Polymorphism in the 5′-Leader Cistron of theβ 2-Adrenergic Receptor Gene Associated with Obesity and Type 2 Diabetes

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Abstract
We screened the 5′-untranslated region of theβ 2-adrenergic receptor gene from 40 obese subjects by the PCR-direct sequencing technique. Two polymorphic sites were identified; a T → C substitution at −47 and a T → C substitution at −20. We further analyzed the association of the polymorphisms with obesity in 574 subjects by PCR and restriction digestion. The substituion at −47 was in tight linkage disequilibrium with that at −20. The polymorphisms were also in linkage disequilibrium with codon 16 and codon 27 polymorphisms. Subjects carrying the −47C/−20C allele had greater body mass index (25.5 ± 4.5 vs. 24.2 ± 4.1 kg/m2, P = 0.007) and higher serum triglyceride levels (166 ± 160 vs. 139 ± 95 mg/dl, P= 0.015) than −47T/−20T homozygotes. The variant allele frequency was significantly higher in obese subjects than in non-obese subjects (0.18 vs. 0.11, P = 0.0026). Furthermore, an increased frequency of the variant allele was shown in diabetic patients compared with non-diabetic subjects (0.19 vs.0.11, P = 0.0005). The association may be attributable to the greater proportion of diabetic patients in the obese group. The exchange at −47 may alter the expression level of the β2-adrenergic receptor gene, because the nucleotide substitution at −47 results in a Cys → Arg exchange at the C terminal of the leader peptide. The −47C/−20C allele may be associated with genetic predisposition to obesity and obesity-related metabolic disorders.
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