Yasuhiro Ogata

The combination of mitochondrial low enzyme-activity aldehyde dehydrogenase 2 allele and superoxide dismutase 2 genotypes increases the risk of hypertension in relation to alcohol consumption.

A cooperative role of mitochondrial aldehyde dehydrogenase 2 (ALDH2) and superoxide dismutase 2 (SOD2) to maintain the vascular function has recently been demonstrated in nitrate tolerance. The present study examined whether the combination of low enzyme-activity variants of ALDH2 and SOD2 increases the risk of hypertension in relation to alcohol consumption. A total of 444 Japanese participants in a health-screening program were evaluated. The risk of hypertension among the individuals harboring both the ALDH2*2 allele and the SOD2 Val/Val genotype was significantly higher in drinkers than in nondrinkers (adjusted odds ratio, 6.22; 95% confidence interval, 2.26–17.1; P<0.001). Among these individuals, the systolic/diastolic blood pressure also increased by 0.24/0.14 mmHg for each 1g/day increase in alcohol consumption (P<0.001/P=0.003). These associations were observed, but the degree was lower among those with the other genotype combinations (0.11/0.10 mmHg; P=0.012/P=0.001). Information about the genetic predisposition to alcohol-related diseases may thus be useful to promote lifestyle modifications for high-risk individuals.

Interactive effects of smoking and glutathione S-transferase polymorphisms on the development of non-alcoholic fatty liver disease

Glutathione S-transferases (GSTs) protect cells against exogenous and endogenous oxidative stress. GST polymorphisms are associated with the development of cardiovascular disease (CVD) and diabetes mellitus (DM), especially in current-smokers. Non-alcoholic fatty liver disease (NAFLD) is a predictor of future CVD or DM, because oxidative stress contributes to their pathogenesis. This study investigated whether the combination of smoking status and GST genotypes could affect the risk for NAFLD. A cross-sectional analysis was conducted among 713 Japanese participants (458 males and 255 females) during a health screening program. The GSTM1 null, GSTT1 null, GSTP1 A/B or B/B and GSTA1 A/B or B/B genotypes were determined and deemed to be high-risk genotypes. The prevalence of NAFLD was 18.7%. Among never-smokers, carriers of one, and those of two or more high-risk GSTM1, GSTP1 or GSTA1 genotypes were at a higher risk for NAFLD than those who were not carriers [odds ratio (95% confidence interval): 2.6 (1.1-5.9) and 3.3 (1.3-8.1), respectively], and the risk was further increased among current-smokers [4.6 (1.6-13.0) and 5.4 (1.2-23.7), respectively]. This is the first report to show that the combination of current-smoking and harboring high-risk GSTM1, GSTP1 and/or GSTA1 genotypes is interactively associated with the risk of NAFLD.

Possible associations between antioxidant enzyme polymorphisms and metabolic abnormalities in patients with schizophrenia

Background This study investigated the possible association between common and potentially functional polymorphisms of antioxidant enzymes and metabolic abnormalities in patients with schizophrenia. Methods The possible associations of the glutathione S-transferase (GST) M1 null and GSTT1 null genotypes, and the superoxide dismutase 2 (SOD2) Val16Ala polymorphism with the risks of being overweight and having metabolic syndrome were examined using a logistic regression analysis in 154 schizophrenic Japanese patients and 203 controls. Results Among smokers with schizophrenia, the risks of being overweight and having decreased high-density lipoprotein cholesterol were significantly higher in those with the GSTM1 null genotype than in those with the present genotype (odds ratio 3.20 and 3.15, P=0.03 and P=0.04, respectively), while among nonsmokers with schizophrenia, the risk of an abnormal waist circumference was lower in those with the GSTM1 null genotype (odds ratio 0.34, P=0.04). The risk of a decreased high-density lipoprotein cholesterol level was significantly higher in patients with the combined GSTM1 null and GSTT1 present genotypes than in those with the present genotypes of both genes (odds ratio 3.60, P<0.01). The SOD2 Val16Ala polymorphism was not associated with risk of metabolic abnormalities in either group. Conclusion The present study suggests that the GSTM1 null genotype, in combination with smoking status or GSTT1 genotype, might be associated with the metabolic abnormalities in patients with schizophrenia.

Combined effects of current-smoking and the aldehyde dehydrogenase 2*2 allele on the risk of myocardial infarction in Japanese patients

Aldehyde dehydrogenase 2 (ALDH2) detoxifies toxic aldehydes, e.g. acetaldehyde in cigarette smoke; however, the interactive effects between smoking status and the ALDH2 genotype on coronary artery disease (CAD) have not been reported. We investigated the effects of smoking status and the ALDH2 genotype, and assessed their interactive and combined effects on the risk of myocardial infarction (MI) or stable angina (SA), including 221 MI and 175 SA subjects and 473 age- and sex-matched controls without CAD. Current-smoking and the ALDH2*2 allele additively increased the risk of MI (adjusted odds ratio 4.54, 95% confidence interval 2.25-9.15), although this combination was not associated with the risk of SA. This combination also increased the peak creatine kinase (CK) level synergistically in the acute MI (AMI) subjects. Moreover, current-smoking was found to be a significant risk factor for an increased peak CK level in the ALDH2*2 allele carriers (B 2220.2IU/L, p=0.008), but not the non-carriers. Additionally, a synergistic effect of this combination on the triglycerides levels was also found in the AMI subjects. These preliminary findings suggest that the combination of current-smoking and the inactive ALDH2*2 allele may increase the risk of MI additively and the infarct size synergistically.

Influence of the PNPLA3 rs738409 Polymorphism on Non-Alcoholic Fatty Liver Disease and Renal Function among Normal Weight Subjects.

In normal weight subjects (body mass index < 25 kg/m2), non-alcoholic fatty liver disease (NAFLD) is likely to coexist with metabolic diseases. The patatin-like phospholipase 3 (PNPLA3) polymorphism rs738409 (c.444C>G) is associated with the risk of NAFLD and/or renal dysfunction; however, the influence of the weight status on the associations remains unknown. We aimed to clarify the associations of the PNPLA3 polymorphism with the risk of NAFLD and/or renal dysfunction, while also paying careful attention to the weight status of the subjects. Cross-sectional and retrospective longitudinal studies with 5.5 ± 1.1 years of follow-up were conducted in 740 and 393 Japanese participants (61.2 ± 10.5 and 67.5 ± 6.0 years), respectively, during a health screening program. Among 591 subjects who did not have a habitual alcohol intake and/or hepatitis B or C virus infections, the PNPLA3 G/G genotype was associated with the risk for NAFLD in normal weight subjects [odds ratio (95% CI): 3.06 (1.11–8.43), P < 0.05]. Among all subjects, carriers of the PNPLA3 G/G genotype with a normal weight had a lower eGFR than those of the C/C genotype [partial regression coefficient (SE): -3.26 (1.48), P < 0.05]. These associations were replicated in the longitudinal analyses. Among the overweight subjects, none of the genotypes were significantly associated in the cross-sectional and longitudinal analyses; however, the power of the analyses was small, especially in the analyses among overweight subjects. The findings of this study suggest that carriers of the PNPLA3 G/G genotype with a normal weight status should nevertheless be carefully monitored for the presence of NAFLD and/or renal dysfunction.

A Large Cohort Study Concerning Age-Dependent Impacts of Anthropometric Variables on Spirometric Parameters in Nonsmoking Healthy Adults

Backgrounds Although height (H) has been considered the principal anthropometric variable governing lung function, the age-dependent differences in its influences on determining spirometric parameters (SPs) have not been conclusively investigated. Moreover, there has been no study centered on age-dependent effects of other anthropometric variables, including body weight (BW) and body fat mass (BFM) on SPs. In addition, the age-dependent influences of these anthropometric variables are anticipated to differ quantitatively between male and female participants. Methods A total of 16,919 nonsmoking healthy Japanese adults (men: 6,116, women: 10,803) were partitioned into six groups stratified by gender and age at intervals of 20-years: young-, middle-, and advanced-age groups of either gender. Using a model in which a SP was described by a logarithmic additive function of age, H, BW, and BFM, we determined the partial regression coefficients of the respective anthropometric variables to predict the reference means of SPs, including FVC, FEV1, FEV1/FVC, PEF, FEF50, and FEF75, in the six groups. Results/Discussion Although the impact of H on FVC and FEV1 was relatively homogeneous irrespective of gender and age, its homogeneity faded for flow parameters, particularly in the female middle- and advanced-age groups, indicating that the age-dependent contribution of H to SPs was enhanced more in women. The impact of BW on SPs differed depending on age, and this effect was also more conspicuous for female participants. H and BW generally exerted positive effects on SPs, whereas BFM had negative effects. Opposite effects of BW and BFM were observed in the female middle-age group in particular. Conclusions The effects of anthropometric variables on spirometric parameters are highly age-dependent, particularly in women, leading to the conclusion that the assumption of age-independent, constant partial regression coefficients of anthropometric variables while predicting the reference mean of a certain spirometric parameter may result in substantial errors.

Novel regression equations predicting lung age from varied spirometric parameters

Although lung age calculated backward from regression formulas constructed for FEV(1) estimation is widely used, it possesses a couple of faults. We developed novel equations predicting lung age from varied spirometric parameters (spirometry-derived lung age (SDL-age)). Applying multiple regression analysis, equations predicting SDL-age were invented using data from 8015 never-smokers with normal spirometry (group I). Validation was made based on data from 6398 never-smokers with normal spirometry (group II). Equations were further applied for 446 subjects with airflow limitation. FEV(1), FEV(1)/FVC, FEF(50), and PEF were selected as explanatory variables for reference value of SDL-age. Normal limits of difference between SDL-age and chronological-age were ± 13.4 years in the male and ± 15.0 years in the female. Established equations predicted SDL-age of group II. SDL-age was older than chronological-age only in subjects with severe airflow limitation. Novel regression equations allowing prediction of reference value of SDL-age and normal limits of difference between SDL-age and chronological-age were elaborated in both genders.

Association between Airflow Limitation Severity and Arterial Stiffness as Determined by the Brachial-Ankle Pulse Wave Velocity: A Cross-Sectional Study

Objective Chronic obstructive pulmonary disease (COPD) is often associated with concomitant systemic manifestations and comorbidities, such as cardiovascular disease. There are limited data regarding airflow limitation (AL) and atherosclerosis in Japanese patients, and the potential association between AL and arterial stiffness has not yet been investigated in Japanese patients. Therefore, the purpose of this study was to investigate the association between AL severity and arterial stiffness using the brachial-ankle pulse wave velocity (baPWV). Methods This cross-sectional study included 1,356 subjects aged 40-79 years without clinical cardiovascular diseases who underwent a comprehensive health screening that included spirometry, the baPWV measurement, and blood sampling during medical check-ups in 2009 at the Japanese Red Cross Kumamoto Health Care Center. AL was defined in accordance with the Global Initiative for COPD criteria (forced expiratory volume in one second / forced vital capacity of < 0.7). A cut-off baPWV value of >1,400 cm/s was used for risk prediction and screening. Results The average baPWV (SD) results were 1,578.0 (317.9), 1,647.3 (374.4), and 1,747.3 (320.1) cm/s in the patients with a normal pulmonary function, mild AL, and moderate-to-severe AL, respectively (p< 0.001). Using logistic regression models adjusted for the age, body mass index, smoking status, hypersensitive C-reactive protein levels, hypertension, hyperglycemia, and dyslipidemia, an increased baPWV (>1,400 cm/s) was significantly associated with moderate-to-severe AL compared with a normal pulmonary function (odds ratio=2.76; 95% confidence intervals, 1.37-5.55; p=0.004). Conclusion Our results indicated an association between AL and increased arterial stiffness. Arterial stiffness may therefore worsen with an increase in the severity of AL.

Glutathione S-transferase K1 genotype and overweight status in schizophrenia patients: A pilot study

Elevated oxidative stress in mitochondria and mitochondrial dysfunction are associated with weight gain in schizophrenia (SCZ) patients. Glutathione S-transferase kappa 1 (GSTK1) protects cells against exogenous and endogenous oxidative stress in the mitochondria. This exploratory study investigated the possible effects of a common GSTK1 polymorphism (rs1917760, G-1308T) on the risk for overweight status among 329 SCZ patients and 305 age- and gender-matched controls and on the GSTK1 mRNA level in peripheral blood mononuclear cells among 14 SCZ patients. The GSTK1 T/T genotype was associated with having a higher BMI value among SCZ male patients, whereas this genotype tended to be associated with a lower BMI value among female patients. Conversely, these associations were not observed among the controls. The GSTK1 T/T genotype was associated with decreased GSTK1 mRNA level among SCZ patients. The GSTK1 T/T genotype may be a novel risk factor for the prediction of overweight status in SCZ male patients, although the results of this pilot study should be verified by a larger study.

Association of CYP2C19 variants and epoxyeicosatrienoic acids on patients with microvascular angina.

Categorization as a cytochrome P450 (CYP) 2C19 poor metabolizer (PM) is reported to be an independent risk factor for cardiovascular disease. Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid by CYP2C19 epoxygenases and anti-inflammatory properties, especially in microvascular tissues. We examined the association of CYP2C19 polymorphisms and EETs on microvascular angina (MVA) caused by coronary microvascular dysfunction. We examined CYP2C19 genotypes in patients with MVA (n = 71) and healthy subjects as control (n = 71). MVA was defined as the absence of coronary artery stenosis and epicardial spasms and the presence of inversion of lactic acid levels between intracoronary and coronary sinuses in acetylcholine-provocation test or the adenosine-triphosphate-induced coronary flow reserve ratio was below 2.5. CYP2C19 PM have two loss-of-functon alleles (*2, *3). We measured serum dihydroxyeicosatrienoic acid (DHET) as representative EET metabolite. MVA group showed significantly higher CYP2C19 PM incidence (35% vs. 16%; P = 0.007) and high sense C-reactive protein (hs-CRP) levels (0.127 ± 0.142 vs. 0.086 ± 0.097 mg/dl; P = 0.043) than those of controls. Moreover, in MVA group, hs-CRP levels in CYP2C19 PM were significantly higher than that of non-PM (0.180 ± 0.107 vs. 0.106 ± 0.149 mg/dl, P = 0.045). Multivariate analysis indicated that smoking, hypertension, high hs-CRP, and CYP2C19 PM are predictive factors for MVA. In MVA group, DHET levels for CYP2C19 PM were significantly lower than that of non-PM [10.9 ± 1.64 vs. 14.2 ± 5.39 ng/ml, P = 0.019 (11,12-DHET); 15.2 ± 4.39 vs. 17.9 ± 4.73 ng/ml, P = 0.025 (14,15-DHET)]. CYP2C19 variants are associated with MVA. The decline of EET-based defensive mechanisms owing to CYP2C19 variants may affect coronary microvascular dysfunction.