Common variants in the β2-(Gln27Glu) and β3-(Trp64Arg) adrenoceptor genes are associated with elevated serum NEFA concentrations and Type II diabetes

Aims/hypothesis. Higher NEFA concentrations predict Type II (non-insulin-dependent) diabetes mellitus but it is not known whether higher NEFA concentrations are genetically determined or reflect coexisting. obesity. To address this question we studied whether common variants in two genes encoding for key regulators of lipolysis, the beta (2)- and beta (3)- adrenoceptors (B2AR and B3AR) are associated with NEFA concentrations and Type II diabetes. Methods. A total of 1054 Swedish subjects with varying degrees of glucose tolerance were genotyped for the Gln27Glu variant in the B2AR and for the Trp64Arg variant in the B3AR genes using PCR-RFLP. Results. The B2AB Gln27 allele was more frequent in 219 Type II diabetic patients than in 237 non-diabetic subjects (59.8% vs 52.3 %; OR = 1.72, p = 0.02) while there was no significant difference in the frequency of the B3AR Arg64 allele. Subjects homozygous for the protective alleles (Glu27 and TrF64) had, however, a lower prevalence of diabetes than subjects with other genotype combinations (OR = 0.58, p = 0.03). Among sibling pairs discordant for the B2AR Gln27Glu polymorphism, siblings with an excess of the Gln27 allele had higher fasting insulin (n = 217; p=0.02) and NEFA concentrations (107 sex-matched pairs; p = 0.01) than siblings with an excess of the Glu27 allele. Among sibling pairs discordant for the B3AR TrpG4Arg variant, siblings with the Arg64 allele had higher 2 h glucose (n = 48; p = 0.01) and NEFA concentrations (16 pairs matched for ses; p < 0.04) than siblings with the Trp64Trp64 genotype. Conclusions/interpretation. Common variants in the beta (2)- and beta (2)- adrenoceptor genes are associated with increased fasting insurin and NEFA concentrations and could increase susceptibility to Type II diabetes.