Kiriko Wada

Impaired glucose tolerance is a risk factor for stroke in a Japanese sample- : the Funagata study

Impaired glucose tolerance (IGT) is a known risk factor for cardiovascular disease, which includes stroke as well as coronary heart disease (CHD). We investigated whether IGT is a risk factor for stroke. The incidence of stroke and CHD in a cohort population (n = 2938) consisting of participants of the 1990-1997 Funagata study was assessed through interviews with the participants and their family members and reviews of death certificates and residence transfer documents through 2002. Glucose tolerance at the baseline was classified according to the criteria of the 1998 World Health Organization (normal glucose tolerance, n = 2189; IGT, n = 320; and diabetes, n = 286). The cumulative incidences among the groups were compared using the Kaplan-Meier product-limit method, and the risks of these conditions were evaluated by person-year and Cox proportional hazard methods. During the 147-month (mean, 116.5 months) follow-up, 158 (normal glucose tolerance, IGT, and diabetes: 94, 35, and 29, respectively) participants experienced a stroke and 94 (54, 16, and 24, respectively) experienced CHD. By the person-year method, IGT and diabetes were shown to be significant risk factors for stroke and CHD (odds ratio, 1.87 [95% confidence interval, 1.73-2.03] and 3.57 [3.21-3.98] for stroke; 1.53 [1.31-1.78] and 3.47 [2.91-4.14] for CHD, respectively). Cox proportional hazard analysis showed that IGT was a risk factor for stroke (age-, sex-, and hypertension-adjusted hazard ratio: 1.51 [95% confidence interval, 1.02-2.24], P = .039) but not for CHD (1.21 [0.69-2.313], .509). Impaired glucose tolerance is a risk factor for future stroke in a Japanese population.

Association of the clusterin gene polymorphisms with type 2 diabetes mellitus.

The association of the clusterin (CLU) gene polymorphism (single nucleotide polymorphisms [SNPs] 1-4: rs1532278, rs1532277, rs2279590, and rs2279591, respectively) with type 2 diabetes mellitus was examined using a population of the Funagata study (n [male-female] = 1631 [741:884]; age, 62.0 ± 12.1 years), a Japanese community-based study. Single nucleotide polymorphisms 1 to 3 were significantly associated with hemoglobin A(1c) levels (P = .0154, .0021, and .0006, respectively) and diabetes (.0310, .0170, and .0021, respectively). A case-control association study of SNP 3 with diabetes by multiple logistic regression analysis showed a significant association of genotype AA (the at-risk genotype) with an odds ratio (OR) of 2.33 (P = .0039) independently of age and sex. The association was marginally validated by a study with another Japanese community-based sample, the Takahata Study (n [male-female] = 2.948 [1333:1615]; age, 63.0 ± 10.2 years) (OR, 1.59; P = .0595; χ(2)P = .0264). When the 2 samples were combined, the association became more significant (OR, 1.75; P = .0025). In subjects with the non-at-risk genotypes, the insulin resistance index--homeostasis model assessment of insulin resistance (HOMA-R)--increased significantly (P < .0001) and the insulin secretion index--HOMA-β--appeared to decrease (P = .1803 and .0097, respectively, for the genotypes AG and GG) as the glucose tolerance progressed toward diabetes (normal glucose tolerance to glucose intolerance to diabetes). However, in subjects with the at-risk genotype, HOMA-R and HOMA-β showed a significant increase already in the subjects with normal glucose tolerance (P = .0239 and .0305, respectively); and as the glucose tolerance progressed toward diabetes, HOMA-R stayed approximately the same, whereas HOMA-β decreased significantly (P = .0332). The CLU gene was associated with diabetes, probably through an increase in insulin resistance primarily and through an impairment of insulin secretion secondarily.

Thyroid Dysfunction in Patients Treated with Tyrosine Kinase Inhibitors, Sunitinib, Sorafenib and Axitinib, for Metastatic Renal Cell Carcinoma

OBJECTIVE Targeted drugs are generally associated with a lower toxicity than conventional systemic cytotoxic drugs and, thus, are administered for long periods. As a result, unusual adverse effects, including thyroid dysfunction, have become important clinical issues. METHODS We retrospectively collected the data and compared the incidence and the time of onset of thyroid dysfunction in 33 patients (M/F: 26/7, age: 34-77) with metastatic renal cell carcinoma treated with the small-molecule tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib and axitinib in Yamagata University Hospital, Japan, from 2005 to 2010. RESULTS The incidence of thyroid dysfunction tended to be higher in patients treated with axitinib (6 of 6: 100%) than in those treated with sunitinib (9 of 15: 60%) or sorafenib (6 of 12: 50%) (P= 0.1113). The median thyroid dysfunction-free survival evaluated using the Kaplan-Meier product-limit method with the log-rank test was significantly shorter in patients treated with axitinib than in those treated with sunitinib/sorafenib (3 vs. 16 weeks, P=0.0198). A multivariate Cox regression model for thyroid dysfunction-free survival with several probable confounding factors as co-variables showed that patients treated with axitinib were more likely to have thyroid dysfunction than the others (hazard ratio: 4.53, 95% confidence interval: 1.40-14.63, P=0.0116). CONCLUSIONS Patients treated with the tyrosine kinase inhibitors developed thyroid dysfunction frequently. Furthermore, those treated with axitinib developed thyroid dysfunction significantly more and at a faster rate than the others. Therefore, when the tyrosine kinase inhibitors, especially axitinib, are used, close monitoring of thyroid function is recommended, at least for the initial 1-2 months, to avoid clinical symptoms derived from thyroid dysfunction.

Hemoglobin A1c in predicting progression to diabetes

The predictive value of hemoglobin A1c (HbA1c) in comparison to fasting plasma glucose (FPG) is evaluated for 5-year incident diabetes (DM), as HbA1c may be more practical than FPG in the screening for DM in the future. Of 1189 non-DM subjects aged 35-89 years old from the Funagata Study, 57 subjects (4.8%) had developed DM on the WHO criteria at 5-year follow-up. The odds ratio (95% confidence interval: CI) for a one standard deviation increase in FPG/HbA1c was 3.40 (2.44-4.74)/3.49 (2.42-5.02). The area under the receiver operating characteristic curve for FPG/HbA1c was 0.786 (95% CI: 0.719-0.853)/0.785 (0.714-0.855). The HbA1c corresponding to FPG 5.56 mmol/l was HbA1c 5.3%. There was no statistical difference in sensitivity between FPG 5.56 mmol/l and HbA1c 5.3% (61.4% vs. 56.1%), while specificity was higher in HbA1c 5.3% than FPG 5.56 mmol/l (87.8% vs. 82.5%, p-value<0.001). The fraction of incident case from those with baseline IGT was similar between the groups, however the fraction of people above the cut-off was significantly lower in HbA1c 5.3% than FPG 5.56 mmol/l (14.3% vs. 19.6%, p-value<0.001). HbA1c is similar to FPG to evaluate DM risk, and HbA1c could be practical and efficient to select subjects for intervention.

Salt consumption-dependent association of the GNB3 gene polymorphism with type 2 DM

The associations of the C825T polymorphism (rs5443) of the G-protein beta3 subunit (GNB3) gene and eight adjacent single nucleotide polymorphisms (SNPs) with diabetes were examined using a Japanese population (n (M/W): 2956 (1335/1621); age: 63.0+/-10.2 years). Fasting plasma glucose (FPG) levels were significantly associated with the C825T polymorphism and two flanking SNPs (rs2301339 and rs5446) (p=0.002, 0.001, and 0.008, respectively). A case-control association study of the C825T polymorphism with diabetes using multiple logistic regression analysis showed a significant association of the genotypes TT+TC with an odds ratio of 0.62 (p=0.008) independent of age, gender, and BMI. The effects of salt consumption on the association were then examined (n=1635). The FPG levels were significantly associated with the C825T polymorphism only in subjects with low salt consumption (<12.44 g/day) (p=0.002). A case-control association study also showed a significant association with diabetes only in subjects with low salt consumption (p=0.006).

Association of the Ser326Cys polymorphism in the OGG1 gene with type 2 DM.

The association of the Ser326Cys polymorphism of the 8-oxoguanine glycosylase 1 (OGG1) gene with type 2 diabetes was examined using a Japanese population (n (M/W): 4585 (2085/2500); age: 62.6 +/- 10.9 years). HbA1c levels and frequency of diabetic subjects were significantly higher in subjects with genotypes with Cys allele than in those without (p = 0.032 and 0.037, respectively). Multiple logistic regression analysis showed that genotypes with Cys allele were significantly associated with diabetes (OR: 1.32, p = 0.0289). In subjects whose glucose tolerance was classified by FPG and 2-h PG (n = 1.634), the association was more substantial (genotypes with Cys allele vs. without, OR: 1.70, p = 0.0059; genotypes Cys/Cys vs. Ser/Ser, OR: 2.19, p = 0.0008). In subjects with genotype Ser/Ser, the insulin secretion index, HOMA-beta, increased in the subjects with glucose intolerance and decreased in the subjects with diabetes, while, in subjects with genotypes Ser/Cys + Cys/Cys, HOMA-beta decreased as the glucose tolerance progressed (p for trend = 0.010).

Expression of BAFF-R and TACI in reactive lymphoid tissues and B-cell lymphomas

Aims:  The receptor for B‐cell‐activating factor belonging to the tumour necrosis factor family (BAFF‐R) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) have been established as binding molecules to BAFF. The aim of this study was to determine the pathological diagnostic roles and clinical significance of these BAFF‐binding receptors in B‐cell neoplasms.

Higher plasma renin activity is a risk factor for total mortality in older Japanese individuals: the Takahata study

Plasma renin activity (PRA) is accepted as a marker for increased risk of cardiovascular diseases. However, the association between PRA and total mortality has not been fully explored in a general population. We here examined whether PRA is associated with increased total mortality in a general Japanese population. The participants of the Takahata study (3502 subjects; age, 62.5 ± 10.4 years), a population-based, longitudinal study of Japanese held from 2004 to 2006, were enrolled and followed up for up to 7 years. The incidence of death and causes of death were monitored annually to the end of 2010 (median follow-up, 2280 days). During the follow-up period, 143 subjects died. Kaplan-Meier analysis showed a significantly increased risk for total mortality in subjects with higher PRA (log-rank P < .001). Cox proportional hazard model analyses with adjustment for factors correlated with PRA (age, sex, weight, diastolic blood pressure, high-density lipoprotein cholesterol, uric acid, B-type natriuretic peptide, serum total protein, antihypertensive treatment, and diabetes) showed that higher PRA was associated with increased total mortality in linear regression models (per 1 increase in log 10 × PRA [nanograms per milliliter per hour]: hazard ratio, 2.12; 95% confidence interval, 1.47-3.06), between groups of patients stratified by quartiles of PRA (highest vs lowest quartile: 2.63, 1.57-4.41) and in subjects with high (≥ 2.0 ng/[mL h]) vs low (<2.0 ng/[mL h]) PRA (1.97, 1.37-2.83). Higher PRA was a significant and independent risk factor for increased total mortality in this Japanese population and may be a marker for subjects at an increased risk of total mortality.

A functional polymorphism of the TNF-α gene that is associated with type 2 DM

To examine the association of the tumor necrosis factor-alpha (TNF-alpha) gene region with type 2 diabetes (DM), 11 single-nucleotide polymorphisms (SNPs) of the region were analyzed. The initial study using a sample set (148 cases vs. 227 controls) showed a significant association of the SNP IVS1G+123A of the TNF-alpha gene with DM (p=0.0056). Multiple logistic regression analysis using an enlarged sample set (225 vs. 716) revealed the significant association of the SNP with DM independently of any clinical traits examined (OR: 1.49, p=0.014). The functional relevance of the SNP were examined by the electrophoretic mobility shift assays using nuclear extracts from the U937 and NIH3T3 cells and luciferase assays in these cells with Simian virus 40 promoter- and TNF-alpha promoter-reporter gene constructs. The functional analyses showed that YY1 transcription factor bound allele-specifically to the SNP region and, the IVS1+123A allele had an increase in luciferase expression compared with the G allele.

Association of the G-protein β3 subunit gene polymorphism with the incidence of cardiovascular disease independent of hypertension: the Funagata study

Association of the C825T G-protein β3 subunit (GNB3) gene polymorphism with cardiovascular disease (CVD) incidence was examined in a population-based longitudinal study of the Japanese individuals. The incidence of CVD (stroke and coronary heart disease (CHD)) was assessed in a cohort population (n=1524) consisting of participants of the 2001–2005 Funagata study through March 2008. Cumulative incidences according to genotype were compared with the Kaplan–Meier product-limit method. During the follow-up, 78 subjects experienced a CVD event (stroke: n=54; CHD: n=30; both consecutively: n=6). At the end of the follow-up (longest and median follow-up periods: 81 and 68 months, respectively), the cumulative incidence of CVD for the TT genotype was significantly higher than that of the C-carriers (0.077 vs 0.042, P=0.004). Blood pressures and the prevalence of hypertension were not different between the genotypes. Cox’s proportional hazard analysis showed that the TT genotype is a significant risk factor for CVD (hazard ratio (HR)=1.82 (95% confidence interval (CI) 1.14–2.89); P=0.012) and stroke (HR=1.76 (95% CI: 1.01–3.07); P=0.048) incidences after adjustment for age, sex, hypertension, hyperlipidemia, diabetes, alcohol drinking and smoking at baseline. The TT genotype of the C825T GNB3 gene polymorphism was found to be a significant risk factor for the incidence of CVD and stroke independent of hypertension and other established CVD risk factors in a Japanese population.