Association of beta-adrenoceptor polymorphisms with cardiac autonomic modulation in Japanese males.

BACKGROUND: The beta1- and beta2-adrenergic receptors (ARs) coexist in the human heart and control sympathetic responses. Several functional genetic variations in the beta-AR genes (ADRB1 or ADRB2) have been identified and implicated as causes of hypertension and cardiovascular disease. We assessed the relationship between 4 representative genetic polymorphisms of beta-AR (Ser49Gly and Arg389Gly in beta1-AR, Arg16Gly and Gln27Glu in beta2-AR) and autonomic nervous system (ANS) function in healthy young Japanese males. METHODS: One hundred forty-nine subjects were genotyped for each beta-AR polymorphism and underwent evaluation of ANS function by power spectral analysis of heart rate variability (HRV) during supine rest and in a standing position. The low-frequency (LF; <0.15 Hz) and high-frequency (HF; >0.15 Hz) components of HRV were quantified by frequency domain analysis and expressed in absolute and normalized units. RESULTS: The beta2-AR Arg16 homozygous group had a significantly lower diastolic and mean blood pressure than the Gly16 group in both Arg16Gly individual and Gln27Glu polymorphism combined diplotype-based analyses. In a supine rest position, subjects homozygous for the beta2-AR Arg16 allele had significantly lower HRV sympathetic indices (LF [%] and LF/HF ratio) but higher HRV parasympathetic indices (HF [%]) than the Gly16 allele carriers. Meanwhile, the beta2-AR Glu27 allele was significantly associated with higher HRV LF power than were Gln27 homozygous subjects. In the analysis of gene-gene interaction, the effects of the beta2-AR Arg16 homozygotes on HRV were more apparent in the presence of the beta1-AR Gly389 allele. No independent associations were observed between the beta1-AR Ser49Gly or Arg389Gly genotypes and HRV indices. CONCLUSIONS: The Arg16Gly polymorphism of the beta2-AR is related to the modulation of sympathovagal balance, and beta2-AR Glu27 allele carriers potentially have increased autonomic activity. Thus, beta-AR genotype-related differences in basic receptor function cause phenotypic differences in cardiac ANS function.

Fibre type distribution and gene expression levels of both succinate dehydrogenase and peroxisome proliferator-activated receptor-gamma coactivator-1alpha of fibres in the soleus muscle of Zucker diabetic fatty rats.

We have reported that a change in muscle fibre type distribution is present in two strains of diabetic rats (Otsuka Long-Evans Tokushima Fatty and Goto-Kakizaki rats). In this study, we determined whether the change in soleus muscle fibre type distribution was caused by diabetes, using obese, diabetic (Zucker diabetic fatty, ZDF), obese, non-diabetic (Zucker fatty, ZF) and non-diabetic, non-obese rats (Zucker lean, ZL). Moreover, we investigated whether the gene expression levels of metabolic key molecules, namely the transcriptional factors of metabolic genes, exemplified by peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), and the oxidative enzymes in mitochondria, exemplified by succinate dehydrogenase (SDH), were changed in type I and II muscle fibres in each type of rat, using the new technique of laser capture microdissection (LCM). Both plasma glucose and glucosylated haemoglobin levels were significantly higher in ZDF than in ZL and ZF rats. A lower percentage of type IIA fibres was observed in the muscles of ZDF rats than in those of ZL and ZF rats. The mRNA expression levels of SDH in type II fibres and of PGC-1alpha in type I fibres were significantly lower in ZDF than in ZL and ZF rats as assessed by LCM and real-time PCR analysis. We have shown, for the first time, that a lower percentage of type IIA fibres was observed in ZDF rats. We have also discovered that the expression levels of the oxidative metabolism-related genes, PGC-1alpha and SDH, decreased in type I and type II fibres, respectively, of ZDF rats.

Alpha-adrenoceptor gene variants and autonomic nervous system function in a young healthy Japanese population.

alpha(1A)-adrenergic receptor (alpha(1A)-AR) regulates the cardiac and peripheral vascular system through sympathetic activation, and alpha(2A)-AR and alpha(2C)-AR subtypes are essential for presynaptic feedback regulation of catecholamine release from the central and peripheral sympathetic nerve. Genetic variations in each human alpha-AR subtype gene have been identified and have been implicated in hypertension and cardiovascular disease. It is not yet clear whether these genetic variations actually have an effect on sympatho-vagal modulation. The aim of the present study was to evaluate the relation between the five representative genetic polymorphisms of alpha-AR subtypes (Arg347Cys of alpha(1A)-AR; C-1291G, Asn251Lys, and DraI RFLP of alpha(2A)-AR; and Del322-325 of alpha(2C)-AR) and autonomic nervous system (ANS) function in young and healthy Japanese males. One hundred forty-nine subjects were genotyped for each alpha-AR polymorphism, and underwent evaluation of ANS function by power spectral analysis of heart rate variability (HRV) during supine rest and in a standing position. In a supine position, the alpha(1A)-AR 347Cys allele was significantly associated with lower HRV sympathetic index (normalized low frequency power [LF(%)] and LF:HF ratio) and higher HRV parasympathetic index [HF(%)]. Meanwhile, subjects with the alpha(2C)-AR Del322-325 allele had markedly higher LF(%) and LF:HF ratio and lower HF(%) than noncarriers. Thus, the alpha(1A)-AR and alpha(2C)-AR genetic variations influence sympatho-vagal balance even in young and healthy normotensive states, which could be postulated to constitute an intermediate phenotype for future pathological episodes of various ANS dysfunction-related diseases.

Association of C825T polymorphism of G protein beta3 subunit with the autonomic nervous system in young healthy Japanese individuals.

BACKGROUND: The T allele of the C825T polymorphism of the G protein beta3 subunit gene (GNB3) is reported to be associated with increased intracellular signal transduction and the prevalence of essential hypertension. Because the two major receptors in the autonomic nervous system (ANS), the adrenergic and muscarinic acetylcholine receptors, are G protein-coupled receptors, it was expected that the GNB3 C825T polymorphism was associated with ANS function. In the present study, we have investigated the association of this polymorphism with ANS in young, healthy Japanese male individuals. METHODS: A total of 94 young, healthy subjects underwent the genotyping for the GNB3 C825T polymorphism and electrocardiogram R-R interval power spectral analysis in supine rest and standing positions. RESULTS: There were no significant differences among genotypes in any of the characteristics investigated (body mass index, blood pressure, plasma glucose, insulin, lipids, and family history of hypertension, diabetes, or obesity). However, in power spectral analysis of heart rate variability, the very-low-frequency component when standing was higher in TT carriers than in CC carriers, and TT and CT carriers had a significantly higher sympathetic nervous system (SNS) index and lower parasympathetic nervous system (PNS) index when standing than CC carriers. In addition, we found that TT carriers showed no chronological variations in either SNS or PNS index after postural change. CONCLUSIONS: These observations suggested that GNB3 C825T polymorphism is associated with ANS in youth. These findings raise the possibility that individuals who are T allele carriers are at increased risk for developing hypertension in relation to ANS function.

T393C polymorphism of GNAS1 associated with the autonomic nervous system in young, healthy Japanese subjects.

1. T393C polymorphism of the gene encoding the Gs-protein alpha-subunit (GNAS1) has been reported recently to be associated with hypertension in which dysfunctions of the autonomic nervous system (ANS) are closely involved. In the present study, the association of this polymorphism with ANS activity was investigated in young, healthy Japanese males. 2. Four hundred and one subjects were genotyped for the T393C polymorphism of GNAS1 by polymerase chain reaction-restriction fragment length polymorphism. Autonomic nervous system activity during supine rest and when standing was assessed in 137 subjects by electrocardiogram R-R interval power spectral analysis. 3. One hundred and fifty-four subjects (38.4%) were homozygous for the T allele (TT), 188 (46.9%) were heterozygous (TC) and 59 (14.7%) were homozygous for the C allele (CC). There were no significant differences as to genotype among the clinical characteristics investigated. In power spectral analysis of heart rate variability, the high-frequency component and parasympathetic nervous system (PNS) index during supine rest were significantly lower in TT and TC carriers than in CC carriers. Furthermore, the increase in heart rate and the responsiveness of sympathetic nervous system index and PNS index to postural change from supine rest to standing were significantly lower in TT and TC carriers than in CC carriers. 4. These observations suggest that the GNAS1 T393C polymorphism is associated with ANS activity in youth, so that it may be useful as a genetic marker for future pathogenesis of hypertension. Follow-up studies are necessary to clarify the prevalence rates of hypertension among 393T allele carriers in the present study.

Alpha(2B)-adrenergic receptor deletion polymorphism associates with autonomic nervous system activity in young healthy Japanese.

Several polymorphisms of genes involved in autonomic nervous system (ANS) function have been reported to affect metabolic regulation. We have investigated the association of an alpha(2B)-adrenergic receptor (alpha(2B)AR) three-amino acid deletion polymorphism with ANS activity in young healthy subjects by means of electrocardiogram R-R interval power spectral analysis. Three hundred eighty-one young healthy Japanese males (mean +/- SE, 20.6 +/- 0.1 yr) were studied. One hundred sixty-eight (44.1%) were homozygotes of Long allele (Long/Long), 162 (42.5%) were heterozygotes (Long/Short), and 51 (13.4%) were homozygotes of Short allele (Short/Short). The allele frequency of Short allele was 0.35. No significant differences were observed in any of the characteristics investigated: body mass index, plasma glucose, plasma insulin, or family history of diabetes and obesity. In R-R spectral analysis of heart rate variability, carriers of Short/Short had significantly greater low frequency and very low frequency than Long/Long, as well as a higher sympathetic nervous system index. These findings suggest that the alpha(2B)AR deletion polymorphism might result in metabolic disorder by altering ANS function.