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1.  Multiple Nonglycemic Genomic Loci Are Newly Associated With Blood Level of Glycated Hemoglobin in East Asians 
Diabetes  2014;63(7):2551-2562.
Glycated hemoglobin A1c (HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [P value = 1.3 × 10−23], HBS1L/MYB [8.5 × 10−15], MYO9B [9.0 × 10−12], and CYBA [1.1 × 10−8] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (<7.0 mmol/L) but elevated HbA1c (≥6.5%), 36.1% had HbA1c <6.5% after adjustment for these six variants. Our East Asian GWAS meta-analysis has identified novel variants associated with HbA1c as well as demonstrated that the effects of known variants are largely transferable across ethnic groups. Variants affecting erythrocyte parameters rather than glucose metabolism may be relevant to the use of HbA1c for diagnosing diabetes in these populations.
PMCID: PMC4284402  PMID: 24647736
2.  Complete Remission of Anaplastic Thyroid Carcinoma after Concomitant Treatment with Docetaxel and Radiotherapy 
Case Reports in Endocrinology  2015;2015:726085.
Anaplastic thyroid carcinoma (ATC) although rare is the most lethal form of thyroid cancer. The mortality rate for ATC is very high, with a median survival time of only 5 months; the survival rate at 1 year after diagnosis is <20%. Management of ATC is extremely difficult and rife with uncertainties. Herein, we describe a 75-year-old woman who presented with ATC and was successfully treated using concomitant treatment with docetaxel and high-dose radiotherapy. This case appears to be the first to have been reported in the literature involving complete remission of ATC confirmed by autopsy, suggesting the therapeutic potential of this combination.
PMCID: PMC4348586  PMID: 25789182
3.  Polymorphisms of genes involved in lipid metabolism and risk of chronic kidney disease in Japanese - cross-sectional data from the J-MICC study 
Chronic kidney disease (CKD) is known to be one of the causes of cardiovascular disease and end-stage renal disease. Among the several treatable risk factors of CKD, that of dyslipidemia is relatively controversial. To clarify the association of polymorphisms in genes involved in lipid metabolism with the risk of CKD in the Japanese population, we used cross-sectional data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study.
A total of 3,268 men and women, aged 35–69 years, were selected from J-MICC Study participants for inclusion in this study. Twenty-eight candidate single nucleotide polymorphisms (SNPs) were selected in 17 genes associated with the risk of lipid metabolism disorders, and genotyping of the subjects was conducted using the multiplex PCR-based invader assay. The prevalence of CKD was determined for stages 3–5 (defined as estimated glomerular filtration rate <60 ml/min/1.73 m2).
Logistic regression analysis revealed that SNPs APOA5 T − 1131C (rs662799), APOA5 T1259C (rs2266788), TOMM40 A/G (rs157580), and CETP TaqIB (rs708272) were significantly associated with CKD risk in those individuals genotyped, with age- and sex-adjusted odds ratios (ORs) per minor allele (and 95% confidence intervals (CIs)) of OR 1.22 (95% CI: 1.06–1.39), 1.19 (1.03–1.37), 1.27 (1.12–1.45), and 0.81 (0.71–0.92), respectively. Analysis of the gene–environment interaction revealed that body mass index (BMI) was a significant effect modifier for APOA5 T − 1131C (rs662799) and a marginally significant effect modifier for APOA5 T/C (rs2266788), with the interaction between BMI ≥30 and individuals with at least one minor allele of each genotype of OR 10.43 (95% CI: 1.29–84.19) and 3.36 (0.87–13.01), respectively.
Four polymorphisms in APOA5, TOMM40, and CETP were shown to be significantly associated with CKD risk, and a significant interaction between the two APOA5 SNPs and BMI on CKD risk was also demonstrated. This suggests the future possibility of personalized risk estimation for this life-limiting disease.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-511X-13-162) contains supplementary material, which is available to authorized users.
PMCID: PMC4210508  PMID: 25311932
Lipid metabolism; Chronic kidney disease; Single nucleotide polymorphism
4.  Gene-Gene Combination Effect and Interactions among ABCA1, APOA1, SR-B1, and CETP Polymorphisms for Serum High-Density Lipoprotein-Cholesterol in the Japanese Population 
PLoS ONE  2013;8(12):e82046.
Gene-gene interactions in the reverse cholesterol transport system for high-density lipoprotein-cholesterol (HDL-C) are poorly understood. The present study observed gene-gene combination effect and interactions between single nucleotide polymorphisms (SNPs) in ABCA1, APOA1, SR-B1, and CETP in serum HDL-C from a cross-sectional study in the Japanese population.
The study population comprised 1,535 men and 1,515 women aged 35–69 years who were enrolled in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. We selected 13 SNPs in the ABCA1, APOA1, CETP, and SR-B1 genes in the reverse cholesterol transport system. The effects of genetic and environmental factors were assessed using general linear and logistic regression models after adjusting for age, sex, and region.
Principal Findings
Alcohol consumption and daily activity were positively associated with HDL-C levels, whereas smoking had a negative relationship. The T allele of CETP, rs3764261, was correlated with higher HDL-C levels and had the highest coefficient (2.93 mg/dL/allele) among the 13 SNPs, which was statistically significant after applying the Bonferroni correction (p<0.001). Gene-gene combination analysis revealed that CETP rs3764261 was associated with high HDL-C levels with any combination of SNPs from ABCA1, APOA1, and SR-B1, although no gene-gene interaction was apparent. An increasing trend for serum HDL-C was also observed with an increasing number of alleles (p<0.001).
The present study identified a multiplier effect from a polymorphism in CETP with ABCA1, APOA1, and SR-B1, as well as a dose-dependence according to the number of alleles present.
PMCID: PMC3869658  PMID: 24376512
5.  Polymorphisms in PPAR Genes (PPARD, PPARG, and PPARGC1A) and the Risk of Chronic Kidney Disease in Japanese: Cross-Sectional Data from the J-MICC Study 
PPAR Research  2013;2013:980471.
Chronic kidney disease (CKD) is well known as a strong risk factor for both end stage renal disease and cardiovascular disease. To clarify the association of polymorphisms in the PPAR genes (PPARD, PPARG, and PPARGC1A) with the risk of CKD in Japanese, we examined this association among the Japanese subjects using the cross-sectional data of J-MICC (Japan Multi-Institutional Collaborative Cohort) Study. The subjects for this analysis were 3,285 men and women, aged 35–69 years, selected from J-MICC Study participants; genotyping was conducted by multiplex polymerase chain reaction-based Invader assay. The prevalence of CKD was determined for CKD stages 3–5 (defined as eGFR < 60 ml/min/1.73 m2). Participants with CKD accounted for 17.3% of the study population. When those with PPARD T-842C T/T were defined as reference, those with PPARD T-842C T/C and C/C demonstrated the OR for CKD of 1.26 (95%CI 1.04–1.53) and 1.31 (95%CI 0.83–2.06), respectively. There were no significant associations between the polymorphisms in other PPAR genes and the risk of CKD. The present study found a significantly increased risk of CKD in those with the C allele of PPARD T-842C, which may suggest the possibility of personalized risk estimation of this life-limiting disease in the near future.
PMCID: PMC3830885  PMID: 24288525
6.  Behavioral and clinical correlates of serum bilirubin concentrations in Japanese men and women 
A considerable interest has been drawn to potential protective effects of bilirubin against oxidative stress-related diseases. Smoking is known to be associated with lower concentrations of serum bilirubin, but other behavioral correlates of serum bilirubin have not been well studied. In this cross-sectional study, we examined the associations of behavioral and clinical factors with serum total bilirubin in Japanese men and women.
The study subjects comprised of 4802 men and 6414 women aged 49–76 years who participated in the baseline survey of an ongoing cohort study on lifestyle-related diseases in Fukuoka, Japan. With consideration to time of the day of blood sampling and fasting hours, the associations with smoking, alcohol intake, body mass index, physical activity, coffee, tea, blood pressure, glycated hemoglobin (HbA1c), HDL cholesterol and non-HDL cholesterol with serum bilirubin were evaluated by analysis of covariance and multiple linear regression analysis.
While smoking was negatively associated with serum bilirubin, alcohol consumption was positively associated with serum bilirubin in both men and women. Coffee consumption was associated with lower bilirubin concentrations in both sexes. In the multiple linear regression analysis, HDL cholesterol was positively and HbA1c was negatively associated with bilirubin in both men and women, and the associations were more evident in women.
Smoking, alcohol use and coffee consumption were important behavioral correlates of serum bilirubin in Japanese men and women. Serum HDL cholesterol was a measurable clinical correlate of bilirubin in women.
PMCID: PMC3852517  PMID: 24090309
Bilirubin; Coffee; Smoking; Alcohol; High-density lipoprotein cholesterol
7.  CYP1A1, GSTM1, GSTT1 and NQO1 polymorphisms and colorectal adenomas in Japanese men 
AIM: To investigate the role of functional genetic polymorphisms of metabolic enzymes of tobacco carcinogens in the development of colorectal adenomas.
METHODS: The study subjects were 455 patients with colorectal adenomas and 1052 controls with no polyps who underwent total colonoscopy in a preretirement health examination at two Self Defense Forces hospitals. The genetic polymorphisms studied were CYP1A1*2A (rs 4646903), CYP1A1*2C (rs 1048943), GSTM1 (null or non-null genotype), GSTT1 (null or non-null genotype) and NQO1 C609T (rs 1800566). Genotypes were determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism or PCR method using genomic DNA extracted from the buffy coat. Cigarette smoking and other lifestyle factors were ascertained by a self-administered questionnaire. The associations of the polymorphisms with colorectal adenomas were examined by means of OR and 95%CI, which were derived from logistic regression analysis. Statistical adjustment was made for smoking, alcohol use, body mass index and other factors. The gene-gene interaction and effect modification of smoking were evaluated by the likelihood ratio test.
RESULTS: None of the five polymorphisms showed a significant association with colorectal adenomas, nor was the combination of GSTM1 and GSTT1. A borderline significant interaction was observed for the combination of CYP1A1*2C and NQO1 (P = 0.051). The OR associated with CYP1A1*2C was significantly lower than unity among individuals with the NQO1 609CC genotype. The adjusted OR for the combination of the CYP1A1*2C allele and NQO1 609CC genotype was 0.61 (95%CI: 0.42-0.91). Although the interaction was not statistically significant (P = 0.24), the OR for individuals carrying the CYP1A1*2C allele and GSTT1 null genotype decreased significantly compared with those who had neither CYP1A1*2C allele nor GSTT1 null genotype (adjusted OR: 0.69, 95%CI: 0.49-0.97). Smoking did not modify the associations of the individual polymorphisms with colorectal adenomas. There was no measurable effect modification of smoking even regarding the combination of the genetic polymorphisms of the phase I and phase II enzymes.
CONCLUSION: Combination of the CYP1A1*2C and NQO1 609CC genotypes was associated with a decreased risk of colorectal adenomas regardless of smoking status.
PMCID: PMC3703190  PMID: 23840148
Colorectal adenoma; Smoking; Polymorphism; CYP1A1; GSTM1; GSTT1; NQO1
8.  Dietary polyphenols and colorectal cancer risk: The Fukuoka colorectal cancer study 
AIM: To investigate the associations between dietary intake of polyphenols and colorectal cancer.
METHODS: The study subjects were derived from the Fukuoka colorectal cancer study, a community-based case-control study. The study subjects were 816 cases of colorectal cancer and 815 community-based controls. The consumption of 148 food items was assessed by a computer-assisted interview. We used the consumption of 97 food items to estimate dietary intakes of total, tea and coffee polyphenols. The Phenol-Explorer database was used for 92 food items. Of the 5 foods which were not listed in the Phenol-Explorer Database, polyphenol contents of 3 foods (sweet potatoes, satoimo and daikon) were based on a Japanese study and 2 foods (soybeans and fried potatoes) were estimated by ORAC-based polyphenol contents in the United States Department of Agriculture Database. Odds ratios (OR) and 95%CI of colorectal cancer risk according to quintile categories of intake were obtained by using logistic regression models with adjustment for age, sex, residential area, parental history of colorectal cancer, smoking, alcohol consumption, body mass index 10 years before, type of job, leisure-time physical activity and dietary intakes of calcium and n-3 polyunsaturated fatty acids.
RESULTS: There was no measurable difference in total or tea polyphenol intake between cases and controls, but intake of coffee polyphenols was lower in cases than in controls. The multivariate-adjusted OR of colorectal cancer according to quintile categories of coffee polyphenols (from the first to top quintile) were 1.00 (referent), 0.81 (95%CI: 0.60-1.10), 0.65 (95%CI: 0.47-0.89), 0.65 (95%CI: 0.46-0.89) and 0.82 (95%CI: 0.60-1.10), respectively (Ptrend = 0.07). Similar, but less pronounced, decreases in the OR were also noted for the third and fourth quintiles of total polyphenol intake. Tea polyphenols and non-coffee polyphenols showed no association with colorectal cancer risk. The site-specific analysis, based on 463 colon cancer cases and 340 rectal cancer cases, showed an inverse association between coffee polyphenols and colon cancer. The multivariate-adjusted OR of colon cancer for the first to top quintiles of coffee polyphenols were 1.00 (referent), 0.92 (95%CI: 0.64-1.31), 0.75 (95%CI: 0.52-1.08), 0.69 (95%CI: 0.47-1.01), and 0.68 (95%CI: 0.46-1.00), respectively (Ptrend = 0.02). Distal colon cancer showed a more evident inverse association with coffee polyphenols than proximal colon cancer. The association between coffee polyphenols and rectal cancer risk was U-shaped, with significant decreases in the OR at the second to fourth quintile categories. There was also a tendency that the OR of colon and rectal cancer decreased in the intermediate categories of total polyphenols. The decrease in the OR in the intermediate categories of total polyphenols was most pronounced for distal colon cancer. Intake of tea polyphenols was not associated with either colon or rectal cancer. The associations of coffee consumption with colorectal, colon and rectal cancers were almost the same as observed for coffee polyphenols. The trend of the association between coffee consumption and colorectal cancer was statistically significant.
CONCLUSION: The present findings suggest a decreased risk of colorectal cancer associated with coffee consumption.
PMCID: PMC3645387  PMID: 23674876
Colorectal cancer; Colon cancer; Rectal cancer; Polyphenols; Coffee; Tea
9.  Genome-wide association study of coronary artery disease in the Japanese 
A new understanding of the genetic basis of coronary artery disease (CAD) has recently emerged from genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs), thus far performed mostly in European-descent populations. To identify novel susceptibility gene variants for CAD and confirm those previously identified mostly in populations of European descent, a multistage GWA study was performed in the Japanese. In the discovery phase, we first genotyped 806 cases and 1337 controls with 451 382 SNP markers and subsequently assessed 34 selected SNPs with direct genotyping (541 additional cases) and in silico comparison (964 healthy controls). In the replication phase, involving 3052 cases and 6335 controls, 12 SNPs were tested; CAD association was replicated and/or verified for 4 (of 12) SNPs from 3 loci: near BRAP and ALDH2 on 12q24 (P=1.6 × 10−34), HLA-DQB1 on 6p21 (P=4.7 × 10−7), and CDKN2A/B on 9p21 (P=6.1 × 10−16). On 12q24, we identified the strongest association signal with the strength of association substantially pronounced for a subgroup of myocardial infarction cases (P=1.4 × 10−40). On 6p21, an HLA allele, DQB1*0604, could show one of the most prominent association signals in an ∼8-Mb interval that encompasses the LTA gene, where an association with myocardial infarction had been reported in another Japanese study. CAD association was also identified at CDKN2A/B, as previously reported in different populations of European descent and Asians. Thus, three loci confirmed in the Japanese GWA study highlight the likely presence of risk alleles with two types of genetic effects – population specific and common – on susceptibility to CAD.
PMCID: PMC3283177  PMID: 21971053
coronary artery disease; gene; association study; Japanese
10.  Meta-analysis of genome-wide association studies identifies 8 new loci for type 2 diabetes in East Asians 
Nature genetics  2011;44(1):67-72.
We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in East Asian populations. The first stage meta-analysis of eight T2D genome-wide association studies (6,952 cases and 11,865 controls) was followed by a second stage in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which were mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, involved in pancreatic beta cell development and insulin gene expression1,2, is known for its association with fasting glucose levels3,4. The evidence of T2D association for PEPD5 and HNF4A6,7 has been detected in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings derived from East Asians provide new perspectives on the etiology of T2D.
PMCID: PMC3582398  PMID: 22158537
11.  Deletion of CDKAL1 Affects High-Fat Diet–Induced Fat Accumulation and Glucose-Stimulated Insulin Secretion in Mice, Indicating Relevance to Diabetes 
PLoS ONE  2012;7(11):e49055.
The CDKAL1 gene is among the best-replicated susceptibility loci for type 2 diabetes, originally identified by genome-wide association studies in humans. To clarify a physiological importance of CDKAL1, we examined effects of a global Cdkal1-null mutation in mice and also evaluated the influence of a CDKAL1 risk allele on body mass index (BMI) in Japanese subjects.
In Cdkal1-deficient (Cdkal1−/−) mice, we performed oral glucose tolerance test, insulin tolerance test, and perfusion experiments with and without high-fat feeding. Based on the findings in mice, we tested genetic association of CDKAL1 variants with BMI, as a measure of adiposity, and type 2 diabetes in Japanese.
Principal Findings
On a standard diet, Cdkal1−/− mice were modestly lighter in weight than wild-type littermates without major alterations in glucose metabolism. On a high fat diet, Cdkal1−/− mice showed significant reduction in fat accumulation (17% reduction in %intraabdominal fat, P = 0.023 vs. wild-type littermates) with less impaired insulin sensitivity at an early stage. High fat feeding did not potentiate insulin secretion in Cdkal1−/− mice (1.0-fold), contrary to the results in wild-type littermates (1.6-fold, P<0.01). Inversely, at a later stage, Cdkal1−/− mice showed more prominent impairment of insulin sensitivity and glucose tolerance. mRNA expression analysis indicated that Scd1 might function as a critical mediator of the altered metabolism in Cdkal1−/− mice. In accordance with the findings in mice, a nominally significant (P<0.05) association between CDKAL1 rs4712523 and BMI was replicated in 2 Japanese general populations comprising 5,695 and 12,569 samples; the risk allele for type 2 diabetes was also associated with decreased BMI.
Cdkal1 gene deletion is accompanied by modestly impaired insulin secretion and longitudinal fluctuations in insulin sensitivity during high-fat feeding in mice. CDKAL1 may affect such compensatory mechanisms regulating glucose homeostasis through interaction with diet.
PMCID: PMC3500257  PMID: 23173044
12.  Effects of 16-Week Consumption of Caffeinated and Decaffeinated Instant Coffee on Glucose Metabolism in a Randomized Controlled Trial 
Objective. Observational studies have shown a protective association between coffee consumption and type 2 diabetes mellitus whereas caffeine or caffeinated coffee acutely deteriorates glucose tolerance. We investigated the effects of chronic drinking of instant coffee on glucose and insulin concentrations during a 75 g oral glucose tolerance test. Methods. Overweight men with a mild-to-moderate elevation of fasting plasma glucose were randomly allocated to a 16-week intervention of consuming 5 cups of caffeinated (n = 17) or decaffeinated (n = 15) instant coffee per day or no coffee (n = 13). Results. The caffeinated coffee group showed statistically significant decreases in the 2-hour concentrations and the area under the curve of glucose while neither decaffeinated coffee nor coffee group showed such a change. Waist circumstance decreased in the caffeinated coffee group, increased in the decaffeinated coffee group, and did not change in the noncoffee group (P = 0.002). With adjustment for the change in waist circumference, caffeinated and decaffeinated coffee consumption were associated with a modest decrease in the postload glucose levels. Conclusion. Both caffeinated and decaffeinated coffee may be protective against deterioration of glucose tolerance.
PMCID: PMC3502017  PMID: 23193459
13.  eNOS genotype modifies the effect of leisure-time physical activity on serum triglyceride levels in a Japanese population 
Nitric oxide is a key molecule not only in the cardiovascular system, but also in the metabolic-endocrine system. The purpose of this study was to examine possible associations of the NOS3 T-786C polymorphism (rs2070744) with serum lipid levels on the basis of lifestyle factors for tailoring prevention of dyslipidemia.
For this cross-sectional study, a total of 2226 subjects aged 35 to 69 years (1084 men and 1142 women) were selected from Japanese participants in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. They were recruited in eight areas throughout Japan between February 2004 and November 2008.
In a stratified analysis by leisure-time physical activity, the likelihood of hypertriglyceridemia (serum triglyceride levels ≥ 150 mg/dL) among subjects with the C allele was significantly lower than those without it in the active group (OR = 0.43, 95% CI = 0.22-0.84 in the fasting group), but not in the sedentary group. A gene-environment interaction between the T-786C polymorphism and leisure-time physical activity for hypertriglyceridemia was significant (P = 0.007 in the fasting group). Additionally, serum triglyceride levels (mean ± SD) across leisure-time physical activity classes decreased significantly only in the TC + CC genotype group (111 ± 60 mg/dL for sedentary, 95 ± 48 mg/dL for moderately active, 88 ± 44 mg/dL for very active, P for trend = 0.008 in the fasting group), but not in the TT genotype group. Total cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol levels had no significant association with the polymorphism.
This study suggests that the NOS3 T-786C polymorphism modifies the effect of leisure-time physical activity on serum triglyceride levels.
PMCID: PMC3543244  PMID: 23122449
Cross-sectional study; Gene-environment interaction; Hypertriglyceridemia; Lifestyle-related disease; NOS3; Tailoring prevention
14.  No effect modification of serum bilirubin or coffee consumption on the association of gamma-glutamyltransferase with glycated hemoglobin in a cross-sectional study of Japanese men and women 
Oxidative stress has been implicated in the development of type 2 diabetes mellitus. Bilirubin is a potent endogenous antioxidant, and coffee is a major source of exogenous antioxidants. Serum gamma-glutamyltransferase (GGT), a marker of oxidative stress, is a strong predictor of the risk of type 2 diabetes mellitus. This study evaluated the effect modification of bilirubin and coffee consumption on the association of serum GGT with glycated hemoglobin (HbA1c) and the combined effect of bilirubin and coffee on HbA1c concentrations.
The subjects were 4492 men and 6242 women aged 49–76 years who participated in the baseline survey of an on-going cohort study on lifestyle-related diseases in Fukuoka, Japan. Geometric means of HbA1c were examined according to quartile categories of GGT, with stratification by serum total bilirubin (≥ 0.6 mg/dL versus less in men and ≥ 0.5 mg/dL versus less in women) and coffee consumption (< 1, 1–3 and ≥ 4 cups of per day). Statistical adjustment was made for age, smoking, alcohol use and body mass index by using analysis of covariance.
HbA1 concentrations increased progressively with increasing levels of GGT in both men and women. The increasing trend of HbA1c concentrations associated with GGT did not differ by either bilirubin status or coffee consumption. Both men and women with high bilirubin had consistently lower concentrations of HbA1c across the GGT quartiles. Higher coffee consumption was associated with lower concentrations of HbA1c in women with low bilirubin (trend P = 0.04), but not with high bilirubin (trend P = 0.37). There was no such association between coffee and HbA1c in men with either low or high bilirubin levels.
Bilirubin is possibly protective against deterioration of glucose metabolism. Further studies are needed regarding the combined effect of bilirubin and coffee on glucose metabolism.
PMCID: PMC3509408  PMID: 23092212
15.  Detailed Analysis of Japanese Population Substructure with a Focus on the Southwest Islands of Japan 
PLoS ONE  2012;7(4):e35000.
Uncovering population structure is important for properly conducting association studies and for examining the demographic history of a population. Here, we examined the Japanese population substructure using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC), which covers all but the northern region of Japan. Using 222 autosomal loci from 4502 subjects, we investigated population substructure by estimating FST among populations, testing population differentiation, and performing principal component analysis (PCA) and correspondence analysis (CA). All analyses revealed a low but significant differentiation between the Amami Islanders and the mainland Japanese population. Furthermore, we examined the genetic differentiation between the mainland population, Amami Islanders and Okinawa Islanders using six loci included in both the Pan-Asian SNP (PASNP) consortium data and the J-MICC data. This analysis revealed that the Amami and Okinawa Islanders were differentiated from the mainland population. In conclusion, we revealed a low but significant level of genetic differentiation between the mainland population and populations in or to the south of the Amami Islands, although genetic variation between both populations might be clinal. Therefore, the possibility of population stratification must be considered when enrolling the islander population of this area, such as in the J-MICC study.
PMCID: PMC3318002  PMID: 22509376
16.  Pro-/anti-inflammatory cytokine gene polymorphisms and chronic kidney disease: a cross-sectional study 
BMC Nephrology  2012;13:2.
The aim of this study was to explore the associations between common potential functional promoter polymorphisms in pro-/anti-inflammatory cytokine genes and kidney function/chronic kidney disease (CKD) prevalence in a large Japanese population.
A total of 3,323 subjects aged 35-69 were genotyped for all 10 single nucleotide polymorphisms (SNPs) in the promoter regions of candidate genes with minor allele frequencies of > 0.100 in Japanese populations. The estimated glomerular filtration rate (eGFR) and CKD prevalence (eGFR < 60 ml/min/1.73 m2) of the subjects were compared among the genotypes.
A higher eGFR and lower prevalence of CKD were observed for the homozygous variants of IL4 -33CC (high IL-4 [anti-inflammatory cytokine]-producing genotype) and IL6 -572GG (low IL-6 [pro-inflammatory cytokine]-producing genotype). Subjects with IL4 CC + IL6 GG showed the highest mean eGFR (79.1 ml/min/1.73 m2) and lowest CKD prevalence (0.0%), while subjects carrying IL4 TT + IL6 CC showed the lowest mean eGFR (73.4 ml/min/1.73 m2) and highest CKD prevalence (17.9%).
The functional promoter polymorphisms IL4 T-33C (rs2070874) and IL6 C-572G (rs1800796), which are the only SNPs that affect the IL-4 and IL-6 levels in Japanese subjects, were associated with kidney function and CKD prevalence in a large Japanese population.
PMCID: PMC3297507  PMID: 22230215
17.  Genetic Polymorphisms of XRCC1, Alcohol Consumption, and the Risk of Colorectal Cancer in Japan 
Journal of Epidemiology  2012;22(1):64-71.
X-ray cross-complementing group 1 (XRCC1) polymorphisms affect DNA repair capacity and may therefore be of importance in colorectal carcinogenesis. Alcohol consumption, an important risk factor for colorectal cancer, may induce carcinogenesis through DNA damage caused by the toxic effects of alcohol or its metabolites. Therefore, we examined the associations of XRCC1 Arg399Gln, Arg280His, and Arg194Trp polymorphisms with colorectal cancer and the impact of the association between alcohol consumption and colorectal cancer risk.
This case-control study in Fukuoka, Japan including 685 cases and 778 controls. The cases were incident patients with histologically confirmed colorectal adenocarcinoma. The controls were randomly selected community subjects.
The XRCC1 399Gln/Gln genotype was significantly associated with colorectal cancer risk (adjusted odds ratio [OR] 1.57, 95% CI 1.01–2.42; relative to 399Arg/Arg genotype). The association was strongest in individuals with high alcohol consumption. The Arg280His polymorphism modified the association between alcohol consumption and colorectal cancer risk (interaction P = 0.049). The OR of colorectal cancer in individuals with the 280His allele was 0.45 (95% CI 0.26–0.78) as compared with the 280Arg/Arg genotype limited to the 399Gln allele (interaction P = 0.001). The adjusted ORs for 399Gln/Gln-280Arg/Arg-194Arg/Arg and 399Arg/Gln-280Arg/Arg-194Arg/Trp were 1.71 (95% CI 1.02–2.87) and 1.57 (95% CI 1.05–2.33), respectively, with 399Arg/Arg-280Arg/Arg-194Arg/Arg as reference (interaction P = 0.418).
The findings are additional evidence that individuals with the XRCC1 399Gln/Gln genotype have an increased risk of colorectal cancer, and that XRCC1 polymorphisms have an important role in colorectal cancer risk associated with alcohol consumption or gene-gene interaction.
PMCID: PMC3798582  PMID: 22186158
XRCC1 polymorphisms; alcohol consumption; colorectal cancer
18.  Successful management of cryptococcosis of the bilateral adrenal glands and liver by unilateral adrenalectomy with antifungal agents: a case report 
BMC Infectious Diseases  2011;11:340.
Cryptococcus species usually affect the central nervous system and lungs in immunocompromised hosts. Although the adrenal glands can be involved in disseminated cryptococcosis, primary adrenal insufficiency caused by the fungal infection is uncommon.
Case presentation
We present a case of primary adrenal insufficiency with bilateral adrenal masses and liver invasion in a 43-year-old man with mild type 2 diabetes mellitus. Cryptococcosis was diagnosed by fine-needle aspiration biopsy of the liver mass. The serum cryptococcal antigen titer was elevated to 1:256. After 6 months of antifungal therapy with fluconazole and amphotericin B, the size of the liver mass was decreased, but no significant changes were observed in the bilateral adrenal masses and the serum cryptococcal antigen titer remained elevated at 1:128. To control the cryptococcosis, a laparoscopic left adrenalectomy was performed, followed by antifungal therapy. After the unilateral adrenalectomy, the size of the remaining right adrenal mass was reduced and the serum cryptococcal antigen titer declined to 1:4.
This is the first report describing adrenal cryptococcosis with adrenal insufficiency and liver invasion without central nervous system involvement. Adrenal cryptococcosis should be considered in the differential diagnosis for patients with bilateral adrenal masses with primary adrenal deficiency. Unilateral adrenalectomy was quite effective in controlling the cryptococcosis in this case. Even in patients with bilateral adrenal cryptococcosis, unilateral adrenalectomy should be an option for treatment of disseminated cryptococcosis.
PMCID: PMC3254187  PMID: 22166121
19.  Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in East Asians 
Nature genetics  2011;43(6):531-538.
We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of East Asian ancestry from the AGEN-BP consortium followed by de novo genotypingin 2 stages of replication involving 10,518 and 20,247 East Asian samples. We identified novel genome-wide significant (P < 5 × 10−8) associations between SBP or DBP and variants at four novel loci: ST7L-CAPZA1, FIGN-GRB14, ENPEP, and NPR3, as well as a novel variant near TBX3. Except for NPR3, all novel findings were significantly replicated for SBP or DBP in independent samples. Sevenloci previously reported in populations of European descent were confirmed. On 12q24.13, we observed an ethnic specific association(implicating rs671 at the ALDH2 locus as the causal variant) that affected SBP, DBP and multiple traits related to coronary artery disease. These findings provide novel insights into blood pressure regulation and potential targets for intervention.
PMCID: PMC3158568  PMID: 21572416
20.  Profile of Participants and Genotype Distributions of 108 Polymorphisms in a Cross-Sectional Study of Associations of Genotypes With Lifestyle and Clinical Factors: A Project in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study 
Journal of Epidemiology  2011;21(3):223-235.
Most diseases are thought to arise from interactions between environmental factors and the host genotype. To detect gene–environment interactions in the development of lifestyle-related diseases, and especially cancer, the Japan Multi-institutional Collaborative Cohort (J-MICC) Study was launched in 2005.
We initiated a cross-sectional study to examine associations of genotypes with lifestyle and clinical factors, as assessed by questionnaires and medical examinations. The 4519 subjects were selected from among participants in the J-MICC Study in 10 areas throughout Japan. In total, 108 polymorphisms were chosen and genotyped using the Invader assay.
The study group comprised 2124 men and 2395 women with a mean age of 55.8 ± 8.9 years (range, 35–69 years) at baseline. Among the 108 polymorphisms examined, 4 were not polymorphic in our study population. Among the remaining 104 polymorphisms, most variations were common (minor allele frequency ≥0.05 for 96 polymorphisms). The allele frequencies in this population were comparable with those in the HapMap-JPT data set for 45 Japanese from Tokyo. Only 5 of 88 polymorphisms showed allele-frequency differences greater than 0.1. Of the 108 polymorphisms, 32 showed a highly significant difference in minor allele frequency among the study areas (P < 0.001).
This comprehensive data collection on lifestyle and clinical factors will be useful for elucidating gene–environment interactions. In addition, it is likely to be an informative reference tool, as free access to genotype data for a large Japanese population is not readily available.
PMCID: PMC3899413  PMID: 21467728
allele frequency; cross-sectional studies; gene–environment interactions; Japan Multi-institutional Collaborative Cohort Study; polymorphism
21.  Clinical and experimental evidence for oxidative stress as an exacerbating factor of diabetes mellitus 
The involvement of reactive oxygen species in various diseases has been demonstrated almost in vitro or in animal studies and clinical studies supporting the involvement of reactive oxygen species are very few. Bilirubin has been recognized as an important antioxidant and also shown to have an inhibitory effect on the activity of NADPH oxidase, which may be an important source for superoxide production in various tissues. When the prevalence of vascular complcations was compared in diabetic patients with and without a congenital hyperbilirubinemia (Gilbert syndrome), the prevalence of retinopathy, macroalbuminuria and coronary artery disease in patients with Gilbert syndrome was about 20% of that in those without Gilbert syndrome. For study of lifestyle-related diseases, the Fukuoka Cohort was constructed from 2003 to 2009 in Kyushu area in Japan, which contains a total of 12,949 persons. Cross-sectional study of the Fukuoka Cohort revealed an inverse relation between serum bilirubin level and the prevalence of type 2 diabetes mellitus. A precursor of bilirubin, biliverdin-treated db/db mice exhibited less albuminuria and nephropathic changes. These effects were paralleled with normalization of oxidative stress markers and expression of NAD(P)H oxidase subunits in kidney. These results suggested that oxidative stress is an exacerbating factor of type 2 diabetes mellitus and that antioxidant therapies are of value to diabetic nephropathy.
PMCID: PMC3022068  PMID: 21297916
bilirubin; Gilbert syndrome; diabetes; cohort; Gunn rat
22.  The Relation of Coffee Consumption to Serum Uric Acid in Japanese Men and Women Aged 49–76 Years 
Objective. Few studies have suggested an inverse relation between coffee intake and serum concentrations of uric acid (UA), but none has addressed the relation in men and women separately. We examined the relation between coffee intake and serum UA levels in free-living middle-aged and elderly men and women in Fukuoka, Japan. Methods. Study subjects were derived from the baseline survey of a cohort study on lifestyle-related diseases, and included 11.662 men and women aged 49–76 years; excluded were those with medication for gout and hyperuricemia, use of diuretic drugs, and medical care for cancer or chronic kidney disease. Statistical adjustment was made for body mass index, alcohol use, hypertension, diabetes mellitus, and other factors. Results. There were inverse associations of coffee consumption with serum UA concentrations and hyperuricemia in men regardless of adjustment for covariates. Women showed a statistically significant, but weaker, inverse association between coffee and serum UA levels after allowance for the confounding factors. Conclusion. The findings add to evidence for a protective association between coffee intake and hyperuricemia.
PMCID: PMC2925214  PMID: 20798877
23.  Confirmation of Multiple Risk Loci and Genetic Impacts by a Genome-Wide Association Study of Type 2 Diabetes in the Japanese Population 
Diabetes  2009;58(7):1690-1699.
To identify novel type 2 diabetes gene variants and confirm previously identified ones, a three-staged genome-wide association study was performed in the Japanese population.
In the stage 1 scan, we genotyped 519 case and 503 control subjects with 482,625 single nucleotide polymorphism (SNP) markers; in the stage 2 panel comprising 1,110 case subjects and 1,014 control subjects, we assessed 1,456 SNPs (P < 0.0025, stage 1); additionally to direct genotyping, 964 healthy control subjects formed the in silico control panel. Along with genome-wide exploration, we aimed to replicate the disease association of 17 SNPs from 16 candidate loci previously identified in Europeans. The associated and/or replicated loci (23 SNPs; P < 7 × 10–5 for genome-wide exploration and P < 0.05 for replication) were examined in the stage 3 panel comprising 4,000 case subjects and 12,569 population-based samples, from which 4,889 nondiabetic control subjects were preselected. The 12,569 subjects were used for overall risk assessment in the general population.
Four loci—1 novel with suggestive evidence (PEPD on 19q13, P = 1.4 × 10–5) and three previously reported—were identified; the association of CDKAL1, CDKN2A/CDKN2B, and KCNQ1 were confirmed (P < 10–19). Moreover, significant associations were replicated in five other candidate loci: TCF7L2, IGF2BP2, SLC30A8, HHEX, and KCNJ11. There was substantial overlap of type 2 diabetes susceptibility genes between the two populations, whereas effect size and explained variance tended to be higher in the Japanese population.
The strength of association was more prominent in the Japanese population than in Europeans for more than half of the confirmed type 2 diabetes loci.
PMCID: PMC2699880  PMID: 19401414
24.  Alendronate improves QOL of postmenopausal women with osteoporosis 
Postmenopausal osteoporosis causes bone fracture as well as pain, physical, psychological and socially adverse effects, which affects a patient’s quality of life (QOL). The effect of alendronate on QOL was investigated compared with that of alfacalcidol in post-menopausal osteoporotic women.
Patients and methods:
A total of 44 postmenopausal osteoporotic women (mean age 69.8 years) with back or joint pain, although capable of walking, were randomly assigned to two groups; group A (n = 25) received 5 mg/day of alendronate, and group B (n = 19) received 0.5 μg/day of alfacalcidol, for the first 4 months. For the following 2 months, the group A received 0.5 μg/day of alfacalcidol and the group B received 5 mg/day of alendronate in a crossover design. The patient’s QOL was evaluated by score of Japanese Osteoporosis Quality of Life Questionnaire (JOQOL), and pain intensity using a visual analog scale (VAS). Bone metabolism was measured by bone mineral density (BMD) and a biomarker for bone resorption, urinary crosslinked N-terminal telopeptide of type I collagen (NTX).
With 4-month treatment, alendronate, but not alfacalcidol, improved pain-related QOL, reduced joint pain by VAS, and increased bone mineral density. Both treatments significantly reduced bone resorption, the inhibition was significantly higher with alendronate (−56.5%) compared with alfacalcidol (−18.1%). After crossover, the patients in group A received alfacalcidol and had a reduced total and daily living activity-related QOL scores, and increased upper back pain by VAS. The group B received alendronate had significantly reduced bone resorption after the 2 months.
Alendronate improves the QOL of Japanese postmenopausal women with osteoporosis by reducing pain intensity as well as increasing bone mineral density.
PMCID: PMC2861847  PMID: 20458350
osteoporosis; bisphosphonates; quality of life; pain; vitamin D
25.  Waist circumference and insulin resistance: a cross-sectional study of Japanese men 
Visceral obesity is positively related to insulin resistance. The nature of the relationship between waist circumference and insulin resistance has not been known in Japanese populations. This study examined the relationship between waist circumference and insulin resistance and evaluated the optimal cutoff point for waist circumference in relation to insulin resistance in middle-aged Japanese men.
Study subjects included 4800 Japanese men aged 39 to 60 years. Insulin resistance was evaluated by the homeostasis model assessment of insulin resistance (HOMA-IR). The relationship of waist circumference with HOMA-IR was assessed by use of adjusted means of HOMA-IR and odds ratios of elevated HOMA-IR defined as the highest quintile (≥2.00). Receiver operating characteristics (ROC) curve analysis using Youden index and the area under curve (AUC) was employed to determine optimal cutoffs of waist circumference in relation to HOMA-IR.
Adjusted geometric means of HOMA-IR and prevalence odds of elevated HOMA-IR were progressively higher with increasing levels of waist circumference. In the ROC curve analysis, the highest value of Youden index was obtained for a cutoff point of 85 cm in waist circumference across different values of HOMA-IR. Multiple logistic regression analysis also indicated that the AUC was consistently the largest for a waist circumference of 85 cm.
Waist circumference is linearly related to insulin resistance, and 85 cm in waist circumference is an optimal cutoff in predicting insulin resistance in middle-aged Japanese men.
PMCID: PMC2635363  PMID: 19138424

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