Polymorphism in the 5 '-leader cistron of the beta(2)-adrenergic receptor gene associated with obesity and type 2 diabetes

We screened the 5'-untranslated region of the beta(2)-adrenergic receptor g ene from 40 obese subjects by the PCR-direct sequencing technique. Two poly morphic sites were identified; a T-->C substitution at -47 and a T-->C subs titution at -20. We further analyzed the association of the polymorphisms w ith obesity in 574 subjects by PCR and restriction digestion. The substitut ion at -47 was in tight linkage disequilibrium with that at -20. The polymo rphisms were also in linkage disequilibrium with codon 16 and codon 27 poly morphisms. Subjects carrying the -47C/-20C allele had greater body mass ind ex (25.5+/-4.5 vs. 24.4+/-4.1 kg/m(2), p=0.007) and higher serum triglyceri de levels (166+/-160 vs. 139+/-95 mg/dl, p=0.015) than -47T/-20T homozygote s. 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 incre ased frequency of the variant allele was shown in diabetic patients compare d 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 obes e group. The exchange at -47 may alter the expression level of the pz-adren ergic 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 obesit y-related metabolic disorders.