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.

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.

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.

[Female sex as a risk factor for adverse drug reactions].

Females have nearly a two-fold greater risk of developing adverse drug reactions(ADRs) than males and they are also more likely to be hospitalized due to ADR. For all drug classes, significant differences exist between the sexes, including class-specific risks and the incidence and/or severity of ADR. We herein present our results regarding the surveillance of ADR in the general population and a questionnaire-based study carried out by the Japan Pharmaceutical Association Drug Event Monitoring Project in Kumamoto Prefecture. Our findings indicate that females are prone to ADR and that high-risk agents for this population should be identified and these subjects closely monitored based on the patient characteristics.

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.

Younger females are at greater risk of vasodilation-related adverse symptoms caused by dihydropyridine calcium channel blockers: results of a study of 11,918 Japanese patients.

BACKGROUND AND OBJECTIVE: Adequate control of blood pressure in younger females is of crucial importance, because they are at higher risk of hypertensive target organ damage compared with males of similar age. In addition, female sex is a risk factor for adverse effects of antihypertensive drugs, especially dihydropyridines. This study set out to assess the incidence of adverse reactions during dihydropyridine use in a real-life clinical setting, focusing on the influence of female sex and age. METHODS: The incidence of adverse reactions to dihydropyridine calcium channel blockers were investigated in 11,918 Japanese patients who participated in the Drug Event Monitoring project of the Japan Pharmaceutical Association conducted in Kumamoto prefecture. A multiple logistic regression analysis was used to determine the association between the incidence of adverse symptoms and female sex, with adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Vasodilation-related adverse symptoms occurred significantly more often in females than in males (OR 1.87, 95% CI 1.28-2.71, p=0.001). Furthermore, among females only, the younger age group (<50 years) complained of vasodilation-related symptoms more frequently (OR 2.39, 95% CI 1.02-5.59, p=0.045) and the older age group (≥80 years) complained of vasodilation-related symptoms less frequently (OR 0.56, 95% CI 0.33-0.95, p=0.030) than the middle age group (50-79 years). CONCLUSION: To the best of our knowledge, this is the first report showing that younger females are at high risk for vasodilation-related adverse symptoms during dihydropyridine use in a real-life clinical setting. These results should be verified in clinical studies using larger samples of young patients and more parameters.

Absence of gargling affects topical adverse symptoms caused by inhaled corticosteroids in females.

OBJECTIVE: Topical adverse events caused by inhaled corticosteroids (ICS) are suspected to be more common in females. Although gargling or mouth washing after inhalation is recommended as the gold standard for preventing adverse events due to ICS, the preventive effects of this method have not been confirmed in real-world studies. This study aimed to examine the association between gargling or mouth washing and the incidence of topical adverse symptoms in males and females in daily practice. METHODS: We analyzed a subpopulation of participants in the Drug Event Monitoring (DEM) project of the Japan Pharmaceutical Association. An anonymous survey was performed in February 2010, to assess the self-perception of topical adverse symptoms during ICS use by conducting interviews of pharmacists using structured questionnaires. RESULTS: A total of 412 males and 480 females were included. The patients used a dry-powder inhaler (DPI) (71.2%), pressurized meter-dose inhaler (pMDI) with (7.5%) or without (16.6%) a spacer or inhalation solution (4.7%) as the delivery device. Topical adverse symptoms occurring after previous prescriptions were reported by 41 (4.6%) subjects. The common symptoms were hoarseness, stomatitis and dry mouth (1.3%, 1.1% and 1.1%, respectively). In the multiple regression model, the presence of symptoms was found to be significantly associated with the absence of gargling or mouth washing after inhalation [adjusted odds ratio (OR): 3.75, 95% confidence interval (95%CI): 1.33-10.59, p = 0.012]. When stratified by gender, the absence of gargling or mouth washing was identified to be a risk factor in females only (OR: 4.32, 95%CI: 1.11-16.87, p = 0.035) and not in males (OR: 3.26, 95%CI: 0.65-16.33, p = 0.151). Furthermore, the association between the absence of gargling or mouth washing and the incidence of topical adverse symptoms was significant in the patients using DPI (OR: 4.85, 95%CI: 1.66-14.14, p = 0.004), but not in those using the other devices. CONCLUSIONS: In this study, the absence of gargling or mouth washing after ICS use was associated with topical adverse symptoms, especially in females. To achieve good adherence to treatment and improve the quality of life, female patients with asthma should strictly practice the gargling or mouth washing method.

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.

Sex differences in the effect of cytochrome P450 2C19 polymorphisms on the risk of diabetic retinopathy: a retrospective longitudinal study in Japanese patients with type 2 diabetes.

Cytochrome P450 2C19 (CYP2C19) is expressed in human endothelial cells and catalyzes the biosynthesis of vasoprotective epoxyeicosatrienoic acids and 19-hydroxyeicosatetraenoic acid from arachidonic acid. This study investigated the association between CYP2C19 polymorphisms and an increased risk of diabetic retinopathy (DR). A clinic-based retrospective longitudinal analysis was carried out that included 383 Japanese patients with type 2 diabetes mellitus. Compared with male extensive metabolizers, female intermediate metabolizers [adjusted odds ratio (OR), 2.43; 95% confidence interval (95% CI), 1.17-5.06] and poor metabolizers (OR, 7.49; 95% CI, 2.64-21.26) were at a significantly higher risk of developing DR. Furthermore, the CYP2C19 poor metabolizer genotype was found to be an independent risk factor for DR only in women when patients were stratified by sex (OR, 4.18; 95% CI, 1.42-12.26). This is the first report showing the interactive effect of sex and CYP2C19 polymorphisms on microvascular disease in humans, although further investigations are needed to verify these findings.

Association between aldehyde dehydrogenase 2 polymorphisms and the incidence of diabetic retinopathy among Japanese subjects with type 2 diabetes mellitus.

BACKGROUND: Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies reactive aldehydes in the micro- and macrovasculature. These substrates, including methylglyoxal and 4-hydroxynonenal formed from glucose and lipids, cause protein carbonylation and mitochondrial dysfunction, forming advanced glycation end products (AGEs). The present study aimed to confirm the association between the inactive ALDH2*2 allele and diabetic retinopathy (DR). METHODS: A retrospective longitudinal analysis was conducted, among 234 Japanese patients with type 2 diabetes mellitus (DM) (156 males and 78 females) who had no DR signs at baseline and were treated for more than half a year. The ALDH2*1/*2 alleles were determined using a real-time TaqMan allelic discrimination assay. Multivariate-adjusted hazard ratios (HRs) and 95% confidential intervals (CIs) for the cumulative incidence of the development of DR were examined using a Cox proportional hazard model, taking drinking habits and the serum γ-glutamyltransferase (GGT) level into consideration. RESULTS: The frequency of the ALDH2*2 allele was 22.3%. Fifty-two subjects cumulatively developed DR during the follow-up period of 5.5 ± 2.5 years. The ALDH2*2 allele carriers had a significantly higher incidence of DR than the non-carriers (HR: 1.92; P = 0.02). The incidence of DR was significantly higher in the drinkers with the ALDH2*2 allele than in those with the ALDH2*1/*1 genotype (HR: 2.61; P = 0.03), while the incidence of DR in the non-drinkers did not differ significantly between the ALDH2 genotype groups (P > 0.05). The incidence of DR was significantly higher in the ALDH2*2 allele carriers with a high GGT level than in the non-carriers with a high or low GGT level (HR: 2.45; P = 0.03; and HR: 2.63; P = 0.03, respectively). CONCLUSIONS: To the best of our knowledge, this is the first report of a significant association between the ALDH2*2 allele and the incidence of DR. These findings provide additional evidence that ALDH2 protects both microvasculature and macrovasculature against reactive aldehydes generated under conditions of sustained oxidative stress, although further investigations in larger cohorts are needed to verify the results.

Risk factors for adverse symptoms during dipeptidyl peptidase-IV inhibitor therapy: a questionnaire-based study carried out by the Japan Pharmaceutical Association Drug Event Monitoring project in Kumamoto Prefecture.

BACKGROUND: Meta-analyses of randomized clinical trials have reported that dipeptidyl peptidase IV (DPP-4) inhibitors are well tolerated and that the incidence of hypoglycemia with the use of DPP-4 inhibitors is similar to that observed with placebos. However, in general, provider-oriented methods using medical record reviews offer lower rates of non-serious, symptomatic adverse drug reactions (ADRs) than patient-oriented methods. Moreover, severe hypoglycemia occurred in three clinical trials using sitagliptin, but in two of these trials this phenomenon has been previously described only in the drug application data in the US. OBJECTIVE: The aim of this study was to assess the profile of patient-reported symptomatic ADRs under DPP-4 inhibitor therapy and to detect risk factors for hypoglycemic and non-hypoglycemic adverse symptoms in daily clinical practice. METHODS: We analyzed a subpopulation of participants in the Drug Event Monitoring (DEM) project of the Japan Pharmaceutical Association. An anonymous survey was conducted in February 2012 to assess the self-perception of adverse symptoms during a median 28 (4-88) days after the last prescription of DPP-4 inhibitors by means of interviews of pharmacists using structured questionnaires. RESULTS: A total of 864 males and 686 females were included. The prescribed DPP-4 inhibitors included sitagliptin (75.4 %), alogliptin (15.5 %), vildagliptin (8.8 %) and linagliptin (0.3 %). Mild hypoglycemic symptoms were reported by 34 individuals (2.2 %) receiving monotherapy of sitagliptin (10/402) or alogliptin (3/65), or combination therapy of sitagliptin (15/767) or alogliptin (6/176) with other hypoglycemic agents. In the multiple regression model, hypoglycemic symptoms were found to be significantly associated with liver disease, female sex and alcohol consumption more than three times per week. Non-hypoglycemic symptoms were reported by 57 individuals (3.7 %), the most common symptoms of which were gastrointestinal symptoms (2.1 %). Combination therapy was only found to be associated with nonhypoglycemic symptoms. CONCLUSIONS: The present study suggested that hypoglycemic symptoms under therapy with sitagliptin or alogliptin may be associated with liver disease, female sex and alcohol consumption, all of which are potentially capable of leading to poor gluconeogenesis because they decrease the counter-regulatory hormonal responses to hypoglycemia.