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Objective: The sympathetic nervous system (SNS) is linked to glucose, lipid, and protein metabolism. The α2A -adrenergic receptor (ADRA2A) is involved in the SNS and mediates inhibition of insulin secretion and lipolysis. The association of ADRA2A single-nucleotide polymorphisms (SNPs) with obesity and/or type 2 diabetes (T2D) was investigated., Design and Methods: Genotyping was performed in a case-control study of 1,177 Swedish individuals, including lean and obese subjects with normal glucose tolerance (NGT) and T2D patients. ADRA2A mRNA expression was measured in pancreatic islets isolated from T2D patients and nondiabetic subjects., Results: SNP rs553668 was associated with T2D in men (odds ratio [OR] = 1.47; 95% confidence interval [CI] = 1.08-2.01; P = 0.015) but this association was lost after adjusting for age and for body mass index (BMI). Associations were also detected when comparing obese NGT and lean NGT subjects (OR = 1.49; 95% CI = 1.07-2.07; P = 0.017), and in obese (OR = 1.62; 95% CI = 1.06-2.49; P = 0.026), but not in lean T2D. In women, multiple logistic regression regarding SNP rs521674 demonstrated an increased OR of 7.61 (95% CI = 1.70-34.17; P = 0.008) for T2D when including age as a covariant. Correcting for BMI removed the significant association. When age was included in the model, association also found when obese T2D patients were compared with lean NGT subjects (P = 0.041). ADRA2A mRNA expression in human pancreatic islets was detectable, but with no statistically significant difference between the diabetic and the control groups., Conclusions: ADRA2A genetic polymorphisms are mainly associated with obesity and possibly with T2D in a Swedish population., (Copyright © 2013 The Obesity Society.)