Background: Genetic polymorphisms in the gene encoding the beta-adrenergic receptors (beta-AR) have a pivotal role in the functions of the autonomic nervous system. Using heart rate variability (HRV) as an indicator of autonomic function, we present a bottom-up genotype-phenotype analysis to investigate the association between beta-AR gene polymorphisms and heart rate dynamics. Methods: A total of 221 healthy Han Chinese adults (59 males and 162 females, aged 33.6 +/- 10.8 years, range 19 to 63 years) were recruited and genotyped for three common beta-AR polymorphisms: beta(1)-AR Ser49Gly, beta(2)-AR Arg16Gly and beta(2)-AR Gln27Glu. Each subject underwent two hours of electrocardiogram monitoring at rest. We applied an information-based similarity (IBS) index to measure the pairwise dissimilarity of heart rate dynamics among study subjects. Results: With the aid of agglomerative hierarchical cluster analysis, we categorized subjects into major clusters, which were found to have significantly different distributions of beta(2)-AR Arg16Gly genotype. Furthermore, the non-randomness index, a nonlinear HRV measure derived from the IBS method, was significantly lower in Arg16 homozygotes than in Gly16 carriers. The non-randomness index was negatively correlated with parasympathetic-related HRV variables and positively correlated with those HRV indices reflecting a sympathovagal shift toward sympathetic activity. Conclusions: We demonstrate a bottom-up categorization approach combining the IBS method and hierarchical cluster analysis to detect subgroups of subjects with HRV phenotypes associated with beta-AR polymorphisms. Our results provide evidence that beta(2)-AR polymorphisms are significantly associated with the acceleration/deceleration pattern of heart rate oscillation, reflecting the underlying mode of autonomic nervous system control.
