variants for obesity in African Americans and between ADRA2A C-1291G SNP and ADBR1 haplotype for obesity in whites. We conclude that common SNPs in adrenergic receptor genes may be important susceptibility loci for obesity and related alterations. Because of the limited size of our populations, our results should be interpreted with caution and should be replicated in larger populations.

Introduction

Obesity is a major health problem in the United States. Sixty-five percent of American adults are overweight, and more than 30% are obese [1]. It is well accepted that obesity in some, but not in all, individuals leads to metabolic alterations including hyperinsulinemia and insulin resistance [2], which can lead to the development of type 2 diabetes mellitus and to cardiovascular diseases and some forms of cancer [3], [4], [5], [6]. Although rare, obesity syndromes can be caused by mutations in single genes. However, the greatest proportion of obesity involves variants in multiple genes interacting with environmental factors, particularly diet [7], [8].

Genes that are involved in the regulation of catecholamine function may be important in obesity because of the role catecholamines play in energy expenditure and lipolysis. Fat stored in the body as triglycerides is hydrolyzed to free fatty acids and glycerol through the process of lipolysis [9]. Activation of β-adrenergic receptors (ADRBs) expressed in adipocytes mediate lipolysis [3], [10], [11], whereas stimulation of α₂-adrenergic receptors (ADRA2) inhibit lipolysis [12]. Insulin is also an important inhibitor of catecholamine-stimulated lipolysis [13] by reducing the ADBR effects of epinephrine and by activating ADRA2 in adipocytes [14].

In addition, catecholamine-stimulated whole-body lipolysis and lipolysis in subcutaneous adipocytes are blunted in obesity [10], [15], [16], thereby limiting lipid mobilization and favoring fat accumulation. The mechanisms underlying lipolytic resistance to catecholamines in obesity are not clear and may include desensitization of ADRB2 function [17], increased activity of ADRA, and the hyperinsulinemia that accompanies obesity [18], [19].

Several mutations in genes encoding ADRA and ADRB have been identified that could alter receptor expression and function. Given the important role that adrenergic receptors play in regulating energy expenditure and lipolysis, it is possible that common genetic polymorphisms in these genes contribute to obesity and to the accompanying metabolic alterations. Numerous studies have reported on the relationship between obesity and genetic variants in adrenergic receptors in different populations with conflicting results [20], [21], [22]. Few, however, have explored associations between adrenergic receptor polymorphisms and obesity and accompanying metabolic alterations in self-identified African Americans and whites. In the present study we tested the hypothesis that obesity and metabolic alterations associate with common polymorphisms in adrenergic receptor genes.