(TIF) Clustering Heart Rate Dynamics Is Associated with β-Adrenergic Receptor Polymorphisms: Analysis by Information-Based Similarity Index BACKGROUND: Genetic polymorphisms in the gene encoding the β-adrenergic receptors (β-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 β-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 β-AR polymorphisms: β(1)-AR Ser49Gly, β(2)-AR Arg16Gly and β(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 β(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 β-AR polymorphisms. Our results provide evidence that β(2)-AR polymorphisms are significantly associated with the acceleration/deceleration pattern of heart rate oscillation, reflecting the underlying mode of autonomic nervous system control. Instantaneous heart rate in response to physiological perturbations often exhibits remarkable oscillations at multiple time scales. These oscillations, known as heart rate variability (HRV), are mainly mediated by the autonomic nervous system via parasympathetic and sympathetic innervations. Analysis of HRV has been suggested to reveal subtle patterns of heart rate dynamics that are relevant to the underlying physiological state and autonomic nervous system function [1] . Prior studies have shown that HRV measures are highly heritable traits that can be used to support genetic association and linkage studies [2, 3, 4, 5] . Family and twin studies have shown a significant genetic influence on a variety of HRV measures [6, 7] . Genetic polymorphisms related to cardiovascular functions have been associated with altered HRV [8, 9, 10, 11] . Recently, we have also made progress in identifying variations in two genes related to neuropsychiatric function that are associated with altered heart rate dynamics in samples of healthy adult and elderly subjects: those encoding brain-derived neurotrophic factor (BDNF) [12] and apolipoprotein E [13] , respectively.