Comorbidities according to airflow limitation severity: data from comprehensive health examination in Japan.

OBJECTIVES: The present study aimed to investigate the relationship between airflow limitation (AL) severity and comorbidities in comprehensive health examination. METHODS: This cross-sectional study included 6661 men and 6044 women aged 40-89 who underwent a lung function test during medical checkups. AL was defined as forced expiratory volume in 1 s/forced vital capacity of < 0.7. Logistic regression analysis was used to assess the association between AL severity and the presence of comorbidities. RESULTS: When compared with the normal lung function group, subjects with AL had a higher prevalence of lung cancer (odd ratio (OR) 9.88, 95% confidence interval (CI) 3.88-25.14) in men, hypertension (OR 1.63, 95% CI 1.26-2.10) in women, diabetes and hyperglycemia (OR 1.23, 95% CI 1.02-1.49 in men, OR 1.61, 95% CI 1.18-2.20 in women) in men and women after adjusting for potential confounders. In men, lung cancer and MetS (the Joint Interim Statement: JIS) were significantly associated with moderate-to-very severe AL after adjustment. In women, hypertension, diabetes and hyperglycemia, MetS (JIS), and MetS (the Japanese Committee of the Criteria for MetS: JCCMS) were significantly associated with mild AL after adjustment. Hypertension was significantly associated with moderate-to-very severe AL after adjustment in women. CONCLUSIONS: Significant relationships were found between AL severity and the presence of comorbid lung cancer in men, hypertension in women, diabetes and hyperglycemia, and MetS in men and women. Knowledge of comorbidities associated with AL should be widely publicized to raise the awareness of chronic obstructive pulmonary disease (COPD).

Sex differences in the impact of CYP2C19 polymorphisms and low-grade inflammation on coronary microvascular disorder.

Categorization as a cytochrome P-450 (CYP) 2C19 poor metabolizer (PM) is reported to be an independent risk factor for cardiovascular disease. It is correlated with an increase in the circulating levels of high-sense C-reactive protein (hs-CRP) in women only, although its role in coronary microcirculation is unclear. We examined sex differences in the impact of the CYP2C19 genotype and low-grade inflammation on coronary microvascular disorder (CMVD). We examined CYP2C19 genotypes in patients with CMVD (n = 81) and in healthy subjects as control (n = 81). CMVD was defined as the absence of coronary artery stenosis and epicardial spasms, the presence of inverted lactic acid levels between the intracoronary and coronary sinuses, or an adenosine triphosphate-induced coronary flow reserve ratio < 2.5. CYP2C19 PMs have two loss-of-function (LOF) alleles (*2, *3). Extensive metabolizers have no LOF alleles, and intermediate metabolizers have one LOF allele. The ratio of CYP2C19 PM and hs-CRP levels in CMVD was significantly higher than that of controls, especially in women (40.9 vs. 13.8%, P = 0.013; 0.11 ± 0.06 vs. 0.07 ± 0.04 mg/dl, P = 0.001). Moreover, in each CYP2C19 genotype, hs-CRP levels in CMVD in CYP2C19 PMs were significantly higher than those of the controls, especially in women (0.15 ± 0.06 vs. 0.07 ± 0.03, P = 0.004). Multivariate analysis for CMVD indicated that the female sex, current smoking, and hypertension were predictive factors, and that high levels of hs-CRP and CYP2C19 PM were predictive factors in women only (odds ratio 3.5, 95% confidence interval 1.26-9.93, P = 0.033; odds ratio 4.1, 95% confidence interval 1.15-14.1, P = 0.038). CYP2C19 PM genotype may be a new candidate risk factor for CMVD via inflammation exclusively in the female population.

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.

Interactive effects of a common γ-glutamyltransferase 1 variant and low high-density lipoprotein-cholesterol on diabetic macro- and micro-angiopathy.

BACKGROUND: We investigated the clinical relevance of a common variant, rs4820599, in the γ-glutamyltransferase (GGT)1 gene, associated with the serum GGT level, in Japanese type 2 diabetes mellitus (T2DM) subjects. METHODS: We conducted a retrospective longitudinal study (4.9 ± 2.5 years) including 352 T2DM patients (T2DM subjects) and a cross-sectional study including 796 health screening program participants (general subjects). A real-time TaqMan allelic discrimination assay was used to identify the genotypes. Risk factors for a high brachial-ankle pulse wave velocity (baPWV) (≥1750 cm/sec) or diabetic retinopathy (DR) were determined using a generalized estimating equations approach, receiver operating characteristic (ROC) analysis or Cox proportional hazards model, etc. RESULTS: The frequency of the GGT1 G allele was 20.8% in the T2DM subjects, and no associations were found between the GGT1 genotype and risk of T2DM. The mean log GGT values in the T2DM and general subjects were significantly higher among G allele carriers than non-carriers. The G allele and a low HDL-C level were identified to be risk factors for a high baPWV in the T2DM subjects [odds ratio (OR) 1.80, P = 0.008; OR 1.71, P = 0.03; respectively), and a significant interactive effect between these factors was found on the risk of a high baPWV and DR. The HDL-C level at baseline was a significant predictor of a high baPWV only in G allele carriers according to the ROC analysis. This result regarding baPWV in the T2DM subjects was replicated in the general population. Meanwhile, the GGT1 genotype was not associated with the risk of DR, although it affected the principal factors involved in the risk of DR, and a low HDL-C level was also found to be a risk factor for DR only in G allele carriers. CONCLUSIONS: We herein describe for the first time the significant interactive effects of the GGT1 G allele and a low HDL-C level on a high baPWV and DR. These findings may encourage future clinical trials comparing the efficacy of agents increasing the HDL-C levels among the GGT1 genotypes. However, well-designed studies in larger cohorts are needed to confirm our results.

Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: multicentre registry study of the Japanese Coronary Spasm Association.

AIMS: Provocation tests of coronary artery spasm are useful for the diagnosis of vasospastic angina (VSA). However, these tests are thought to have a potential risk of arrhythmic complications, including ventricular tachycardia (VT), ventricular fibrillation (VF), and brady-arrhythmias. We aimed to elucidate the safety and the clinical implications of the spasm provocation tests in the nationwide multicentre registry study by the Japanese Coronary Spasm Association. METHODS AND RESULTS: A total of 1244 VSA patients (M/F, 938/306; median 66 years) who underwent the spasm provocation tests were enrolled from 47 institutes. The primary endpoint was defined as major adverse cardiac events (MACEs). The provocation tests were performed with either acetylcholine (ACh, 57%) or ergonovine (40%). During the provocation tests, VT/VF and brady-arrhythmias developed at a rate of 3.2 and 2.7%, respectively. Overall incidence of arrhythmic complications was 6.8%, a comparable incidence of those during spontaneous angina attack (7.0%). Multivariable logistic regression analysis demonstrated that diffuse right coronary artery spasm (P < 0.01) and the use of ACh (P < 0.05) had a significant correlation with provocation-related VT/VF. During the median follow-up of 32 months, 69 patients (5.5%) reached the primary endpoint. The multivariable Cox proportional hazard model revealed that mixed (focal plus diffuse) type multivessel spasm had an important association with MACEs (adjusted hazard ratio, 2.84; 95% confidence interval, 1.34-6.03; P < 0.01), whereas provocation-related arrhythmias did not. CONCLUSION: The spasm provocation tests have an acceptable level of safety and the evaluation of spasm type may provide useful information for the risk prediction of VSA patients.

The Association of the Cholesterol Efflux Capacity with the Paraoxonase 1 Q192R Genotype and the Paraoxonase Activity.

AIMS: Paraoxonase 1 (PON1) binds to high-density lipoprotein (HDL) and protects against atherosclerosis. However, the relationship between functional PON1 Q192R polymorphism, which is associated with the hydrolysis of paraoxon (POXase activity) and atherosclerotic cardiovascular disease (ASCVD), remains controversial. As the effect of PON1 Q192R polymorphism on the HDL function is unclear, we investigated the relationship between this polymorphism and the cholesterol efflux capacity (CEC), one of the biological functions of HDL, in association with the PON1 activity. METHODS: The relationship between PON1 Q192R polymorphisms and CEC was investigated retrospectively in 150 subjects without ASCVD (50 with the PON1 Q/Q genotype, 50 with the Q/R genotype, and 50 with the R/R genotype) who participated in a health screening program. The POXase and arylesterase (AREase: hydrolysis of aromatic esters) activities were used as measures of the PON1 activity. RESULTS: The AREase activity was positively correlated with CEC independent of the HDL cholesterol levels. When stratified by the PON1 Q192R genotype, the POXase activity was also positively correlated with CEC independent of HDL cholesterol. PON1 Q192R R/R genotype carriers had a lower CEC than Q/Q or Q/R genotype carriers, despite having a higher POXase activity. Moreover, in a multiple regression analysis, the PON1 Q192R genotype was associated with the degree of CEC, independent of the HDL cholesterol and POXase activity. CONCLUSIONS: The PON1 Q192R R allele is associated with reduced CEC in Japanese people without ASCVD. Further studies on the impact of this association on the severity of atherosclerosis and ASCVD development are thus called for.

Impaired Cholesterol Efflux Capacity rather than Low HDL-C Reflects Oxidative Stress under Acute Myocardial Infarction.

AIMS: Acute myocardial infarction (AMI) causes irreversible damage to cardiomyocytes due to the discontinuation of oxygen supply and leads to systemic oxidative stress. It has been reported that high-density lipoprotein (HDL) particles have antioxidant capacity, and reduced antioxidant capacity is associated with decreased cholesterol efflux capacity (CEC). The purpose of this study was to clarify the usefulness of CEC measurement in patients with AMI. METHODS: We investigated the association between CEC and oxidative stress status in a case-control study. This study included 193 AMI cases and 445 age- and sex-matched controls. We examined the associations of CEC with HDL-cholesterol (HDL-C) and oxidized human serum albumin (HSA), an index of systemic oxidative stress status, and the effect of aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which has been reported to affect HDL-C level and risk for MI, on these associations. RESULTS: Both bivariable and multivariable analyses showed that CEC was positively correlated with HDL-C levels in both AMI cases and controls, with a weaker correlation in AMI cases than in controls. In AMI cases, oxidized HSA levels were associated with CEC in both bivariable and multivariable analyses, but not with HDL-C. These associations did not differ among the ALDH2 genotypes. CONCLUSIONS: CEC, but not HDL-C level, reflects systemic oxidative stress status in patients with AMI. CEC measurement for patients with AMI may be useful in that it provides information on systemic oxidative stress status as well as atherosclerosis risk.

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.

Gender differences in the clinical characteristics and outcomes of patients with vasospastic angina--a report from the Japanese Coronary Spasm Association.

BACKGROUND: Accumulating evidence has demonstrated the gender differences in the clinical characteristics and outcomes of patients with ischemic heart disease. However, it remains to be elucidated whether it is also the case for vasospastic angina (VSA). METHODS AND RESULTS: We enrolled a total of 1,429 VSA patients (male/female, 1090/339; median age 66 years) in our nationwide multicenter registry by the Japanese Coronary Spasm Association. As compared with male patients, female patients were characterized by older age (median 69 vs. 66 years), lower incidence of smoking (20% vs. 72%) and less significant organic stenosis (9% vs. 16%) (all P=0.001). Multivariate analysis demonstrated that the predictors of major adverse cardiac events (MACE) were considerably different by genders; women were more associated with age and electrical abnormalities, whereas men with structural abnormalities. Overall 5-year MACE-free survival was comparable between both genders. However, when the patients were divided into 3 groups by age [young (<50 years), middle-aged (50-64 years) and elderly (≥65 years)], the survival was significantly lower in the young female group (young 82%, middle-aged 92%, elderly 96%, P<0.01), where a significant interaction was noted between age and smoking. In contrast, the survival was comparable among the 3 age groups of male patients. CONCLUSIONS: These results indicate that there are gender differences in the characteristics and outcomes of VSA patients, suggesting the importance of gender-specific management of the disorder.

Additive Effects of Drinking Habits and a Susceptible Genetic Polymorphism on Cholesterol Efflux Capacity.

AIMS: High levels of high-density lipoprotein cholesterol (HDL-C) are not necessarily effective in preventing atherosclerotic cardiovascular disease, and cholesterol efflux capacity (CEC) has attracted attention regarding HDL functionality. We aimed to elucidate whether drinking habits are associated with CEC levels, while also paying careful attention to confounding factors including serum HDL-C levels, other life style factors, and rs671 (＊2), a genetic polymorphism of the aldehyde dehydrogenase 2 (ALDH2) gene determining alcohol consumption habit. METHODS: A cross-sectional study was performed in 505 Japanese male subjects who were recruited from a health screening program. Associations of HDL-C and CEC levels with drinking habits and ALDH2 genotypes were examined. RESULTS: The genotype frequencies of ALDH2 ＊1/＊1 (homozygous wild-type genotype), ＊1/＊2 and ＊2/＊2 (homozygous mutant genotype) were 55%, 37% and 8%, respectively. Both HDL-C and CEC levels were higher in ALDH2 ＊1/＊1 genotype carriers than in ＊2 allele carriers. Although HDL-C levels were higher in subjects who had a drinking habit than in non-drinkers, CEC levels tended to be lower in subjects with ≥ 46 g/day of alcohol consumption than in non-drinkers. Furthermore, CEC levels tended to be lower in ALDH2 ＊1/＊1 genotype carriers with a drinking habit of ≥ 46 g/day than non-drinkers, while for ＊2 allele carriers, CEC levels tended to be lower with a drinking habit of 23-45.9 g/day compared to no drinking habit. CONCLUSIONS: Our results suggest that heavy drinking habits may tend to decrease CEC levels, and in the ALDH2 ＊2 allele carriers, even moderate drinking habits may tend to decrease CEC levels.

Serum Fatty Acid Composition Balance by Fuzzy C-Means Method in Individuals with or without Metabolic Dysfunction-Associated Fatty Liver Disease.

Circulating fatty acid composition is assumed to play an important role in metabolic dysfunction-associated fatty liver disease (MAFLD) pathogenesis. This study aimed to investigate the association between the overall balance of serum fatty acid composition and MAFLD prevalence. This cross-sectional study involved 400 Japanese individuals recruited from a health-screening program. We measured fatty acids in serum lipids using gas chromatography-mass spectrometry. The serum fatty acid composition balance was evaluated using fuzzy c-means clustering, which assigns individual data points to multiple clusters and calculates the percentage of data points belonging to multiple clusters, and serum fatty acid mass%. The participants were classified into four characteristic subclasses (i.e., Clusters 1, 2, 3, and 4), and the specific serum fatty acid composition balance (i.e., Cluster 4) was associated with a higher MAFLD prevalence. We suggest that the fuzzy c-means method can be used to determine the circulating fatty acid composition balance and highlight the importance of focusing on this balance when examining the relationship between MAFLD and serum fatty acids.

C-reactive protein levels, airflow obstruction, and chronic kidney disease.

OBJECTIVES: There is some evidence that chronic obstructive pulmonary disease and chronic kidney disease (CKD) may be related, perhaps through systemic inflammation, which is common to both. However, this relationship has not yet been clearly demonstrated. The aim of this study was to investigate the association between airflow obstruction, CKD, and C-reactive protein (CRP) levels in Japanese men. METHODS: The study included 11,587 men, aged 40-88 years, who underwent a health check-up. Airflow obstruction was defined as a forced expiratory volume in 1 s/forced vital capacity of <70%, and its severity was based on the Global Initiative for Chronic Obstructive Lung Disease guidelines (GOLD). CKD was defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m(2). RESULTS: Airflow obstruction was present in 7.9% of the participants, and 10.6% of the participants had CKD. The average CRP levels were 0.11 ± 0.36, 0.13 ± 0.41, and 0.18 ± 0.41 mg/L for subjects with normal lung function, GOLD stage I, and GOLD stage II-IV, respectively. With regard to CKD, the average CRP levels were 0.11 ± 0.32 and 0.18 ± 0.6 mg/L for subjects without and with CKD, respectively. Analysis of covariance showed no significant differences between the CRP level and lung function status or CKD after age was adjusted for. Logistic regression analysis showed no association among subjects with the three different lung function statuses after age, body mass index, hypertension, diabetes, hyper-low-density-lipoprotein-cholesterolemia, smoking, physical activity, and alcohol intake were controlled for. CONCLUSIONS: Based on the results of this study, we conclude that there is no interrelationship between CRP level, airflow obstruction, and CKD.

Association between frequency of drinking alcohol and chronic kidney disease in men.

OBJECTIVES: Chronic kidney disease (CKD) is a major public health problem. Epidemiological studies of the relationship between alcohol intake and CKD are scarce in Japan. This cross-sectional study aims to investigate the relationship between frequency of drinking alcohol and CKD in Japanese men. METHODS: The subjects were 9,196 men (mean ± standard deviation age, 57.9 ± 5.1 years) who underwent a health check-up. CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m(2). Frequency of alcohol drinking was obtained from questionnaire and divided into five categories: nondrinkers, once or twice a week, three or four times a week, five or six times a week, and everyday drinkers. RESULTS: Multivariable-adjusted [age, body mass index, hypertension, diabetes, hyper-low-density lipoprotein (LDL) cholesterolemia, smoking, and physical activity] odds ratios and 95% confidence intervals (CIs) were calculated using logistic regression analysis. Compared with the results for the nondrinkers, the multivariable-adjusted odds ratios of CKD were as follows: 0.76 (95% CI 0.60-0.95) for 1-2 drinks per week, 0.74 (95% CI 0.59-0.93) for 3-4 drinks per week, 0.79 (95% CI 0.64-0.97) for 5-6 drinks per week, and 0.60 (95% CI 0.51-0.71) for everyday drinkers. There was a significant inverse trend across increasing frequency of drinking alcohol (p = 0.001 for trend). CONCLUSIONS: An inverse association was found between frequency of drinking alcohol and CKD in apparently healthy men.

Standard-dose statin therapy provides incremental clinical benefits in normocholesterolemic diabetic patients.

BACKGROUND: Randomized trials have established statins as an agent for prevention of coronary heart disease (CHD). The purpose of this study was to assess the hypothesis that standard-dose statin therapy has a beneficial effect in normocholesterolemic diabetic patients with CHD. METHODS AND RESULTS: A prospective, randomized, open, blinded-endpoint trial was conducted from 2002 to 2004 at 55 hospitals in Japan to evaluate the effect of statins on subsequent cardiovascular events. A total number of 1,016 CHD patients (301 patients with type 2 diabetes mellitus [DM] and 715 non-DM patients) with serum total cholesterol levels of 180-240 mg/dl were randomly divided into non-statin and statin treatments. Clinical parameters were comparable between DM and non-DM groups. Serum low-density lipoprotein (LDL)-cholesterol levels were equally decreased after statin treatment in the 2 groups. Statin treatment improved prognosis in both the DM and non-DM groups; however, the number needed to treat (NNT) and relative risk reduction (RRR) were remarkable especially in the DM group (NNT=8, RRR=67%) compared with the non-DM group (NNT=30, RRR=24%). CONCLUSIONS: Standard-dose statin therapy provides incremental clinical benefits in DM patients with normal cholesterol levels compared with non-DM patients. The data suggest that DM patients may enjoy the pleiotropic effects of statins, independent of the LDL-cholesterol lowering effects of these agents.

Prostaglandin E2-EP4 Axis Promotes Lipolysis and Fibrosis in Adipose Tissue Leading to Ectopic Fat Deposition and Insulin Resistance.

Lipolysis, the breakdown of triglyceride storage in white adipose tissue, supplies fatty acids to other tissues as a fuel under fasting conditions. In morbid obesity, fibrosis limits adipocyte expandability, resulting in enforced lipolysis, ectopic fat distribution, and ultimately insulin resistance. Although basal levels of lipolysis persist even after feeding, the regulatory mechanisms of basal lipolysis remain unclear. Here, we show the important role of adipocyte prostaglandin (PG) E2-EP4 receptor signaling in controlling basal lipolysis, fat distribution, and collagen deposition during feeding-fasting cycles. The PGE2-synthesis pathway in adipocytes, which is coupled with lipolysis, is activated by insulin during feeding. By regulating the lipolytic key players, the PGE2-EP4 pathway sustains basal lipolysis as a negative feedback loop of insulin action, and perturbation of this process leads to "metabolically healthy obesity." The potential role of the human EP4 receptor in lipid regulation was also suggested through genotype-phenotype association analyses.

A Pilot Study Assessing the Possible Combined Effect of Physical Activity and PNPLA3 rs738409 Polymorphism on the Risk for Non-Alcoholic Fatty Liver Disease in the Japanese Elderly General Population.

PURPOSE: The patatin-like phospholipase domain containing protein 3 (PNPLA3) rs738409 polymorphism (c.444C>G) is the most well-known genetic risk factor for non-alcoholic fatty liver disease (NAFLD), but whether or not physical activity influences the association between the PNPLA3 genotype and risk of NAFLD is unclear. PATIENTS AND METHODS: A retrospective longitudinal analysis was conducted among 352 Japanese subjects. Each type of physical activity was assigned a metabolic equivalent (MET), and the subjects were classified into sedentary, low or high groups using the "METS*T" (METs × hours per week) value of 5 or 21 as a threshold. RESULTS: Among the PNPLA3 G/G genotype carriers, the high and low METS*T groups had a lower risk of NAFLD than the sedentary METS*T group (odds ratio [95% confidence interval]: 0.14 [0.02-0.99] and 0.16 [0.03-1.04], respectively). Furthermore, the PNPLA3 C/C or C/G genotype carriers showed no significant difference in the risk of NAFLD among the three METS*T groups. CONCLUSION: The PNPLA3 rs738409 genotype may be associated with the beneficial effects of physical activity on the risk of NAFLD among elderly Japanese individuals. Further comprehensive investigations are therefore needed to verify the preliminary results.

The DsbA-L gene is associated with respiratory function of the elderly via its adiponectin multimeric or antioxidant properties.

Oxidative stress and inflammation play a key role in the age-related decline in the respiratory function. Adipokine in relation to the metabolic and inflammatory systems is attracting growing interest in the field of respiratory dysfunction. The present clinical and experimental studies investigated the role of the disulfide bond-forming oxidoreductase A-like protein (DsbA-L) gene, which has antioxidant and adiponectin multimeric (i.e. activation) properties, on the respiratory function of the elderly. We performed a retrospective longitudinal genotype-phenotype relationship analysis of 318 Japanese relatively elderly participants (mean age ± standard deviation: 67.0 ± 5.8 years) during a health screening program and an in vitro DsbA-L knock-down evaluation using 16HBE14o-cells, a commonly evaluated human airway epithelial cell line. The DsbA-L rs1917760 polymorphism was associated with a reduction in the ratio of forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) and %FEV1 and with the elevation of the prevalence of FEV1/FVC < 70%. We also confirmed that the polymorphism was associated with a decreased respiratory function in relation to a decrease in the ratio of high-molecular-weight adiponectin/total adiponectin (as a marker of adiponectin multimerization) and an increase in the oxidized human serum albumin (as an oxidative stress marker). Furthermore, we clarified that DsbA-L knock-down induced oxidative stress and up-regulated the mucus production in human airway epithelial cells. These findings suggest that the DsbA-L gene may play a role in protecting the respiratory function of the elderly, possibly via increased systemic adiponectin functions secreted from adipocytes or through systemic and/or local pulmonary antioxidant properties.

Higher Blood Uric Acid in Female Humans and Mice as a Protective Factor against Pathophysiological Decline of Lung Function.

The oxidant/antioxidant imbalance plays a pivotal role in the lung. Uric acid (UA), an endogenous antioxidant, is highly present in lung tissue, however, its impact on lung function under pathophysiological conditions remains unknown. In this work, pharmacological and genetic inhibition of UA metabolism in experimental mouse models of acute and chronic obstructive pulmonary disease (COPD) revealed that increased plasma UA levels improved emphysematous phenotype and lung dysfunction in accordance with reduced oxidative stress specifically in female but not in male mice, despite no impact of plasma UA induction on the pulmonary phenotypes in nondiseased mice. In vitro experiments determined that UA significantly suppressed hydrogen peroxide (H2O2)-induced oxidative stress in female donor-derived primary human bronchial epithelial (NHBE) cells in the absence of estrogen, implying that the benefit of UA is limited to the female airway in postmenopausal conditions. Consistently, our clinical observational analyses confirmed that higher blood UA levels, as well as the SLC2A9/GLUT9 rs11722228 T/T genotype, were associated with higher lung function in elderly human females. Together, our findings provide the first unique evidence that higher blood UA is a protective factor against the pathological decline of lung function in female mice, and possibly against aging-associated physiological decline in human females.

Beta-3-adrenergic Receptor rs4994 Polymorphism Is a Potential Biomarker for the Development of Nonalcoholic Fatty Liver Disease in Overweight/Obese Individuals.

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases. Obesity is the most common and well-established risk factor for NAFLD, but there are large interindividual differences in the relationship between weight status and the development of NAFLD. Beta-3-adrenergic receptor (ADRB3) plays a key role in the development of visceral obesity and insulin resistance; however, the effect of ADRB3 polymorphisms on the risk of NAFLD remains unclear. We investigated whether or not a common rs4994 polymorphism (T190C) in the ADRB3 gene is associated with the risk of NAFLD through an increase in the body mass index (BMI) among the general population. We performed cross-sectional and longitudinal analyses in a total of 591 Japanese health screening program participants. Among the overweight or obese subjects, but not normal-weight subjects, individuals with the C/C genotype had a higher risk of developing NAFLD in comparison to those with other genotypes in the cross-sectional analysis (odds ratio: 4.40, 95% confidence interval (CI): 1.08-17.93). Meanwhile, the receiver operating characteristic curve indicated that the association between an increase in the BMI and the presence of NAFLD in subjects with the C/C genotype (area under the curve: 0.91, 95% CI: 0.78-1.00) was more pronounced in comparison to subjects with other genotypes. These above-described findings were verified by the analyses using a replicated data set consisting of 5,000 random samples from original data sets. Furthermore, among the 291 subjects for whom longitudinal medical information could be collected and who did not have NAFLD at baseline, the Cox proportional hazard model also confirmed that overweight or obese status and the C/C genotype were concertedly related to the increased risk of NAFLD development. These results suggest that genotyping the ADRB3 rs4994 polymorphism may provide useful information supporting the development of personalized BMI-based preventive measures against NAFLD.