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.

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.

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.

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.

Modeling of the Weight Status and Risk of Nonalcoholic Fatty Liver Disease in Elderly Individuals: The Potential Impact of the Disulfide Bond-Forming Oxidoreductase A-Like Protein (DsbA-L) Polymorphism on the Weight Status.

Nonalcoholic fatty liver disease (NAFLD) is closely associated with obesity. Disulfide bond-forming oxidoreductase A-like protein (DsbA-L) is known to be a key molecule in protection against obesity and obesity-induced inflammation. In the present study, we used a modeling and simulation approach in an attempt to develop body mass index (BMI) and BMI-based NAFLD prediction models incorporating the DsbA-L polymorphism to predict the BMI and NAFLD in 341 elderly subjects. A nonlinear mixed-effect model best represented the sigmoidal relationship between the BMI and the logit function of the probability of NAFLD prevalence. The final models for BMI and NAFLD showed that DsbA-L rs1917760 polymorphism, age, and gender were associated with the BMI, whereas gender, patatin-like phospholipase 3 rs738409 polymorphism, HbA1c, and high-density and low-density lipoprotein cholesterol levels were associated with the risk of NAFLD. This information may aid in the genetic-based prevention of obesity and NAFLD in the general elderly population.

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.

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.

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.

Association between the aldehyde dehydrogenase 2*2 allele and smoking-related chronic airway obstruction in a Japanese general population: a pilot study.

Aldehyde dehydrogenase 2 (ALDH2) detoxifies exogenous and endogenous toxic aldehydes; however, its protective effect against cigarette smoke in airways is unknown. We therefore examined whether the inactive ALDH2*2 allele is associated with smoking-related chronic airway obstruction. We conducted a cross-sectional study including 684 Japanese participants in a health screening program, and a retrospective longitudinal study in the elderly subgroup. The risks of airway obstruction in the ever-smokers with the ALDH2*1/*2 and *2/*2 genotypes were two and three times higher, respectively, than in the never-smokers with the ALDH2*1/*1 genotype. Moreover, the combined effect of smoking and the ALDH2*2 allele was prominent in the asthmatic subjects. In a longitudinal association analysis, the combination of the ALDH2 genotype and pack-years of smoking synergistically increased the risk of airway obstruction. The number of pack-years of smoking at baseline was identified to be a significant predictor of airway obstruction only in the ALDH2*2 allele carriers. In addition, the ALDH2*2 allele was also associated with the incidence of smoking-related airway obstruction, in the Cox proportional hazards model. This pilot study demonstrated for the first time a significant gene-environment interaction between the ALDH2*2 allele and cumulative exposure to cigarette smoke on the risk of airway obstruction.

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.