Neuronal activity in the monkey prefrontal cortex during a duration discrimination task with visual and auditory cues.

To investigate neuronal processing involved in the integration of auditory and visual signals for time perception, we examined neuronal activity in prefrontal cortex (PFC) of macaque monkeys during a duration discrimination task with auditory and visual cues. In the task, two cues were consecutively presented for different durations between 0.2 and 1.8 s. Each cue was either auditory or visual and was followed by a delay period. After the second delay, subjects indicated whether the first or the second cue was longer. Cue- and delay-responsive neurons were found in PFC. Cue-responsive neurons mostly responded to either the auditory or the visual cue, and to either the first or the second cue. The neurons responsive to the first delay showed activity that changed depending on the first cue duration and were mostly sensitive to cue modality. The neurons responsive to the second delay exhibited activity that represented which cue, the first or second cue, was presented longer. Nearly half of this activity representing order-based duration was sensitive to cue modality. These results suggest that temporal information with visual and auditory signals was separately processed in PFC in the early stage of duration discrimination and integrated for the final decision.

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.

Locomotor kinematics and EMG activity during quadrupedal versus bipedal gait in the Japanese macaque.

Several qualitative features distinguish bipedal from quadrupedal locomotion in mammals. In this study we show quantitative differences between quadrupedal and bipedal gait in the Japanese monkey in terms of gait patterns, trunk/hindlimb kinematics, and electromyographic (EMG) activity, obtained from 3 macaques during treadmill walking. We predicted that as a consequence of an almost upright body axis, bipedal gait would show properties consistent with temporal and spatial optimization countering higher trunk/hindlimb loads and a less stable center of mass (CoM). A comparatively larger step width, an ~9% longer duty cycle, and ~20% increased relative duration of the double-support phase were all in line with such a strategy. Bipedal joint kinematics showed the strongest differences in proximal, and least in distal, hindlimb joint excursions compared with quadrupedal gait. Hindlimb joint coordination (cyclograms) revealed more periods of single-joint rotations during bipedal gait and predominance of proximal joints during single support. The CoM described a symmetrical, quasi-sinusoidal left/right path during bipedal gait, with an alternating shift toward the weight-supporting limb during stance. Trunk/hindlimb EMG activity was nonuniformally increased during bipedal gait, most prominently in proximal antigravity muscles during stance (up to 10-fold). Non-antigravity hindlimb EMG showed altered temporal profiles during liftoff or touchdown. Muscle coactivation was more, but muscle synergies less, frequent during bipedal gait. Together, these results show that behavioral and EMG properties of bipedal vs. quadrupedal gait are quantitatively distinct and suggest that the neural control of bipedal primate locomotion underwent specific adaptations to generate these particular behavioral features to counteract increased load and instability. NEW & NOTEWORTHY Bipedal locomotion imposes particular biomechanical constraints on motor control. In a within-species comparative study, we investigated joint kinematics and electromyographic characteristics of bipedal vs. quadrupedal treadmill locomotion in Japanese macaques. Because these features represent (to a large extent) emergent properties of the underlying neural control, they provide a comparative, behavioral, and neurophysiological framework for understanding the neural system dedicated to bipedal locomotion in this nonhuman primate, which constitutes a critical animal model for human bipedalism.

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.

CYP2C19 variants and epoxyeicosatrienoic acids in patients with microvascular angina.

BACKGROUND: 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 impact of CYP2C19 polymorphisms and EETs on the patients with microvascular angina (MVA) caused by coronary microvascular dysfunction. METHODS AND RESULTS: We examined CYP2C19 genotypes in patients with MVA (n = 81). MVA was defined as 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. In MVA, the patients with CYP2C19 PM were 34.6% and high sense C-reactive protein (hs-CRP) levels in CYP2C19 PM were significantly higher than that of non-PM group (0.165 ± 0.116 vs. 0.097 ± 0.113 mg/dL, P = 0.026). Moreover, DHET levels in CYP2C19 PM were significantly lower than that of non-PM (10.4 ± 4.58 vs. 15.6 ± 11.1 ng/mL, P = 0.003 (11,12-DHET); 12.1 ± 3.79 vs. 17.3 ± 6.49 ng/mL, P = 0.019 (14,15-DHET)). CONCLUSIONS: The decline of EET owing to CYP2C19 variants may affects coronary microvascular dysfunction via chronic inflammation.

Common variants of HNF1A gene are associated with diabetic retinopathy and poor glycemic control in normal-weight Japanese subjects with type 2 diabetes mellitus.

AIM: This study investigated the associations between the common hepatocyte nuclear factor-1A (HNF1A) variants and the risk of diabetic retinopathy (DR) in relation to the glycemic control and weight status. METHODS: A retrospective longitudinal analysis was conducted among 354 Japanese patients with type 2 diabetes mellitus (T2DM) (mean follow-up duration: 5.8±2.5 years). The multivariable-adjusted hazard ratio (HR) for the cumulative incidence of DR was calculated using a Cox proportional hazard model. During the observation period, the longitudinal associations of the HNF1A diplotypes with the risk of DR and the clinical parameters were also analyzed using the generalized estimating equations approach. RESULTS: The combination of risk variants, i.e., rs1169288-C, rs1183910-A and rs2464196-A, was defined as the H1 haplotype. The incidence of DR was higher in the H1/H1 diplotype cases than in the others (HR 2.75 vs. non-H1/non-H1; p=0.02). Only in normal-weight subjects, the risks of DR and poor glycemic control were higher in the H1/H1 diplotype cases than in the others [odds ratio 4.08 vs. non-H1/non-H1, p=0.02; odds ratio 3.03, p=0.01; respectively]. CONCLUSIONS: This study demonstrated that the common HNF1A diplotype of three risk variants may be an independent risk factor for the development of DR resulting from poor glycemic control in normal-weight patients with T2DM. These results need to be replicated in larger and more varied study populations.

Helicobacter pylori Seropositivity in Patients with Interleukin-1 Polymorphisms Is Significantly Associated with ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Helicobacter pylori infection and interleukin-1 polymorphisms are associated with an increased risk of gastric cancer. We examined the prevalence of Helicobacter pylori seropositivity and interleukin-1 polymorphisms between ST-segment elevation myocardial infarction and non-ST-segment elevation acute coronary syndrome patients. METHODS: We recruited consecutive acute coronary syndrome patients, and 101 non-ST-segment elevation acute coronary syndrome patients and 103 ST-segment elevation myocardial infarction patients were enrolled. Interleukin-1 polymorphism analyses were performed for single nucleotide polymorphism in interleukin-1 beta-511 and the variable number of tandem repeats polymorphism in the interleukin-1 receptor antagonist by polymerase chain reaction. Immunoglobulin G antibodies against Helicobacter pylori and high sensitivity C-reactive protein were also measured. RESULTS: The rates of the simultaneous presence of interleukin-1 polymorphisms and Helicobacter pylori-seropositivity between non-ST-segment elevation acute coronary syndrome and ST-segment elevation myocardial infarction groups were 25.7% and 42.7%, respectively (P = 0.012). Helicobacter pylori-seropositive subjects with interleukin-1 polymorphisms showed significantly higher levels of high sensitivity C-reactive protein (0.04-0.12 vs. 0.02-0.05; P<0.001). Multivariate logistic regression analysis revealed that the carriage of Helicobacter pylori-seropositivity and interleukin-1 polymorphisms was significantly associated with ST-segment elevation myocardial infarction (odds ratio, 2.32; 95% confidence interval, 1.23-4.37; P = 0.009). The C-statistic of conventional risk factors was 0.68 (P<0.001) and that including Helicobacter pylori-seropositivity and interleukin-1 polymorphisms was 0.70 (P<0.001); continuous net reclassification improvement was 34% (P = 0.0094) and integrated discrimination improvement was 3.0% (P = 0.014). CONCLUSIONS: The coincidence of Helicobacter pylori-seropositivity and interleukin-1 polymorphisms was significantly associated with higher levels of high sensitivity C-reactive protein and the increased risk of ST-segment elevation myocardial infarction.

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.

Sex Differences in the Renal Function Decline of Patients with Type 2 Diabetes.

Aims. We aimed to investigate the sex differences in the renal function decline among patients with type 2 diabetic mellitus (T2DM), focusing on the differences in the risk factors at early stage of renal dysfunction. Methods. A clinic-based retrospective longitudinal study (follow-up duration: 8.1 ± 1.4 years) was conducted to assess the sex differences in the annual estimated glomerular filtration rate (eGFR) change in 344 (247 male and 97 female) Japanese T2DM patients. The sex differences in the risk factors of annual eGFR decline were subjected to linear regression analyses. Results. The mean annual eGFR change was -3.5 ± 2.7%/year in females and -2.0 ± 2.2%/year in males (P < 0.001). Baseline retinopathy and proteinuria were significantly associated with a larger eGFR decline, irrespective of sex, while HbA1c and LDL-cholesterol levels were significantly associated with an eGFR decline in females only. Interactive effects were observed between sex and the HbA1c, LDL-cholesterol, retinopathy, or proteinuria levels on the annual eGFR decline. Conclusions. The increased susceptibility to poor metabolic control seemed to contribute to a higher risk of renal dysfunction in females with T2DM. Our study highlights the importance of aggressive therapeutic intervention to improve metabolic profiles at early stage, especially in females.

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.

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.

Safety analysis of zolpidem in elderly subjects 80 years of age or older: adverse event monitoring in Japanese subjects.

OBJECTIVES: Prescriptions of non-benzodiazepine sedative hypnotics, e.g. zolpidem, for insomnia in elderly subjects 80 years of age or older have markedly increased in the USA. However, a meta-analysis of the risks and benefits of hypnotics in older people reported the benefits associated with hypnotics use are outweighed by the risks. This study aimed to investigate the safety of zolpidem administration in extremely old elderly. METHODS: The prevalence of adverse reactions to zolpidem was investigated in a subpopulation of participants in the Drug Event Monitoring project of the Japan Pharmaceutical Association. A total of 1011 (316 males and 695 females) zolpidem users, including 261 (25.8%) subjects 80 years of age or older without cognitive or mental complications, were eligible for the analysis. RESULTS: The elderly and female patients were prescribed significantly lower doses of zolpidem than their counterparts. Adverse symptoms after the last prescription were reported by 60 (5.9%) subjects. The most common symptoms were impaired balance and/or falls (1.8%) and morning drowsiness (1.3%). The multiple logistic regression analyses showed that subjects 80 years of age or older were at lower risk of adverse symptoms (odds ratio 0.39, 95% confidence intervals: 0.17-0.88). CONCLUSION: Our findings in a real-world clinical setting suggest that low-dose zolpidem can be safely prescribed to subjects 80 years of age or older without cognitive or mental complications.

Patients with both CYP2C19 loss-of-function allele and peripheral endothelial dysfunction are significantly correlated with adverse cardiovascular events following coronary stent implantation.

BACKGROUND: There is some controversy regarding the effect of CYP2C19 polymorphism on clinical outcome in patients receiving dual antiplatelet therapy (DAPT). Peripheral endothelial dysfunction has recently been reported to predict adverse cardiovascular events. We hypothesized that CYP2C19 loss-of-function (LOF) allele carriers with peripheral endothelial dysfunction had worse prognosis. The aim of this study was to evaluate an additive effect of peripheral endothelial dysfunction on clinical outcome following percutaneous coronary intervention (PCI) in patients with a CYP2C19 variant. METHODS: We enrolled 434 patients on DAPT following PCI. CYP2C19 genotype was examined, and we divided patients into two groups: carriers, who had at least one CYP2C19 LOF allele, and non-carriers. Peripheral endothelial dysfunction was examined using reactive hyperemia-peripheral arterial tonometry index (RHI), and we divided patients into low and high RHI. Thus, subjects were divided into four groups, and clinical events were followed up. RESULTS: A total of 55 patients had a cardiovascular event. Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular events in carriers with low RHI (log-rank test: p=0.007). Multivariate Cox proportional hazards analysis identified both CYP2C19 LOF allele possession (hazard ratio (HR): 1.94; 95% confidence interval (CI): 1.1-3.69; p=0.045) and low RHI (HR: 2.15; 95% CI: 1.22-3.78; p=0.008) as independent and significant predictors of future cardiovascular events. CONCLUSIONS: CYP2C19 LOF allele carriers with peripheral endothelial dysfunction were significantly correlated with cardiovascular events. The additional evaluation of peripheral endothelial function along with CYP2C19 polymorphism might improve risk stratification after coronary stent implantation.

Higher risk of sulfonylurea-associated hypoglycemic symptoms in women with type 2 diabetes mellitus.

BACKGROUND: Although some evidence suggests that women may be at greater risk for hypoglycemia, no conclusion has been reached, and female sex has not been taken into account in antidiabetic drug-induced hypoglycemia. This study aimed to determine whether females are at a higher risk of sulfonylurea (SU)-associated hypoglycemia in daily clinical practice. METHODS: The incidence of adverse reactions of SU was investigated in 2119 Japanese patients who participated in the Drug Event Monitoring project of the Japan Pharmaceutical Association, which was conducted in Kumamoto prefecture. A multiple logistic regression analysis was used to determine the association between the incidence of hypoglycemic symptoms and female sex, with adjusted odds ratios (ORs) and 95 % confidence intervals (95 % CIs). RESULTS: Female sex was found to be significantly associated with hypoglycemic symptoms (female vs. male; OR 2.04; 95 % CI 1.22-3.41; p = 0.007). The concomitant use of other antihyperglycemic agents (≥2 vs. 0 concomitant drug; OR 2.80; 95 % CI 1.17-6.67; p = 0.021), a shorter duration of diabetes medication (<3 vs. ≥24 months; OR 4.14; 95 % CI 1.06-16.14; p = 0.041) and a longer follow-up period (OR 1.02; 95 % CI 1.00-1.04; p = 0.041) were identified as risk factors for hypoglycemia that were specific to females. CONCLUSION: To the best of our knowledge, this is the first report to focus on female sex as a potential risk factor for SU-associated hypoglycemia. Our results support the importance of individualized therapy, which may be effective not only for reducing the risk of hypoglycemia in females but also the risk of its consequences, such as cardiovascular disease, dementia and increased mortality.

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.

Impact of esomeprazole on platelet reactivity and clinical outcome according to CYP2C19 genotype in coronary heart disease patients during dual antiplatelet therapy.

OBJECTIVES: The aim of this study was to investigate the effect of CYP2C19 polymorphism and co-therapy with esomeprazole on the antiplatelet efficacy of clopidogrel. BACKGROUND: The antiplatelet efficacy of clopidogrel depends on CYP2C19 polymorphism or the co-administration of some kind of proton pump inhibitor (PPI). METHODS: CYP2C19 genotype and the residual platelet reactivity (RPR) were measured in 361 coronary heart disease patients (male, mean age 69yrs), and the risk of cardiovascular events over a 3-month follow-up was assessed to evaluate the impact of co-administration of esomeprazole during dual antiplatelet therapy with aspirin and clopidogrel. RESULTS: The values of RPR did not differ between esomeprazole and non-esomeprazole groups (4389 ± 1112 versus 4079 ± 1355 AU·min, P=0.103). RPR value was higher in intermediate metabolizers (IM) than in extensive metabolizers (EM) (4089 ± 1252 versus 3697 ± 1215 AU·min P=0.012) and, similarly, higher in poor metabolizers (PM) than in IM (4884 ± 1027 versus 4089 ± 1252 AU·min, P<0.001). There were no differences in RPR between esomeprazole and non-esomeprazole groups according to CYP2C19 genotype (EM, 3954 ± 1192 versus 3645 ± 1220 AU·min, P=0.361; IM, 4401 ± 1063 versus 4051 ± 1271 AU·min, P=0.293; PM, 4917 ± 669 versus 4876 ± 1099 AU·min, P=0.907, respectively). There was also no difference in clinical outcomes between esomeprazole and non-esomeprazole groups in the three-month follow-up (0% versus 0.92%, P=0.487). CONCLUSIONS: These results suggest that concomitant use of esomeprazole with clopidogrel is not associated with reduced antiplatelet efficacy of clopidogrel or increased risk of cardiovascular events, irrespective of CYP2C19 genotype.