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Hisashi Fukuda,
Minako Imamura,
Yasushi Tanaka,
Minoru Iwata, Hiroshi Hirose,
Kohei Kaku,
Hiroshi Maegawa,
Hirotaka Watada,
Kazuyuki Tobe,
Atsunori Kashiwagi,
Ryuzo Kawamori,
Shiro Maeda
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ABSTRACT: By an association mapping for the candidate locus in chromosome 21q, rs3746876 within KCNJ15 was shown to be associated with type 2 diabetes in Japanese populations. However, the association of rs3746876 with type 2 diabetes has not been validated in an independent cohort. The aim of the present study was to ascertain the association of rs3746876 with type 2 diabetes in an independent larger Japanese sample. We genotyped 7885 Japanese participants (4967 individuals with type 2 diabetes and 2918 control individuals) for rs3746876 with polymerase-chain reaction-invader assay. The association of rs3746876 with type 2 diabetes was examined by using logistic regression analysis. Quantitative traits analyses for homeostasis model assessment (HOMA) of β-cell function, HOMA of insulin resistance, fasting plasma glucose, fasting immunoreactive insulin and body mass index (BMI) were performed in control individuals by using multiple-linear regression analysis. We observed a significant association of rs3746876-T with type 2 diabetes (P=0.0281, odds ratio (OR)=0.82, 95% confidence interval (CI, 0.68-0.98)), but the direction of effect was opposite to that in the original report. The association of rs3746876 with type 2 diabetes was more significant in obese patients (BMI25 kg m(-2), P=0.0025, OR=0.62, 95% CI, 0.45-0.84). We did not observe significant association of rs3746876 with any of the quantitative traits in the control individuals. We could not replicate the original finding for the association of rs3746876 with type 2 diabetes, although rs3746876 was significantly associated with obese type 2 diabetes in the present Japanese population.Journal of Human Genetics advance online publication, 18 April 2013; doi:10.1038/jhg.2013.28.
Journal of Human Genetics 04/2013; · 2.57 Impact Factor
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ABSTRACT: The number of home blood pressure (BP) measurements on one occasion has continued to be discussed. Therefore, we evaluated the variability of the first and second measurements on one occasion. The subjects except hypertensive patients (393 males, 212 females; mean age 38.7 y) were recruited from one company. Home blood pressure was measured with a semiautomatic device, and subjects were instructed to perform triplicate morning and evening measurements on 7 consecutive days. The standard deviation of systolic blood pressure (SBP) was significantly greater in the first measurement than in the second measurement, but there was no significant difference in standard deviation of diastolic blood pressure. As for the coefficient of variation (CV), CV of morning SBP alone was significantly greater in the first measurement (5.3% ± 0.1%) than in the second measurement (4.9% ± 0.1%). Therefore, factors related to CV of morning SBP in the first measurement were studied, which indicated that it was significantly greater in smokers (5.8% ± 0.1%) than in nonsmokers (5.2% ± 0.1%), and in women (5.6% ± 0.1%) than in men (5.2% ± 0.1%). In conclusion, CV of morning SBP was significantly greater in the first measurement than in the second measurement. The coefficient of variation of morning SBP in the first measurement might be influenced to some extent by the presence or absence of smoking habit and gender. Therefore, physicians should pay special attention to the above-mentioned fact in the future.
Clinical and Experimental Hypertension 05/2012; 34(4):237-42. · 1.07 Impact Factor
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ABSTRACT: AimsVascular endothelial growth factor (VEGF) is a primary mediator of retinal angiogenesis, and higher levels of intraocular
VEGF are observed in patients with active proliferative diabetic retinopathy. Meanwhile, whether serum VEGF level is associated
with diabetic retinopathy (DR) or not is controversial.
MethodsTo investigate the significance of serum VEGF levels in diabetic patients with DR, we measured serum VEGF levels in 138 type
2 diabetic patients hospitalized for treatment of a hyperglycemic state, all of whom were not complicated by VEGF-related
diseases, such as malignancy, cardiovascular disease or infectious disease.
ResultsSerum VEGF level was significantly increased in diabetic patients with DR as compared to those without DR. Moreover, multiple
regression analysis and stepwise regression analysis revealed that body mass index and presence or absence of DR were associated
with serum VEGF level; in particular, the presence of DR was strongly correlated with increased serum VEGF level.
ConclusionsIncreased serum VEGF level may be closely associated with the presence of DR in type 2 diabetic patients. Whether this conclusion
is true for general type 2 diabetic patients is a subject for future investigation because of several limitations of this
study, including sample selection bias.
KeywordsDiabetic complication–Diabetic retinopathy–Vascular endothelial growth factor (VEGF)–Type 2 diabetes
04/2012; 2(1):19-25.
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Minako Imamura,
Shiro Maeda,
Toshimasa Yamauchi,
Kazuo Hara,
Kazuki Yasuda,
Takashi Morizono,
Atsushi Takahashi,
Momoko Horikoshi,
Masahiro Nakamura,
Hayato Fujita, [......],
Kohei Kaku,
Chikako Ito,
Yasushi Tanaka,
Kazuyuki Tobe,
Atsunori Kashiwagi,
Ryuzo Kawamori,
Masato Kasuga,
Naoyuki Kamatani,
Yusuke Nakamura,
Takashi Kadowaki
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ABSTRACT: To identify a novel susceptibility locus for type 2 diabetes, we performed an imputation-based, genome-wide association study (GWAS) in a Japanese population using newly obtained imputed-genotype data for 2 229 890 single-nucleotide polymorphisms (SNPs) estimated from previously reported, directly genotyped GWAS data in the same samples (stage 1: 4470 type 2 diabetes versus 3071 controls). We directly genotyped 43 new SNPs with P-values of <10(-4) in a part of stage-1 samples (2692 type 2 diabetes versus 3071 controls), and the associations of validated SNPs were evaluated in another 11 139 Japanese individuals (stage 2: 7605 type 2 diabetes versus 3534 controls). Combined meta-analysis using directly genotyped data for stages 1 and 2 revealed that rs515071 in ANK1 and rs7656416 near MGC21675 were associated with type 2 diabetes in the Japanese population at the genome-wide significant level (P < 5 × 10(-8)). The association of rs515071 was also observed in European GWAS data (combined P for all populations = 6.14 × 10(-10)). Rs7656416 was in linkage disequilibrium to rs6815464, which had recently been identified as a top signal in a meta-analysis of East Asian GWAS for type 2 diabetes (r(2) = 0.76 in stage 2). The association of rs7656416 with type 2 diabetes disappeared after conditioning on rs6815464. These results indicate that the ANK1 locus is a new, common susceptibility locus for type 2 diabetes across different ethnic groups. The signal of association was weaker in the directly genotyped data, so the improvement in signal indicates the importance of imputation in this particular case.
Human Molecular Genetics 03/2012; 21(13):3042-9. · 7.64 Impact Factor
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Hisashi Fukuda,
Minako Imamura,
Yasushi Tanaka,
Minoru Iwata, Hiroshi Hirose,
Kohei Kaku,
Hiroshi Maegawa,
Hirotaka Watada,
Kazuyuki Tobe,
Atsunori Kashiwagi,
Ryuzo Kawamori,
Shiro Maeda
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ABSTRACT: The DUSP9 locus on chromosome X was identified as a susceptibility locus for type 2 diabetes in a meta-analysis of European genome-wide association studies (GWAS), and GWAS in South Asian populations identified 6 additional single nucleotide polymorphism (SNP) loci for type 2 diabetes. However, the association of these loci with type 2 diabetes have not been examined in the Japanese. We performed a replication study to investigate the association of these 7 susceptibility loci with type 2 diabetes in the Japanese population.
We genotyped 11,319 Japanese participants (8,318 with type 2 diabetes and 3,001 controls) for each of the 7 SNPs-rs5945326 near DUSP9, rs3923113 near GRB14, rs16861329 in ST6GAL1, rs1802295 in VPS26A, rs7178572 in HMG20A, rs2028299 near AP3S2, and rs4812829 in HNF4A-and examined the association of each of these 7 SNPs with type 2 diabetes by using logistic regression analysis.
All SNPs had the same direction of effect (odds ratio [OR]>1.0) as in the original reports. One SNP, rs5945326 near DUSP9, was significantly associated with type 2 diabetes at a genome-wide significance level (p = 2.21×10(-8); OR 1.39, 95% confidence interval [CI]: 1.24-1.56). The 6 SNPs derived from South Asian GWAS were not significantly associated with type 2 diabetes in the Japanese population by themselves (p≥0.007). However, a genetic risk score constructed from 6 South Asian GWAS derived SNPs was significantly associated with Japanese type 2 diabetes (p = 8.69×10(-4), OR = 1.06. 95% CI; 1.03-1.10).
These results indicate that the DUSP9 locus is a common susceptibility locus for type 2 diabetes across different ethnicities, and 6 loci identified in South Asian GWAS also have significant effect on susceptibility to Japanese type 2 diabetes.
PLoS ONE 01/2012; 7(9):e46263. · 4.09 Impact Factor
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ABSTRACT: This study aimed to predict the 6-year incidence of metabolic syndrome (MetS) using an artificial neural network (ANN) system and multiple logistic regression (MLR) analysis based on clinical factors, including the insulin resistance index calculated by homeostasis model assessment (HOMA-IR).
Subjects were recruited from participants in annual health check-ups in both 2000 and 2006. A total of 410 Japanese male teachers and other workers at Keio University, 30-59 years of age at baseline, participated in this retrospective cohort study.
Clinical parameters were randomly divided into a training dataset and a validation dataset, and the ANN system and MLR analysis were applied to predict individual incidences. The leave some out cross validation method was used for validation.
The sensitivity of the prediction was 0.27 for the MLR model and 0.93 for the ANN system, while specificities were 0.95 and 0.91, respectively. Sensitivity analysis employing the ANN system identified BMI, age, diastolic blood pressure, HDL-cholesterol, LDL-cholesterol and HOMA-IR as important predictors, suggesting these factors to be non-linearly related to the outcome.
We successfully predicted the 6-year incidence of MetS using an ANN system based on clinical data, including HOMA-IR and serum adiponectin, in Japanese male subjects.
Computers in biology and medicine 11/2011; 41(11):1051-6. · 1.27 Impact Factor
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Emiko Noguchi,
Hiromi Sakamoto,
Tomomitsu Hirota,
Kaori Ochiai,
Yoshimasa Imoto,
Masafumi Sakashita,
Fumitake Kurosaka,
Akira Akasawa,
Shigemi Yoshihara,
Noriko Kanno, [......],
Nobuyuki Hizawa,
Toru Sakamoto,
Hironori Masuko,
Yusuke Nakamura,
Ichiro Nomura,
Mayumi Tamari,
Tadao Arinami,
Teruhiko Yoshida,
Hirohisa Saito,
Kenji Matsumoto
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ABSTRACT: Asthma is a complex phenotype influenced by genetic and environmental factors. We conducted a genome-wide association study (GWAS) with 938 Japanese pediatric asthma patients and 2,376 controls. Single-nucleotide polymorphisms (SNPs) showing strong associations (P<1×10(-8)) in GWAS were further genotyped in an independent Japanese samples (818 cases and 1,032 controls) and in Korean samples (835 cases and 421 controls). SNP rs987870, located between HLA-DPA1 and HLA-DPB1, was consistently associated with pediatric asthma in 3 independent populations (P(combined) = 2.3×10(-10), odds ratio [OR] = 1.40). HLA-DP allele analysis showed that DPA1*0201 and DPB1*0901, which were in strong linkage disequilibrium, were strongly associated with pediatric asthma (DPA1*0201: P = 5.5×10(-10), OR = 1.52, and DPB1*0901: P = 2.0×10(-7), OR = 1.49). Our findings show that genetic variants in the HLA-DP locus are associated with the risk of pediatric asthma in Asian populations.
PLoS Genetics 07/2011; 7(7):e1002170. · 8.69 Impact Factor
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ABSTRACT: The waist circumference (WC) cut-off values in the diagnostic criteria of metabolic syndrome (MetS) established in Japan (Japanese criteria) differ from those established by the International Diabetes Federation (IDF) for Asians (IDF criteria).
To settle this contradiction, a cross-sectional study of Japanese aged 20-65 years was performed. After excluding subjects suffering from significant diseases other than those constituting MetS, excessive drinkers, and regular smokers, 835 males and 1,304 females were examined. WC was measured at the umbilical level (UWC) and midway between the ribs and iliac crest (MWC) according to both criteria in each subject.
Upper limits of reference intervals of MWC estimated in subjects free from MetS were 84.6 and 84.3 cm in older (40-65 years) and younger (20-39) males, and 78.4 and 70.5 cm in older and younger females, respectively; those of UWC were 86.4, 86.2, 87.9 and 78.9 cm, respectively. Receiver operating characteristic (ROC) curves for MWC to predict UWC reproduced the relationships of the two types of cut-off values in each population.
WC cut-off values in the Japanese and IDF criteria have the potential to be valid as cut-off values of UWC and MWC in Japanese, respectively. Their difference can be explained by the variation in the WC definition, and they can stand together without inconsistency. Acceptance of the recently prevailing view that the WC standard in IDF for Asian males should be 85 cm and the introduction of new criteria for younger females in consideration of their generation differences in both criteria could facilitate their higher compatibility.
Journal of atherosclerosis and thrombosis 06/2011; 18(9):735-43. · 2.69 Impact Factor
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ABSTRACT: Losartan, an angiotensin II receptor blocker (ARB), has been reported to increase serum level of high-molecular weight (HMW) adiponectin, which has beneficial effects on insulin resistance and atherosclerosis. On the other hand, treatment with diuretics was reported to decrease the adiponectin level. In the present study, we investigated the effects of changing the treatment to losartan/hydrochlorothiazide (HCTZ) on blood pressure (BP) and various metabolic parameters in Japanese male hypertensive subjects. This study included 15 subjects whose therapy was changed from a usual dosage of ARB to losartan 50mg/HCTZ 12.5mg daily, and also 14 subjects who continued losartan treatment (50mg/day). Serum HMW-adiponectin concentration was assayed using a commercially available HMW-specific ELISA kit. In the losartan/HCTZ patient group, systolic/diastolic BP decreased from 146/95 to 130/84 mmHg (P = 0.0012 for both). The HbA1c level tended to increase from 5.44 ± 0.39 to 5.55 ± 0.44% (P = 0.0554) and serum creatinine level slightly increased from 0.82 ± 0.12 to 0.87 ± 0.12 mg/dl (P = 0.0015). In contrast, serum TG (125 ± 77 to 149 ± 112 mg/dl), uric acid, and HMW-adiponectin levels (3.24 ± 2.97 to 3.36 ± 2.43 μg/ml) were unchanged. In the 14 patients who continued losartan treatment, systolic/diastolic BP was unchanged from 134/86 to 129/80 mmHg. The HbA1c level tended to increase from 5.26 ± 0.63 to 5.39 ± 0.71% (P = 0.0880), serum creatinine and uric acid levels were unchanged, serum lipids tended to improve, and serum HMW-adiponectin levels increased from 3.03 ± 1.06 to 3.46 ± 1.28 μg/ml (P = 0.0105). In summary, changing treatment to losartan/HCTZ, when changed from a usual dosage of ARB, exerted good BP control, while the HMW-adiponectin level was unchanged in male hypertensive subjects.
Clinical and Experimental Hypertension 01/2011; 33(1):41-6. · 1.07 Impact Factor
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Toshihiko Ohshige,
Minoru Iwata,
Shintaro Omori,
Yasushi Tanaka, Hiroshi Hirose,
Kohei Kaku,
Hiroshi Maegawa,
Hirotaka Watada,
Atsunori Kashiwagi,
Ryuzo Kawamori,
Kazuyuki Tobe,
Takashi Kadowaki,
Yusuke Nakamura,
Shiro Maeda
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ABSTRACT: Several novel susceptibility loci for type 2 diabetes have been identified through genome-wide association studies (GWAS) for type 2 diabetes or quantitative traits related to glucose metabolism in European populations. To investigate the association of the 13 new European GWAS-derived susceptibility loci with type 2 diabetes in the Japanese population, we conducted a replication study using 3 independent Japanese case-control studies.
We examined the association of single nucleotide polymorphisms (SNPs) within 13 loci (MTNR1B, GCK, IRS1, PROX1, BCL11A, ZBED3, KLF14, TP53INP1, KCNQ1, CENTD2, HMGA2, ZFAND6 and PRC1) with type 2 diabetes using 4,964 participants (2,839 cases and 2,125 controls) from 3 independent Japanese samples. The association of each SNP with type 2 diabetes was analyzed by logistic regression analysis. Further, we performed combined meta-analyses for the 3 studies and previously performed Japanese GWAS data (4,470 cases vs. 3,071 controls). The meta-analysis revealed that rs2943641 in the IRS1 locus was significantly associated with type 2 diabetes, (P = 0.0034, OR = 1.15 95% confidence interval; 1.05-1.26) and 3 SNPs, rs10930963 in the MTNR1B locus, rs972283 in the KLF14 locus, and rs231362 in the KCNQ1 locus, had nominal association with type 2 diabetes in the present Japanese samples (P<0.05).
These results indicate that IRS1 locus may be common locus for type 2 diabetes across different ethnicities.
PLoS ONE 01/2011; 6(10):e26911. · 4.09 Impact Factor
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ABSTRACT: In 1996, adiponectin was reported to be the most abundant transcript in adipose tissue. Animal studies revealed that administering adiponectin improves insulin resistance and blood glucose levels and inhibits atherosclerosis. In the present article, we review the significance of measuring serum high-molecular-weight (HMW) adiponectin levels in human subjects. Our cross-sectional studies revealed that the serum HMW adiponectin concentration was 1.9 times higher in healthy Japanese females than males and had a strong positive correlation with HDL-cholesterol but a negative correlation with BMI and the homeostasis model assessment insulin resistance index (HOMA-IR). They also indicated that the serum HMW adiponectin concentration had a stronger association with HOMA-IR and metabolic syndrome than the total adiponectin concentration. Our longitudinal study, a 6-year follow-up of Japanese men, suggested that a decreased level of HMW adiponectin is a predictor of progression to metabolic syndrome. In another intervention study, lifestyle modification for 3 months induced a decrease in BMI and waist circumference and an increase in serum HMW adiponectin but not the total adiponectin level in 16 Japanese males with metabolic syndrome. Administering thiazolidinediones to diabetic patients increased the serum HMW adiponectin concentration 3 fold and improved glucose and lipid profiles and blood pressure. Some people may inherit a lower serum concentration of adiponectin, and have a higher risk of developing cardiovascular diseases.It is suggested that HMW adiponectin is a useful marker for the evaluation and care of subjects with metabolic syndrome and related disorders.
Journal of atherosclerosis and thrombosis 12/2010; 17(12):1201-11. · 2.69 Impact Factor
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Norihisa Saeki,
Akira Saito,
Il Ju Choi,
Keitaro Matsuo,
Sumiko Ohnami,
Hirohiko Totsuka,
Suenori Chiku,
Aya Kuchiba,
Yeon-Su Lee,
Kyong-Ah Yoon, [......],
Wataru Yasui,
Kazuhiko Aoyagi,
Hiroki Sasaki,
Kazuyoshi Yanagihara,
Hitoshi Katai,
Tadakazu Shimoda,
Teruhiko Yoshida,
Yusuke Nakamura,
Setsuo Hirohashi,
Hiromi Sakamoto
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ABSTRACT: Two major types of gastric cancer, intestinal and diffuse, develop through distinct mechanisms; the diffuse type is considered to be more influenced by genetic factors, although the mechanism is unknown. Our previous genome-wide association study associated 3 single nucleotide polymorphisms (SNPs) with diffuse-type gastric cancer (DGC); 1 was a functional SNP (rs2294008) in prostate stem cell antigen (PSCA), but the loci of the other 2 were not investigated.
We performed high-density mapping to explore a linkage disequilibrium status of the 2 SNPs at chromosome 1q22. A DGC case-control study was conducted using DNA from 606 cases and 1264 controls (all Japanese individuals) and validated using DNA from Japanese (304 cases, 1465 controls) and Korean (452 cases, 372 controls) individuals. The effects of SNPs on function were analyzed by reporter assays and analyses of splice variants.
A region of a strong linkage disequilibrium with the 2 SNPs contained mucin 1 (MUC1) and other 4 genes and SNPs significantly associated with DGC (rs2070803: P = 4.33 × 10(-13); odds ratio [OR], 1.71 by meta-analysis of the studies on the 3 panels) but not with intestinal-type gastric cancer. Functional studies demonstrated that rs4072037 (P = 1.43 × 10(-11); OR, 1.66 by meta-analysis) in MUC1 affects promoter activity and determines the major splicing variants of MUC1 in the gastric epithelium. Individuals that carry both SNPs rs2294008 in PSCA and rs4072037 in MUC1 have a high risk for developing DGC (OR, 8.38).
MUC1 is the second major DGC susceptibility gene identified. The SNPs rs2070803 and rs4072037 in MUC1 might be used to identify individuals at risk for this type of gastric cancer.
Gastroenterology 11/2010; 140(3):892-902. · 11.68 Impact Factor
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Toshimasa Yamauchi,
Kazuo Hara,
Shiro Maeda,
Kazuki Yasuda,
Atsushi Takahashi,
Momoko Horikoshi,
Masahiro Nakamura,
Hayato Fujita,
Niels Grarup,
Stephane Cauchi, [......],
Chikako Ito,
Yasushi Tanaka,
Atsunori Kashiwagi,
Ryuzo Kawamori,
Masato Kasuga,
Philippe Froguel,
Oluf Pedersen,
Naoyuki Kamatani,
Yusuke Nakamura,
Takashi Kadowaki
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ABSTRACT: We conducted a genome-wide association study of type 2 diabetes (T2D) using 459,359 SNPs in a Japanese population with a three-stage study design (stage 1, 4,470 cases and 3,071 controls; stage 2, 2,886 cases and 3,087 controls; stage 3, 3,622 cases and 2,356 controls). We identified new associations in UBE2E2 on chromosome 3 and in C2CD4A-C2CD4B on chromosome 15 at genome-wide significant levels (rs7612463 in UBE2E2, combined P = 2.27 × 10⁻⁹; rs7172432 in C2CD4A-C2CD4B, combined P = 3.66 × 10⁻⁹). The association of these two loci with T2D was replicated in other east Asian populations. In the European populations, the C2CD4A-C2CD4B locus was significantly associated with T2D, and a combined analysis of all populations gave P = 8.78 × 10⁻¹⁴, whereas the UBE2E2 locus did not show association to T2D. In conclusion, we identified two new loci at UBE2E2 and C2CD4A-C2CD4B associated with susceptibility to T2D.
Nature Genetics 10/2010; 42(10):864-8. · 35.53 Impact Factor
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ABSTRACT: We questioned whether the ratio of C-reactive protein to high-molecular-weight adiponectin (C/A ratio), compared to each value alone, is more useful to predict insulin resistance and/or metabolic syndrome.
We measured serum CRP and HMW adiponectin levels in 841 Japanese men who had participated in an annual health checkup. Correlations of the C/A ratio with metabolic parameters were assessed, and its predictive values for insulin resistance and MetS were compared with CRP or HMW adiponectin alone.
The C/A ratio was higher in subjects with MetS (n = 114) than in those without MetS (0.46 ± 0.67 vs. 0.23 ± 0.39, p<0.0001). The C/A ratio was correlated with a larger number of metabolic parameters than CRP, but the correlation was comparable to HMW adiponectin. Likewise, the area under the curve of the C/A ratio in receiver operator characteristic analysis for MetS was greater than that of CRP, but comparable to that of HMW adiponectin. However, the AUC of the C/A ratio in ROC analysis for insulin resistance (HOMA-IR >2.5) was greater than that of CRP or HMW adiponectin alone.
While the C/A ratio provided little advantage to predict MetS, it might be more useful to predict insulin resistance than CRP or HMW adiponectin alone.
Journal of atherosclerosis and thrombosis 09/2010; 17(9):944-52. · 2.69 Impact Factor
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ABSTRACT: Little is known about the attitudes of doctors and patients to the use of home blood pressure monitoring (HBPM) and its relationship with compliance to exercise, diet, and antihypertensive medication and blood pressure (BP) control. We conducted a cross-sectional internet survey in treated patients with hypertension in Japan. Overall, 500 questionnaires were returned; 292 respondents (58.4%) reported that their doctor had recommended HBPM and among them 106 (36.3%) reported satisfactory adherence to HBPM. Compared to patients with poor adherence to HBPM, patients with satisfactory adherence to HBPM were more likely to have satisfactory compliance with exercise, diet and medication but no significant difference in BP control.
Clinical and Experimental Hypertension 07/2010; 32(4):210-3. · 1.07 Impact Factor
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Takashi Kohno,
Hideo Kunitoh,
Yoko Shimada,
Kouya Shiraishi,
Yuko Ishii,
Koichi Goto,
Yuichiro Ohe,
Yutaka Nishiwaki,
Aya Kuchiba,
Seiichiro Yamamoto, Hiroshi Hirose,
Akira Oka,
Noriko Yanagitani,
Ryusei Saito,
Hidetoshi Inoko,
Jun Yokota
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ABSTRACT: Adenocarcinoma (ADC) is the commonest histological type of lung cancer, and its weak association with smoking indicates the necessity to identify high-risk individuals for targeted screening and/or prevention. By a genome-wide association study (GWAS), we identified an association of polymorphisms in the 6p21.31 locus containing four human leukocyte antigen (HLA) class II genes with lung ADC risk. DQA1*03 of the HLA-DQA1 gene was defined as a risk allele with odds ratio (OR) of 1.36 [95% confidence interval (CI) = 1.21-1.54, P = 5.3 x 10(-7)] by analysis of 1656 ADC cases and 1173 controls. DQA1*03 and the minor allele for a polymorphism, rs2736100, in TERT, another lung cancer susceptibility locus identified in recent GWASs on Europeans and Americans, were indicated to independently contribute to ADC risk with per allele OR of 1.43 (95% CI = 1.31-1.56, P = 7.8 x 10(-16)). Individuals homozygous both for the DQA1*03 and minor TERT alleles were defined as high-risk individuals with an OR of 4.76 (95% CI = 2.53-9.47, P = 4.2 x 10(-7)). The present results indicated that individuals susceptible to lung ADC can be defined by combined genotypes of HLA-DQA1 and TERT.
Carcinogenesis 05/2010; 31(5):834-41. · 5.70 Impact Factor
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Siew-Kee Low,
Aya Kuchiba,
Hitoshi Zembutsu,
Akira Saito,
Atsushi Takahashi,
Michiaki Kubo,
Yataro Daigo,
Naoyuki Kamatani,
Suenori Chiku,
Hirohiko Totsuka,
Sumiko Ohnami, Hiroshi Hirose,
Kazuaki Shimada,
Takuji Okusaka,
Teruhiko Yoshida,
Yusuke Nakamura,
Hiromi Sakamoto
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ABSTRACT: Pancreatic cancer shows very poor prognosis and is the fifth leading cause of cancer death in Japan. Previous studies indicated some genetic factors contributing to the development and progression of pancreatic cancer; however, there are limited reports for common genetic variants to be associated with this disease, especially in the Asian population. We have conducted a genome-wide association study (GWAS) using 991 invasive pancreatic ductal adenocarcinoma cases and 5,209 controls, and identified three loci showing significant association (P-value<5x10(-7)) with susceptibility to pancreatic cancer. The SNPs that showed significant association carried estimated odds ratios of 1.29, 1.32, and 3.73 with 95% confidence intervals of 1.17-1.43, 1.19-1.47, and 2.24-6.21; P-value of 3.30x10(-7), 3.30x10(-7), and 4.41x10(-7); located on chromosomes 6p25.3, 12p11.21 and 7q36.2, respectively. These associated SNPs are located within linkage disequilibrium blocks containing genes that have been implicated some roles in the oncogenesis of pancreatic cancer.
PLoS ONE 01/2010; 5(7):e11824. · 4.09 Impact Factor
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ABSTRACT: Cardiovascular diseases are the major cause of mortality in patients with diabetes mellitus. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine and plays an important role in cardiovascular diseases. The objective of this study was to evaluate the relation between the genotypes of the MCP-1 A-2518G polymorphism and the development of carotid atherosclerosis in patients with type 2 diabetes.
The subjects were 303 unrelated patients who were diagnosed with type 2 diabetes mellitus. To evaluate macroangiopathy, we measured carotid artery intima-media thickness (IMT) by ultrasonography. The MCP-1 A-2518G polymorphism was determined by TaqMan PCR method.
IMT in patients with the MCP-1 -2518 AG or GG genotype was significantly greater than the AA-genotype (P=0.007). Simple regression analysis showed that age, systolic blood pressure, LDL-cholesterol, the MCP-1 -2518 AG+GG polymorphism, and HbA1c level were correlated with IMT (P<0.0001, <0.0001, 0.006, 0.007, 0.025, respectively). In multiple regression analysis, the MCP-1 -2518 AG+GG polymorphism was the third strongest independent determinant of IMT in patients with type 2 diabetes (P=0.021), subsequent to age and systolic blood pressure.
Assessment of the MCP-1 A-2518G polymorphism would be useful in identifying the risk of developing carotid atherosclerosis in patients with type 2 diabetes.
Diabetes research and clinical practice 09/2009; 86(3):193-8. · 2.16 Impact Factor
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ABSTRACT: Bariatric surgery has been shown to improve glucose tolerance, although the mechanism has not been fully elucidated. Animal studies have suggested important roles of bile acid (BA) as a regulator of energy homeostasis and glucose metabolism. However, little is known about its role in humans. We investigated the longitudinal changes of BA, incretins, and adipokines after significant weight reduction in 34 Japanese adults with morbid obesity who underwent laparoscopic bariatric surgery. In subjects who underwent malabsorptive or restrictive surgery, body mass index had markedly decreased from 43.0 +/- 6.5 (SD) to 37.8 +/- 5.7 kg/m(2) and from 45.3 +/- 11.2 to 41.5 +/- 10.5 kg/m(2), respectively, at 1 month after surgery. Glycated hemoglobin decreased from 6.1% +/- 1.5% to 5.2% +/- 0.4% and from 6.2% +/- 1.3% to 5.4% +/- 0.7%, and total BA level increased from 3.1 +/- 3.5 to 7.2 +/- 5.3 mumol/L and from 3.2 +/- 2.6 to 9.4 +/- 10.0 mumol/L, respectively. At baseline, serum concentration of primary BA was positively correlated with plasma gastric inhibitory polypeptide level (r = 0.548, P = .001); and change in primary BA level was positively correlated with changes in plasma gastric inhibitory polypeptide (r = 0.626, P = .001) and serum immunoreactive insulin level (r = 0.592, P = .002) at 1 month after surgery. Furthermore, plasma glucagon-like peptide-1 and serum high-molecular weight adiponectin levels increased in both surgeries. These hormonal changes might explain the mechanism(s) of improved glucose tolerance after bariatric surgery in morbidly obese subjects.
Metabolism: clinical and experimental 07/2009; 58(10):1400-7. · 2.59 Impact Factor
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ABSTRACT: Patients with Mycobacterium avium-intracellulare complex (MAC) pulmonary disease often suffer from weight loss. Adipokines are factors secreted by adipocytes, including leptin and adiponectin, as well as some inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6). Body mass index (BMI) is known to be inversely correlated with adiponectin and positively with leptin, TNF-alpha, and IL-6.
We aimed to evaluate the levels of serum adipokines, including adiponectin, leptin, TNF-alpha, and IL-6 in patients with MAC pulmonary disease.
Forty consecutive patients with MAC pulmonary disease (8 males; median age 62 years; median BMI 18.1) were examined. Serum levels of adiponectin, leptin, TNF-alpha, and IL-6 were measured with ELISA. Age-, sex- and BMI-matched healthy subjects served as controls.
Serum adiponectin was significantly elevated in patients with MAC pulmonary disease compared with the controls (p < 0.01). In both the patients and controls, serum adiponectin levels were inversely correlated with BMI (p < 0.05). No significant correlation was observed between serum adiponectin levels and C-reactive protein or lung function. Serum leptin levels, which were positively correlated with BMI, did not differ between patients and controls. Serum levels of TNF-alpha and IL-6 were significantly greater in patients with MAC pulmonary disease than in controls. The levels of TNF-alpha and IL-6 were not correlated with BMI and other adipokines examined.
The results of the present study indicate that, in patients with MAC pulmonary disease, adiponectin is inappropriately secreted and may play a role in the pathophysiology of the disease.
Respiration 07/2009; 79(5):383-7. · 2.26 Impact Factor
