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Genetic Variation in the Renin-Angiotensin System and Autonomic Nervous System Function in Young Healthy Japanese Subjects

Department of Endocrinology, Metabolism, and Diabetes Mellitus (M.N., K.Y., N.A.), Kinki University School of Medicine, Osaka-Sayama 589-8511, Japan; Laboratory of Metabolism (T.M., K.Y., K.T.) and Laboratory of Applied Physiology (T.M.), Graduate School of Human and Environmental Studies, and Department of Genomic Drug Discovery Science (T.A., G.T.), Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan; and Diabetic Center (K.Y.), Tsunashimakai-Kosei Hospital, Himeji 670-0074, Japan

Address all correspondence and requests for reprints to: Koichiro Yasuda, M.D., Ph.D., Laboratory of Metabolism, Graduate School of Human and Environmental Studies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. E-mail: yasuda3{at}tom.life.h.kyoto-u.ac.jp.

Context: The renin-angiotensin system (RAS) interacts with the autonomic nervous system (ANS) in the regulation of blood pressure and cardiovascular function. Several genetic polymorphisms in the RAS have been identified and have been implicated as a cause of hypertension and cardiovascular disease.

Objective: The aim of the present study was to evaluate the relation between genetic polymorphisms of the RAS (M235T of AGT gene, insertion/deletion of ACE gene, A1166C of AT₁R gene, and A1675G of AT₂R gene) and ANS function.

Subjects: One hundred forty-nine young healthy Japanese males were genotyped for each RAS polymorphism.

Main Outcome Measures: ANS function was evaluated by power spectral analysis of heart rate variability (HRV) during supine rest and in a standing position.

Results: In a supine position, subjects homozygous for the AGT 235T allele had a higher HRV sympathetic index than 235M allele carriers, whereas the orthostatic change in this index was relatively blunted in AGT 235TT carriers. In the analysis of gene-gene interaction, these effects of the AGT 235T homozygotes on HRV sympathetic index were more apparent in the presence of the ACE D allele. Meanwhile, the AT₁R 1166C allele was significantly associated with higher HRV low-frequency power and sympathetic index in a standing position. These data suggest that the AGT M235T polymorphism is associated with sympathetic predominance at rest, and AT₁R 1166C allele carriers have potentially increased sympathetic response.

Conclusions: Cardiac autonomic function can be modulated by genetic variation in the RAS even in young and healthy states.