Synergistic effect of polymorphisms of uncoupling protein 1 and beta3-adrenergic receptor genes on autonomic nervous system activity.

OBJECTIVE: To investigate the association of the promoter region -3826 A to G polymorphism of the uncoupling protein 1 (UCP1) gene with autonomic nervous system (ANS) activity and the interaction of the polymorphism with the Trp64Arg polymorphism of the beta3 adrenergic receptor (beta3AR). SUBJECTS: Three-hundred and forty-nine young (mean age 20.4+/-2.1 y old), healthy Japanese males. MEASUREMENTS: DNA was extracted from whole blood and genotyped by polymerase chain reaction restriction fragment length polymorphism. Plasma glucose, plasma insulin and body mass index (BMI) were measured. Frequency of family history of diabetes or obesity was determined by interview. Subjects randomly chosen from each genotype were examined for ANS activity during supine rest and standing by electrocardiogram power spectral analysis of heart rate variability. RESULTS: UCP1 or beta3AR polymorphism was not associated with BMI, plasma glucose, plasma insulin and frequency of family history of diabetes or obesity. The inhibitory effect of UCP1 polymorphism on ANS activity was observed only with occurrence of the variant of beta3AR. The very low frequency component associated with thermoregulation in the sympathetic nervous system of homozygotes of UCP1 (GG) at supine rest was significantly lower than normal (AA, 203.2+/-50.3 vs 462.2+/-83.6 ms(2); mean+/-s.e., P=0.021). A higher response to postural change to standing was also observed in both sympathetic and parasympathetic nervous activities of AA than of GG. CONCLUSION: While UCP1 polymorphism alone does not affect ANS activity, it has a synergistic effect with beta3AR polymorphism in decreasing sympathetic nervous system activity.