Yixuan Song

HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis.

INTRODUCTION Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Recently, strong associations of HLA-B*1502 and HLA-B*5801 with carbamazepine- and allopurinol-induced severe cutaneous adverse reactions were found in Han Chinese patients, respectively, but ethnic differences in the associations have been reported. The objective of this study is to clarify the involvement of HLA-B*1502 and HLA-B*5801 in Japanese SJS/TEN patients. METHODS HLA-B genotyping was performed on 58 Japanese SJS/TEN patients between July 2006 and April 2008 from multicenters in Japan. RESULTS There were no HLA-B*1502 carriers among 58 SJS/TEN patients. This patient group included seven carbamazepine-related and 11 aromatic anti-epileptic agent-related SJS/TEN patients. In addition, there were five HLA-B*5801 carriers, which included four allopurinol-related SJS/TEN patients. CONCLUSION While HLA-B*1502 is unlikely to be associated with carbamazepine-related or aromatic anti-epileptic agent-related SJS/TEN, HLA-B*5801 was significantly associated with allopurinol-related SJS/TEN in Japanese.

HLA-B*1511 is a risk factor for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients

Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life‐threatening severe cutaneous adverse reactions. Recently, strong associations of HLA‐B*1502 with carbamazepine‐induced SJS/TEN have been found in Han Chinese patients. These associations have been confirmed in several Asian populations, excluding Japanese. SJS patients carrying HLA‐B*1508, HLA‐B*1511, or HLA‐B*1521, which are members of the HLA‐B75 type along with HLA‐B*1502, were detected in studies in India and Thailand. In the current study, we genotyped the HLA‐B locus from 14 Japanese typical and atypical SJS/TEN patients in whom carbamazepine was considered to be involved in the onset of adverse reactions. Although there were no HLA‐B*1502 carriers, four patients had HLA‐B*1511. Our data suggest that HLA‐B*1511, a member of HLA‐B75, is a risk factor for carbamazepine‐induced SJS/TEN in Japanese.

Human leukocyte antigen genotypes in carbamazepine‐induced severe cutaneous adverse drug response in Japanese patients

Dear Editor, Carbamazepine is a widely used antiepileptic drug, which occasionally induces adverse drug responses, including hepatoand nephrotoxicities, movement and behavioral disorders, and skin lesions. Various kinds of cutaneous adverse drug response (cADR) are relatively frequent for this drug, and on rare occasions it induces drug-induced hypersensitivity syndrome (DIHS), Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which are the severer manifestations. It would be advantageous if genotyping prior to prescription could predict the occurrence of these severe cADR. Recently, carbamazepine-induced SJS/TEN has been shown to closely associate with a human leukocyte antigen (HLA) genotype B*1502 in a HanChinese population. Following this study, Lonjou et al. reported preliminary results from a European study (RegiSCAR) of twelve carbamazepine-induced SJS/TEN cases (nine French and three German). Among these, only four possessed the HLA-B*1502 allele and all of them had Asian ancestry. This indicates that this HLA genotype may not be a universal marker for cADR and that ethnicity may matter. To this end, we studied HLA genotypes in Japanese patients who experienced carbamazepine-induced severe cADR. All patients were recruited from Yokohama City University Hospital and Shizuoka National Epilepsy Center between April 2005 and March 2007. The study was approved by the local internal review boards. The patients with severe cADR incited by carbamazepine who needed hospitalization were eligible. We did not limit to SJS/TEN but broadly collected various types of serious carbamazepineinduced cADR. Altogether, 22 cases were included in the study. The original diseases for the prescription of carbamazepine were epilepsy (n = 11), post-therapeutic neuralgia (n = 4) and others (n = 7, including depression, obsessive compulsive disorder and stroke). Types of cADR were erythematous maculopapular and multiform (n = 6), erythroderma (n = 3), DIHS (n = 4), SJS (n = 2) and other drug eruptions (n = 7). High-resolution HLA typing was performed by using the polymerase chain reaction sequencespecific primer (PCR-SSP) method (MitsubishiChemical BCL Laboratory, Tokyo, Japan). Table 1 shows the HLA-B alleles and their frequencies in the patients, together with those reported for a general Japanese population. None of the 22 cases including the two cases of SJS possessed the B*1502 genotype. When each allele frequency was compared on a 2 × 2 contingency table using Fisher’s exact test, only the B*3902 allele gave a weak sign of association (P = 0.04), which did not remain statistically significant after adjusting with multiple testing. Thus, we concluded that the HLA-B genotypes of the patients do not to largely deviate from that in the general Japanese population. Table 2 shows the HLA-A alleles and their frequencies in the patients together with those reported for a general Japanese population. When each allele frequency was compared on a 2 × 2 contingency table using Fisher’s exact test, the A*3101 allele gave a statistically significant association (P = 0.0004), which remained after adjusting with multiple testing. The odds ratio was calculated to be 4.33 (95% confidence interval, 2.07–9.06). However, we should interpret this result cautiously because the sample size was small and there is a possibility of spurious association. After B*1502 was postulated as a genetic marker, many studies have been attempted to

Interaction of angiotensin I-converting enzyme insertion-deletion polymorphism and daily salt intake influences hypertension in Japanese men.

The contribution of angiotensin I–converting enzyme insertion-deletion polymorphism (ACE I/D) to salt-sensitivity hypertension has been extensively studied by means of salt-loading tests, but whether or not the interaction with daily salt intake affects blood pressure still remains to be clarified. We therefore conducted a cross-sectional study of 284 Japanese male workers (age range, 20–64 years) to examine the effect of ACE I/D genotype and daily salt intake on hypertension. Blood pressure was measured and the ACE I/D was identified by polymerase chain reaction (PCR). Daily salt intake was calculated from a food frequency questionnaire (FFQ). In multivariate analyses, we explored the interaction of ACE I/D and salt intake by means of logistic regression analysis and multiple linear regression analysis. ACE I/D per se was not associated with blood pressure levels or hypertension. ACE I/D interacted with daily salt intake and correlated with hypertension (p for interaction=0.047). In the ID+II genotype, hypertension was increased by high salt intake (p=0.005), while in the DD genotype it was not (p=0.257). The interaction was more prominent in the overweight group (p=0.039) than in non-overweight group. In the overweight group, high salt intake induced a 10.5 mmHg higher diastolic blood pressure in the ID+II genotype than in the DD genotype (p=0.042). Our results suggest that ACE I/D and daily salt intake constitute a gene-environment interaction, which may be further modulated by overweight.

Socioeconomic Status is Significantly Associated with Dietary Salt Intakes and Blood Pressure in Japanese Workers (J-HOPE Study)

The association of socioeconomic status (SES) with nutrients intakes attracts public attention worldwide. In the current study, we examined the associations of SES with dietary salt intake and health outcomes in general Japanese workers (2,266) who participated in this Japanese occupational cohort. SES was assessed by a self-administered questionnaire. Dietary intakes were assessed with a validated, brief, self-administered diet history questionnaire (BDHQ). Multiple linear regression and stratified analysis were used to evaluate the associations of salt intake with the confounding factors. Education levels and household incomes were significantly associated with salt intake, as well as blood pressures (P < 0.05). After adjusting for age, sex and total energy intake, both years of education and household income significantly affect the salt intake (for education, β = −0.031, P = 0.040; for household income, β = −0.046, P = 0.003). SES factors also affect the risk of hypertension, those subjects with higher levels of education or income had lower risk to become hypertensive (ORs for education was 0.904, P < 0.001; ORs for income was 0.956, P = 0.032). Our results show that SES is an independent determinant of salt intake and blood pressure, in order to lower the risk of hypertension, the efforts to narrow the social status gaps should be considered by the health policy-makers.

Altered DNA methylation status of human brain derived neurotrophis factor gene could be useful as biomarker of depression

Brain‐derived neurotrophic factor (BDNF) is involved in the survival, development, and synaptic plasticity of neurons. BDNF is believed to be associated with the pathophysiology of psychiatric disorders. Several studies have suggested the relevance of DNA methylation in its promoter region with depression. Here, we report different methylation statuses in groups with different depressive scores or undergoing different levels of job‐stress. DNA samples were extracted from the saliva of 774 Japanese workers, and the methylation status was determined using the Illumina HumanMethylation 450 K Microarray. Depressive symptoms were measured using the Kesslers K6 questionnaire. Job‐stress scales were assessed via a self‐administered questionnaire. Independent DNA pools were formed based on K6 and job‐strain scores, and the methylation levels were compared among these pools. The average DNA methylation rate was significantly decreased in the highest K6 score group compared to the lowest group (methylated signals, 14.2% vs. 16.5%, P = 2 · 16 × 10−198). This difference remained for the CpG island in the promoter region (10.4% vs. 5.8%, P = 3 · 67 × 10−133). Regarding the job‐strain score, there was a slight increase in the methylation level of the whole gene in the group with the highest score compared to that with the lowest score; however, these groups showed no difference in the promoter region. Our results revealed significant changes in the DNA methylation status of the complete human BDNF gene in persons with depression compared to normal individuals, especially in the promoter region of exon 1. This indicates that DNA methylation in this gene is a promising biomarker for diagnosing depression.

The combined impact of 12 common variants on hypertension in Japanese men, considering GWAS results

Genome-wide association studies have identified several polymorphisms that appear to be on hypertension-susceptible regions. We performed the current replication study in order to evaluate the association of these loci with hypertension in healthy Japanese males and then examined the combined effect of 12 independent variants. Overall, 735 Japanese men from two independent cohorts were recruited. Association with hypertension was assessed in 16 polymorphisms on 12 genes and 12 were chosen to evaluate the combined impact. Polymorphisms on the COMT, ATP2B1, CYP11A1 and the CSK genes were confirmed to be associated with hypertension and blood pressure (BP). Current findings also replicated previous results for the CYP11B2 and PTGIS genes. Although there were no significant associations found for other variants, our results suggested there was a combined impact for 12 loci. Individuals carrying more risk alleles had a higher risk of hypertension (P for the slope=0.002). Blood pressures also increased in conjunction with an increasing risk allele score (P for trend=7.84 × 10−6 and 1.85 × 10−5 for SBP and DBP, respectively). Our results confirmed the associations between hypertension or blood pressure and four gene variants. We also found a significant combined effect of the 12 gene loci.

Folate intake and depressive symptoms in Japanese workers considering SES and job stress factors: J-HOPE study

BackgroundRecently socioeconomic status (SES) and job stress index received more attention to affect mental health. Folate intake has been implicated to have negative association with depression. However, few studies were published for the evidence association together with the consideration of SES and job stress factors. The current study is a part of the Japanese study of Health, Occupation and Psychosocial factors related Equity (J-HOPE study) that focused on the association of social stratification and health and our objective was to clarify the association between folate intake and depressive symptoms in Japanese general workers.MethodsSubjects were 2266 workers in a Japanese nationwide company. SES and job stress factors were assessed by self-administered questionnaire. Folate intake was estimated by a validated, brief, self-administered diet history questionnaire. Depressive symptoms were measured by Kessler’s K6 questionnaire. “Individuals with depressive symptoms” was defined as K6≧9 (in K6 score of 0–24 scoring system). Multiple logistic regression and linear regression model were used to evaluate the association between folate and depressive symptoms.ResultsSeveral SES factors (proportion of management positions, years of continuous employment, and annual household income) and folate intake were found to be significantly lower in the subjects with depressive symptom (SES factors: p < 0.001; folate intake: P = 0.001). There was an inverse, independent linear association between K6 score and folate intake after adjusting for age, sex, job stress scores (job strains, worksite supports), and SES factors (p = 0.010). The impact of folate intake on the prevalence of depressive symptom by a multiple logistic model was (ORs[95% CI]: 0.813 [0.664-0.994]; P =0.044).ConclusionsOur cross-sectional study suggested an inverse, independent relation of energy-adjusted folate intake with depression score and prevalence of depressive symptoms in Japanese workers, together with the consideration of SES and job stress factors.

Association of the catechol-O-methyl transferase gene Val158Met polymorphism with blood pressure and prevalence of hypertension : interaction with dietary energy intake

BACKGROUND Previous studies of a functional variant of the catechol-O-methyl transferase (COMT) gene, Val158Met, have provided inconsistent results with regard to blood pressure or hypertension. We examined the effect of this variant, the considering environmental factors of daily salt and energy intakes. METHODS A total of 735 Japanese men (mean age, 47 years) were recruited from two separate occupational cohorts from Kanagawa and Kyoto prefectures. Participants were genotyped for the presence of COMT Val158Met (rs4680, G/A). Daily salt and energy intakes were evaluated by the food frequency questionnaire (FFQ). RESULTS Met/Met carriers had higher adjusted systolic blood pressure (SBP) (+4.79 mm Hg, P < 0.001) and diastolic blood pressure (DBP) (+2.33 mm Hg, P = 0.001) than Met/Val or Val/Val carriers. There was a significant association between being a Met/Met carrier and having a higher prevalence of hypertension (odds ratio = 2.448, 95% confidence interval = 1.426-4.205, P = 0.001). When salt and energy intakes were dichotomized, the effect of Val158Met on hypertension was observed only in the high-energy intake group, and was equivalent between low- and high-salt groups. CONCLUSION The Met allele of COMT Val158Met is associated with higher blood pressure and higher prevalence of hypertension in Japanese men, and energy intake may interact with this effect.

Association between a polymorphism of aminolevulinate dehydrogenase (ALAD) gene and blood lead levels in Japanese subjects.

This cross-sectional study investigated the relationship between the aminolevulinate dehydrogenase (ALAD) genotype and blood lead levels among 101 Japanese workers. Blood lead concentration measurement, biomarkers, and genotyping were performed. The minor allele frequency (MAF) for ALAD (ALAD2) was 0.08. Although the blood lead level in the subjects with heterozygous GC genotype was significantly higher than those with homozygous GG genotype, there were no significant differences for hemoglobin, hematocrit, serum and urinary ALA levels among genotypes. ALAD2 genotype was significantly associated with the blood lead concentration, even in the environmental lead exposed subjects. Further confirmation with a large sample size is needed.