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The pathobiological role of estrogen is controversial in colorectal cancer. Cytosine-adenine (CA) repeat in the estrogen receptor (ER)-β gene (ESR2-CA) is a microsatellite, as well as representative of ESR2 polymorphism. Though its function is unknown, we previously showed that a shorter allele (germline) increased the risk of colon cancer in older women, whereas it decreased it in younger postmenopausal women. ESR2-CA and ER-β expressions were examined in cancerous (Ca) and non-cancerous (NonCa) tissue pairs from 114 postmenopausal women, and comparisons were made considering tissue types, age/locus, and the mismatch repair protein (MMR) status. ESR2-CA repeats

Alcohol consumption is an established risk factor for cancer, but little is known regarding the effect of genetic polymorphisms in alcohol metabolism genes on alcohol-related cancer risk in the Japanese population. Associations between the ADH1B gene (alcohol dehydrogenase 1B), single nucleotide polymorphism (SNP) rs1229984 and cancer have been extensively studied yet evidence is inconsistent. This population-based case-control study primarily aimed to clarify any association between SNP rs1229984 in both overall and specific cancer risk in a Japanese population. The functional non-synonymous SNP rs1229984 (Arg48His) was genotyped using DNA samples from 1,359 consecutive autopsy cases registered in The Japanese Single Nucleotide Polymorphisms for Geriatric Research database. Medical and pathological record data from this database were used to categorise cases and controls. Results included 1,359 participants, 816 cases and 543 controls. Multinomial logistic regression analyses showed no significant association between rs1229984 presence and overall cancer risk in both dominant and recessive genetic inheritance models [Arg/Arg+Arg/His vs. His/His: Adjusted odds ratio (OR)=0.66 (95% CI=0.39-1.13; P=0.129), Arg/Arg vs. Arg/His+His/His: OR=0.95 (95% CI=0.75-1.20; P=0.657)]. However, results showed those homozygous for rs1229984 (genotype His/His) were at significantly decreased odds of lung cancer than other genotypes [recessive model: OR=0.64 (95% CI=0.44-0.93; P=0.020]. In conclusion, there was no significant association between rs1229984 and odds of overall or specific cancers except in lung cancer where His/His genotype decreased odds. To the best of our knowledge, the association between His/His and decreased odds of lung cancer is a novel finding. These findings require further validation in larger studies.

Clonal mosaicism (a detectable post-zygotic mutational event in cellular subpopulations) is common in cancer patients. Detected segments of clonal mosaicism are usually bundled into large-locus regions for statistical analysis. However, low-frequency genes are overlooked and are not sufficient to elucidate qualitative differences between cancer patients and non-patients. Therefore, it is of interest to develop and describe a tool named Sub-GOFA for Sub-Gene Ontology function analysis in clonal mosaicism using semantic similarity. Sub-GOFA measures the semantic (logical) similarity among patients using the sub-GO network structures of various sizes segmented from the gene ontology (GO) for clustering analysis. The sub-GO's root-terms with significant differences are extracted as disease-associated genetic functions. Sub-GOFA selected a high ratio of cancer-associated genes under validation with acceptable threshold.

Collagen type XVII α1 (COL17A1) encodes a hemidesmosomal protein at the epidermal-dermal junction and its variants are implicated in blistering skin diseases. Recent experiments in rodents revealed that Col17a1 has critical roles in stem cells of epidermal origin and in melanoma carcinogenesis. In the present study, it was investigated whether germline variants in COL17A1 are associated with skin cancer and other cancer types using indexed consecutive autopsy cases from the Japanese Geriatric Single Nucleotide Polymorphism database (n=2,343; mean age, 80 years). The database included 12 patients with skin cancer. A total of 53 COL17A1 missense variants on an exome chip were analyzed. One variant, p.Ser1029Ala (rs118166857), which had a minor allele frequency of 1.0%, exhibited a nominal positive sign of association with skin cancer [Fisher's exact P=0.002, odds ratio (OR)=16.93, 95% CI: 4.44-64.64]. This variant was detected in 2/2 patients with mucosal malignant melanoma (mMM) and 1/3 patients with extramammary Paget's disease, and in none of the patients with non-melanoma cancer, e.g., squamous cell and basal cell carcinoma. Other cancer types were searched in the database and the p.Ser1029Ala variant was indicated to be nominally associated with breast cancer (P=0.006, OR=4.17, 95% CI: 1.72-10.11). In the two mMM cases, targeted exome sequencing of 55 cancer-predisposing genes (including tumor protein 53, BRCA1/2 and mismatch repair genes) detected no apparent pathogenic variants, but revealed variants of unknown significance in axin 2, DNA directed polymerase ζ catalytic subunit and contactin 6. Since COL17A1 provides a niche for melanocyte stem cells, it was hypothesized that the p.Ser1029Ala variant in the COL17A1 ectodomain may affect the microenvironment, e.g., the cell competition. This is a working hypothesis generated from human autopsy cases and warrants further epidemiological and molecular biological validation.

Placenta-derived extracellular vesicles and their cargoes, especially microRNAs (EV-miRNAs), may contribute to fetal and placental development. During pregnancy, the levels of several maternal blood EV-miRNAs, including miRNAs of placental origin, vary among individuals and change throughout gestation. However, the effects of these miRNAs on fetal growth and trimester-specificity have not been fully elucidated. The purpose of this study is to test the hypothesis that the serum levels of two extracellular vesicles (EV)-miRNAs (miR-127-3p and miR-26b-5p), which may be involved in fetoplacental regulation, would be significantly associated with fetal growth in a trimester-specific manner. This is a single-center birth cohort of maternal serum samples obtained at both the second and third trimesters. To minimize the influence of confounding factors, the analysis was limited to singleton vaginal deliveries, resulting in 27 participants being included in this study. EV RNAs were isolated using a membrane affinity method, and the relative expression levels of miR-127-3p and miR-26b-5p were measured using the RT-qPCR method with miR-484 as control. The associations between the two EV-miRNAs and fetal and placental growth were evaluated using a linear regression model and compared between the two trimesters. EV-miR-127-3p levels tended to correlate inversely with the z-scores of birth weight for gestational age (BWGA) and placental weight for gestational age (PWGA) in the second trimester, but not in the third trimester. EV-miR-26b-5p levels were positively associated with birth weight in the second trimester, but this association was weakened in the third trimester. Our results suggest a trimester-specific association of circulating miRNA levels with fetal and placental growth. The precise roles of EV-miR-127-3p and EV-miR-26b-5p in fetal and placental development warrant further investigation.

The association between distress caused by tinnitus and psychological factors such as depression and anxiety has been examined and reported. However, prognostic factors remain poorly understood because there are only a few reports on genetic associations. We theorized there might be an association between the grade of tinnitus distress and the genetic background related to psychological factors which might lead us to identify prognostic markers. We enrolled 138 patients who had suffered from tinnitus for over 3 months. Using Tinnitus Handicap Inventory (THI) scores, we examined the association between tinnitus distress and a genetic background related to depression or anxiety. A significant association between single nucleotide polymorphism rs131702 of the Breakpoint Cluster Region (BCR) gene and the severe THI score was identified. In addition, there was an association with the severity of the State-Trait Anxiety Inventory, an index of state anxiety severity. No association was found with the Self-Rating Depression Scale, an index of depression severity. It is reported that rs131702 of BCR in Japanese patients are related to bipolar II depression characterized by fluctuation between abnormal mood states of mania and depression. Our results indicate that rs131702 of BCR is independent of depression in this study and is, therefore, a prognostic factor unique to tinnitus. We conclude that the severity of tinnitus is associated with genes related to depression.

An exome‑wide association study (EWAS) was performed to identify genetic variants, particularly low‑frequency or rare coding variants with a moderate to large effect size, that confer susceptibility to atrial fibrillation in Japanese. The EWAS for atrial fibrillation was performed with 13,166 subjects (884 patients with atrial fibrillation and 12,282 controls) using an Illumina HumanExome‑12 DNA Analysis BeadChip or Infinium Exome‑24 BeadChip arrays. The association of atrial fibrillation with allele frequencies of 41,243 single nucleotide polymorphisms (SNPs) that passed quality control was examined with Fisher's exact test. Based on Bonferroni's correction, a P

// Yoshiji Yamada 1, 2 , Jun Sakuma 2, 3, 4 , Ichiro Takeuchi 2, 4, 5 , Yoshiki Yasukochi 1, 2 , Kimihiko Kato 1, 6 , Mitsutoshi Oguri 1, 7 , Tetsuo Fujimaki 8 , Hideki Horibe 9 , Masaaki Muramatsu 10 , Motoji Sawabe 11 , Yoshinori Fujiwara 12 , Yu Taniguchi 12 , Shuichi Obuchi 13 , Hisashi Kawai 13 , Shoji Shinkai 14 , Seijiro Mori 15 , Tomio Arai 16 and Masashi Tanaka 17 1 Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Japan 2 CREST, Japan Science and Technology Agency, Kawaguchi, Japan 3 Computer Science Department, College of Information Science, University of Tsukuba, Tsukuba, Japan 4 RIKEN Center for Advanced Intelligence Project, Tokyo, Japan 5 Department of Computer Science, Nagoya Institute of Technology, Nagoya, Japan 6 Department of Internal Medicine, Meitoh Hospital, Nagoya, Japan 7 Department of Cardiology, Kasugai Municipal Hospital, Kasugai, Japan 8 Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Japan 9 Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi, Japan 10 Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan 11 Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan 12 Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 13 Research Team for Promoting Support System for Home Care, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 14 Research Team for Social Participation and Health Promotion, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 15 Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan 16 Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan 17 Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan Correspondence to: Yoshiji Yamada, email: yamada@gene.mie-u.ac.jp Keywords: diabetes mellitus, fasting plasma glucose, blood glycosylated hemoglobin, polymorphism, exome-wide association study Received: March 31, 2017 Accepted: June 09, 2017 Published: July 17, 2017 ABSTRACT We performed exome-wide association studies to identify single nucleotide polymorphisms that either influence fasting plasma glucose level or blood hemoglobin A 1c content or confer susceptibility to type 2 diabetes mellitus in Japanese. Exome-wide association studies were performed with the use of Illumina Human Exome-12 DNA Analysis or Infinium Exome-24 BeadChip arrays and with 11,729 or 8635 subjects for fasting plasma glucose level or blood hemoglobin A 1c content, respectively, or with 14,023 subjects for type 2 diabetes mellitus (3573 cases, 10,450 controls). The relation of genotypes of 41,265 polymorphisms to fasting plasma glucose level or blood hemoglobin A 1c content was examined by linear regression analysis. After Bonferroni’s correction, 41 and 17 polymorphisms were significantly ( P < 1.21 × 10 −6 ) associated with fasting plasma glucose level or blood hemoglobin A 1c content, respectively, with two polymorphisms (rs139421991, rs189305583) being associated with both. Examination of the relation of allele frequencies to type 2 diabetes mellitus with Fisher’s exact test revealed that 87 polymorphisms were significantly ( P < 1.21 × 10 −6 ) associated with type 2 diabetes mellitus. Subsequent multivariable logistic regression analysis with adjustment for age and sex showed that four polymorphisms (rs138313632, rs76974938, rs139012426, rs147317864) were significantly ( P < 1.44 × 10 −4 ) associated with type 2 diabetes mellitus, with rs138313632 and rs139012426 also being associated with fasting plasma glucose and rs76974938 with blood hemoglobin A 1c . Five polymorphisms—rs139421991 of CAT , rs189305583 of PDCL2 , rs138313632 of RUFY1 , rs139012426 of LOC100505549 , and rs76974938 of C21orf59 —may be novel determinants of type 2 diabetes mellitus.

// Yoshiji Yamada 1, 2 , Jun Sakuma 2, 3, 4 , Ichiro Takeuchi 2, 4, 5 , Yoshiki Yasukochi 1, 2 , Kimihiko Kato 1, 6 , Mitsutoshi Oguri 1, 7 , Tetsuo Fujimaki 8 , Hideki Horibe 9 , Masaaki Muramatsu 10 , Motoji Sawabe 11 , Yoshinori Fujiwara 12 , Yu Taniguchi 12 , Shuichi Obuchi 13 , Hisashi Kawai 13 , Shoji Shinkai 14 , Seijiro Mori 15 , Tomio Arai 16 and Masashi Tanaka 17 1 Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Japan 2 CREST, Japan Science and Technology Agency, Kawaguchi, Japan 3 Computer Science Department, College of Information Science, University of Tsukuba, Tsukuba, Japan 4 RIKEN Center for Advanced Intelligence Project, Tokyo, Japan 5 Department of Computer Science, Nagoya Institute of Technology, Nagoya, Japan 6 Department of Internal Medicine, Meitoh Hospital, Nagoya, Japan 7 Department of Cardiology, Kasugai Municipal Hospital, Kasugai, Japan 8 Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Japan 9 Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi, Japan 10 Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan 11 Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan 12 Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 13 Research Team for Promoting Support System for Home Care, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 14 Research Team for Social Participation and Health Promotion, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 15 Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan 16 Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan 17 Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan Correspondence to: Yoshiji Yamada, email: yamada@gene.mie-u.ac.jp Keywords: hypertension, blood pressure, genetics, exome-wide association study, polymorphism Received: March 19, 2017 Accepted: April 05, 2017 Published: April 27, 2017 ABSTRACT We performed exome-wide association studies to identify genetic variants that influence systolic or diastolic blood pressure or confer susceptibility to hypertension in Japanese. The exome-wide association studies were performed with the use of Illumina HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays and with 14,678 subjects, including 8215 individuals with hypertension and 6463 controls. The relation of genotypes of 41,843 single nucleotide polymorphisms to systolic or diastolic blood pressure was examined by linear regression analysis. After Bonferroni’s correction, 44 and eight polymorphisms were significantly ( P < 1.19 × 10 –6 ) associated with systolic or diastolic blood pressure, respectively, with six polymorphisms (rs12229654, rs671, rs11066015, rs2074356, rs3782886, rs11066280) being associated with both systolic and diastolic blood pressure. Examination of the relation of allele frequencies to hypertension with Fisher’s exact test revealed that 100 of the 41,843 single nucleotide polymorphisms were significantly ( P < 1.19 × 10 –6 ) associated with hypertension. Subsequent multivariable logistic regression analysis with adjustment for age and sex showed that five polymorphisms (rs150854849, rs202069030, rs139012426, rs12229654, rs76974938) were significantly ( P < 1.25 × 10 –4 ) associated with hypertension. The polymorphism rs12229654 was thus associated with both systolic and diastolic blood pressure and with hypertension. Six polymorphisms (rs12229654 at 12q24.1, rs671 of ALDH2 , rs11066015 of ACAD10 , rs2074356 and rs11066280 of HECTD4 , and rs3782886 of BRAP ) were found to be associated with both systolic and diastolic blood pressure, with those at 12q24.1 or in ACAD10 or BRAP being novel determinants of blood pressure in Japanese.

In this study, we performed exome-wide association studies (EWASs) to identify genetic variants that confer susceptibility to ischemic stroke, intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH). EWAS for ischemic stroke was performed using 1,575 patients with this condition and 9,210 controls, and EWASs for ICH and SAH were performed using 673 patients with ICH, 265 patients with SAH and 9,158 controls. Analyses were performed with Illumina HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The relation of allele frequencies for 41,339 or 41,332 single nucleotide polymorphisms (SNPs) that passed quality control to ischemic or hemorrhagic stroke, respectively, was examined with Fisher's exact test. Based on Bonferroni's correction, a P-value of

// Yoshiji Yamada 1, 2 , Jun Sakuma 2, 3, 4 , Ichiro Takeuchi 2, 4, 5 , Yoshiki Yasukochi 1, 2 , Kimihiko Kato 1, 6 , Mitsutoshi Oguri 1, 7 , Tetsuo Fujimaki 8 , Hideki Horibe 9 , Masaaki Muramatsu 10 , Motoji Sawabe 11 , Yoshinori Fujiwara 12 , Yu Taniguchi 12 , Shuichi Obuchi 13 , Hisashi Kawai 13 , Shoji Shinkai 14 , Seijiro Mori 15 , Tomio Arai 16 and Masashi Tanaka 17 1 Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Japan 2 CREST, Japan Science and Technology Agency, Kawaguchi, Japan 3 Computer Science Department, College of Information Science, University of Tsukuba, Tsukuba, Japan 4 RIKEN Center for Advanced Intelligence Project, Tokyo, Japan 5 Department of Computer Science, Nagoya Institute of Technology, Nagoya, Japan 6 Department of Internal Medicine, Meitoh Hospital, Nagoya, Japan 7 Department of Cardiology, Kasugai Municipal Hospital, Kasugai, Japan 8 Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Japan 9 Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi, Japan 10 Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan 11 Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan 12 Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 13 Research Team for Promoting Support System for Home Care, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 14 Research Team for Social Participation and Health Promotion, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 15 Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan 16 Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan 17 Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan Correspondence to: Yoshiji Yamada, email: yamada@gene.mie-u.ac.jp Keywords: myocardial infarction, coronary artery disease, genetics, polymorphism, exome-wide association study Received: January 27, 2017 Accepted: March 02, 2017 Published: March 23, 2017 ABSTRACT We performed exome-wide association studies to identify genetic variants—in particular, low-frequency variants with a large effect size—that confer susceptibility to coronary artery disease or myocardial infarction in Japanese. The exome-wide association studies were performed with 12,698 individuals (3488 subjects with coronary artery disease including 2438 with myocardial infarction, 9210 controls) and with the use of the Illumina HumanExome-12 DNA Analysis or Infinium Exome-24 BeadChip. The relation of allele frequencies for 41,339 single nucleotide polymorphisms that passed quality control to coronary artery disease or myocardial infarction was examined with Fisher’s exact test. The exome-wide association study for coronary artery disease revealed that 126 single nucleotide polymorphisms were significantly ( P

// Yoshiji Yamada 1, 2 , Jun Sakuma 2, 3, 4 , Ichiro Takeuchi 2, 4, 5 , Yoshiki Yasukochi 1, 2 , Kimihiko Kato 1, 6 , Mitsutoshi Oguri 1, 7 , Tetsuo Fujimaki 8 , Hideki Horibe 9 , Masaaki Muramatsu 10 , Motoji Sawabe 11 , Yoshinori Fujiwara 12 , Yu Taniguchi 12 , Shuichi Obuchi 13 , Hisashi Kawai 13 , Shoji Shinkai 14 , Seijiro Mori 15 , Tomio Arai 16 and Masashi Tanaka 17 1 Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Japan 2 CREST, Japan Science and Technology Agency, Kawaguchi, Japan 3 Computer Science Department, College of Information Science, University of Tsukuba, Tsukuba, Japan 4 RIKEN Center for Advanced Intelligence Project, Tokyo, Japan 5 Department of Computer Science, Nagoya Institute of Technology, Nagoya, Japan 6 Department of Internal Medicine, Meitoh Hospital, Nagoya, Japan 7 Department of Cardiology, Kasugai Municipal Hospital, Kasugai, Japan 8 Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Japan 9 Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi, Japan 10 Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan 11 Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan 12 Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 13 Research Team for Promoting Support System for Home Care, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 14 Research Team for Social Participation and Health Promotion, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 15 Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan 16 Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan 17 Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan Correspondence to: Yoshiji Yamada, email: yamada@gene.mie-u.ac.jp Keywords: body mass index, obesity, metabolic syndrome, genetics, exome-wide association study Received: February 15, 2017 Accepted: March 14, 2017 Published: April 07, 2017 ABSTRACT We have performed exome-wide association studies to identify genetic variants that influence body mass index or confer susceptibility to obesity or metabolic syndrome in Japanese. The exome-wide association study for body mass index included 12,890 subjects, and those for obesity and metabolic syndrome included 12,968 subjects (3954 individuals with obesity, 9014 controls) and 6817 subjects (3998 individuals with MetS, 2819 controls), respectively. Exome-wide association studies were performed with Illumina HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The relation of genotypes of single nucleotide polymorphisms to body mass index was examined by linear regression analysis, and that of allele frequencies of single nucleotide polymorphisms to obesity or metabolic syndrome was evaluated with Fisher’s exact test. The exome-wide association studies identified six, 11, and 40 single nucleotide polymorphisms as being significantly associated with body mass index, obesity ( P

// Yoshiji Yamada 1, 2 , Jun Sakuma 2, 3, 4 , Ichiro Takeuchi 2, 4, 5 , Yoshiki Yasukochi 1, 2 , Kimihiko Kato 1, 6 , Mitsutoshi Oguri 1, 7 , Tetsuo Fujimaki 8 , Hideki Horibe 9 , Masaaki Muramatsu 10 , Motoji Sawabe 11 , Yoshinori Fujiwara 12 , Yu Taniguchi 12 , Shuichi Obuchi 13 , Hisashi Kawai 13 , Shoji Shinkai 14 , Seijiro Mori 15 , Tomio Arai 16 and Masashi Tanaka 17 1 Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Japan 2 CREST, Japan Science and Technology Agency, Kawaguchi, Japan 3 Computer Science Department, College of Information Science, University of Tsukuba, Tsukuba, Japan 4 RIKEN Center for Advanced Intelligence Project, Tokyo, Japan 5 Department of Computer Science, Nagoya Institute of Technology, Nagoya, Japan 6 Department of Internal Medicine, Meitoh Hospital, Nagoya, Japan 7 Department of Cardiology, Kasugai Municipal Hospital, Kasugai, Japan 8 Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Japan 9 Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi, Japan 10 Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan 11 Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan 12 Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 13 Research Team for Promoting Support System for Home Care, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 14 Research Team for Social Participation and Health Promotion, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 15 Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan 16 Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan 17 Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan Correspondence to: Yoshiji Yamada, email: yamada@gene.mie-u.ac.jp Keywords: chronic kidney disease, hyperuricemia, glomerular filtration rate, serum uric acid, exome-wide association study Received: February 12, 2017 Accepted: March 08, 2017 Published: March 30, 2017 ABSTRACT We have performed exome-wide association studies to identify genetic variants that influence renal function-related traits or confer susceptibility to chronic kidney disease or hyperuricemia in Japanese. Exome-wide association studies for estimated glomerular filtration rate and the serum concentration of creatinine were performed with 12,565 individuals, that for the serum concentration of uric acid with 9934 individuals, and those for chronic kidney disease or hyperuricemia with 5161 individuals (3270 cases, 1891 controls) or 11,686 individuals (2045 cases, 9641 controls), respectively. The relation of genotypes of single nucleotide polymorphisms to estimated glomerular filtration rate or the serum concentrations of creatinine or uric acid was examined by linear regression analysis, and that of allele frequencies of single nucleotide polymorphisms to chronic kidney disease or hyperuricemia was examined with Fisher’s exact test. The exome-wide association studies revealed that 25, seven, and six single nucleotide polymorphisms were significantly ( P

We performed an exome-wide association study (EWAS) to identify genetic variants - in particular, low‑frequency or rare variants with a moderate to large effect size - that confer susceptibility to aortic aneurysm with 8,782 Japanese subjects (456 patients with aortic aneurysm, 8,326 control individuals) and with the use of Illumina HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The correlation of allele frequencies for 41,432 single nucleotide polymorphisms (SNPs) that passed quality control to aortic aneurysm was examined with Fisher's exact test. Based on Bonferroni's correction, a P-value of

Background CYP2A6 is an enzyme involved in oxidation of a number of environmental chemicals, including nicotine, pro-carcinogenic nitrosamines and polycyclic aromatic hydrocarbons (PAHs). The whole gene deletion of CYP2A6 (CYP2A6*4) is prevalent in East Asian population. Whether or not CYP2A6*4 associates with cancer is still controversial. Methods We undertook an association study to determine whether deletion of CYP2A6 gene associates with total cancer and major cancer types employing data of consecutive autopsy cases registered in the Japanese single-nucleotide polymorphisms for geriatric research (JG-SNP) database. The presence of cancer were inspected at the time of autopsy and pathologically confirmed. Genotyping for CYP2A6 wild type (W) and deletion (D) was done by allele specific RT-PCR method. Results Among 1373 subjects, 826 subjects (60.2%) were cancer positive and 547 subjects (39.8%) were cancer negative. The genotype frequency in the whole study group for WW, WD and DD were 65.0, 30.6 and 4.4%, respectively, which obeyed the Hardy-Weinberg equilibrium (p = 0.20). Total cancer presence, as well as major cancers including gastric, lung, colorectal, and blood cancers did not show any positive association with CYP2A6 deletion. When male and female were separately analyzed, CYP2A6 deletion associated with decreased gastric cancer risk in female (OR = 0.49, 95%CI: 0.25–0.95, p = 0.021, after adjustment for age, smoking and drinking). When smoker and non-smoker were separately analyzed, CYP2A6 deletion associated with decreased total cancer in female nonsmokers (OR = 0.67, 95%CI: 0.45–0.99, p = 0.041 after adjustment). On the other hand, CYP2A6 deletion associated increase blood cancers in smokers (OR = 2.05, 95%CI: 1.19–3.53, p = 0.01 after adjustment). Conclusion The CYP2A6 deletion may not grossly affect total cancer. It may associate with individual cancers in sex and smoking dependent manner. Further studies with larger sample size are warranted to confirm our results.

The HOTAIR gene encodes a long noncoding RNA (lncRNA), which functions in development and tumorigenesis. A single nucleotide polymorphism (SNP) rs920778 in the HOTAIR gene, has been recurrently studied for susceptibility to many cancers including oesophageal cancer, gastric cancer, lung cancer, and hepatocellular carcinoma. Most of these studies were conducted in Chinese populations, and a few in Turkish, Iranian, and Portuguese populations. They mostly give rise to controversial results. It still remains largely unknown whether the cancer risk is conferred in a Japanese population. Here, we established an association study on the representative SNP rs920778, to examine its contribution to the presence of cancer in consecutive autopsy cases in the JG-SNP database. A total of 1373 subjects (mean age 80) including 827 cancer positive and 546 cancer negative subjects were analyzed. As a result, the occurrence of overall cancer was not associated with the rs920778 polymorphism (p > 0.05). For each cancer type, we did not find association except for lung cancer (p = 0.04) which was more likely a by-chance association after multiple testing. Our findings imply that rs920778 polymorphism does not affect total cancer presence and the effect on specific cancer types is also weak in the Japanese population.

Mid-to-late gestation is a unique period in which women experience dynamic changes in lipid metabolism. Although the recent intensive epigenome-wide association studies (EWAS) using peripheral leukocytes have revealed that lipid-related traits alter DNA methylation, the influence of pregnancy-induced metabolic changes on the methylation levels of these differentially methylated sites is not well known. In this study, we performed a prospective cohort study of pregnant women (n = 52) using the MassARRAY EpiTYPER assay and analyzed the methylation levels of variably methylated sites, including CPT1A intron 1 and SREBF1 intron 1 CpGs, which were previously verified to be robustly associated with adiposity traits. Although methylation of SREBF1 was associated with body mass index (BMI) and low-density lipoprotein cholesterol at mid-gestation, this association was attenuated at late gestation, which was consistent with the metabolic switch from an anabolic to a catabolic state. However, the BMI association with CPT1A intron 1 methylation appeared to strengthen at late gestation, this association was mediated by pre-pregnancy BMI-dependent change in the leukocyte proportion during mid-to-late gestation. Thus, the methylation of adiposity-related differentially methylated regions was sensitive to metabolic and immunological changes during mid-to-late gestation.

Cardiometabolic diseases are characterized as a combination of multiple risk factors for cardiovascular disease (CVD) and metabolic diseases including diabetes mellitus, dyslipidemia, hypertension and abdominal obesity. This cluster of abnormalities individually and interdependently leads to atherosclerosis and CVD morbidity and mortality. In the past decade, genome-wide association studies (GWASs) have identified a series of cardiometabolic disease-associated variants that can collectively explain a small proportion of the variability. Intriguingly, the susceptibility variants imputed from GWASs usually do not reside in the coding regions, suggesting a crucial role of the noncoding elements of the genome. In recent years, emerging evidence suggests that noncoding RNA (ncRNA) is functional for physiology and pathophysiology of human diseases. These include microRNAs and long noncoding RNAs (lncRNAs) that are now implicated in human diseases. The ncRNAs can interact with each other and with proteins, to interfere gene expressions, leading to the development of many human disorders. Although evidence suggests the functional role of lncRNAs in cardiometabolic traits, the molecular mechanisms of gene regulation underlying cardiometabolic diseases remain to be better defined. Here, we summarize the recent discoveries of lncRNA variations in the context of cardiometabolic diseases.

A genetic risk score (GRS) was developed for predicting fracture risk based on lifetime prevalence of femoral fractures in 924 consecutive autopsies of Japanese males. A total of 922 non-synonymous single nucleotide polymorphisms (SNPs) located in 62 osteoporosis susceptibility genes were genotyped and evaluated for their association with the prevalence of femoral fracture in autopsy cases. GRS values were calculated as the sum of risk allele counts (unweighted GRS) or the sum of weighted scores estimated from logistic regression coefficients (weighted GRS). Five SNPs (α-ʟ-iduronidase rs3755955, C7orf58 rs190543052, homeobox C4 rs75256744, G patch domain-containing gene 1 rs2287679, and Werner syndrome rs2230009) showed a significant association (P

Single nucleotide polymorphisms (SNPs) related with metabolic syndrome may influence cancer. Our study aimed to replicate association studies of 30 selected polymorphisms pertaining to 21 genes and cancer phenotypes in Japanese elderly population. All polymorphisms were determined by genotyping on the samples collected from 1503 consecutive autopsy cases registered in the Japanese SNPs for geriatric research (JGSNP) data base. Current study consisted of 807 (54%) males and 696 (46%) females with a mean age of 80.3 ± 8.9 years. Number of males with cancer was 520 (57%) and females 398 (43%) in total of 918 (61%) cancer present cases and 585 (39%) controls without cancer. Our pathological cancer phenotypes consisted of gastric cancer (n=178), lung cancer (n=163), colorectal (n=137) and others. Our results indicated that rs1800470 (P10L) located TGFβI gene has significant association with overall cancer (CT: CC adjusted odds ratio (OR) 95% confidence interval (95% CI)=1.386 (1.017 – 1.888), p=0.007, TT: CC adjusted OR (95% CI)=1.438 (1.106 – 1.870), p=0.039, CT + TT: CC, adjusted OR (95% CI)=1.421 (1.111 – 1.816), p=0.005), and also with lung cancer ( CT + TT: CC adjusted OR (95% CI)=1.562 (1.024 – 2.383), p=0.039) in all subjects. We also found rs2243250 located in IL4 gene is associated with elevated risk of acute leukemia (TT + CT: CC adjusted OR (95% CI)=2.286 (1.243 – 4.206), p = 0.008). Furthermore, rs2077647 on ESRI gene was associated with decreased risk of acute leukemia (GG + AG: AA, adjusted OR (95% CI)=0.516 (0.319 – 0.835), p=0.007). We found that rs1800470, rs2243250 and rs2077647 polymorphisms may influence cancer in Japanese elderly population. Our study warrants further confirmations with larger samples.

Werner syndrome is a rare autosomal recessive disorder caused by mutations in the human WRN gene and characterized by the early onset of normal aging symptoms. Given that patients with this disease exhibit osteoporosis, the present study aimed to determine whether the WRN gene contributes to the etiology of osteoporosis. A genetic association study of eight non-synonymous polymorphisms in the WRN gene and the incidence of femoral fracture was undertaken in 1,632 consecutive Japanese autopsies in which 140 patients had experienced the fracture during their lifetime. The results were validated in 251 unrelated postmenopausal Japanese women with osteoporosis and 269 non-institutionalized, community-dwelling Japanese adults. A statistically significant association was observed between rs2230009 (c.340G > A)—which results in a Val to Ile substitution—and fracture risk; the incidence of femoral fracture increased dose-dependently with the number of A alleles (p = 0.0120). Femoral neck bone and whole bone densities were lower among postmenopausal women with osteoporosis and community-dwelling adults, respectively, if they were of the AG instead of the GG genotype. The results suggest that Japanese subjects bearing at least one A allele of rs2230009 of the WRN gene are at a significantly higher risk of femoral fracture, possibly due to decreased bone density.

Maternal low-protein (MLP) diet can lead to hepatic steatosis, which only develops with ageing. It is still unclear whether the young offspring show any signs of past exposure to prenatal adverse conditions. We hypothesized that early nutritional insult would first affect the dynamic responsiveness to nutritional challenges rather than the static state. We analyzed the transcriptome and metabolome profiles of the hepatic response to fasting/refeeding in young male mice offspring to identify changes induced by early gestational MLP diet. Restricted MLP exposure strictly to early gestation was achieved by the embryo transfer method. As a result, the fasting-induced upregulation of genes related to long-chain fatty acid metabolism and of stress response genes related to protein folding were significantly diminished in MLP pups. Lipid profiling after fasting showed that the hepatic signature of triacylglycerols was shifted to longer acyl-chains and higher saturation by the MLP diet. Bioinformatic analyses suggested that these phenomenological changes may be partially linked to the peroxisome proliferator activated receptor α (PPARα) pathway. Taken together, early gestational MLP diet affected the hepatic dynamic response to nutritional stress in seemingly healthy young offspring, accompanied with partial deterioration of PPARα action.

Background/aim Alpha-kinase 2 (ALPK2), suggested to be a novel tumour-suppressor gene down-regulated by oncogenic KRAS, plays a pivotal role in luminal apoptosis in normal colonic crypts. The aim of this study was to determine the association between ALPK2 germline variants and colorectal cancer. Materials and methods Missense single nucleotide variants in the exons of the ALPK2 gene in 2,343 consecutive autopsy cases (1,446 cases with cancer and 897 cases without cancer) were screened using HumanExome BeadChip arrays. To address the functional effect of a missense ALPK2 variant, a 3D floating cell culture was performed using HCT116-derived human colorectal cancer cells stably expressing wild-type (wt) ALPK2 (HCT116-wtALPK2) or amino acid-substituted (sub) ALPK2 (HCT116-subALPK2). Results We identified that one of the ALPK2 germline variants, rs55674018 (p.Q1853E), was significantly associated with the presence of cancer (adjusted odds ratio(OR)=4.39; 95% confidence interval(CI)=1.31-14.78, p=0.001). The p.Q1853E variant was present in the East Asian population and located in the immunoglobulin-like domain. Notably, the basolateral polarity of actin in the surface of HCT116-wtALPK2 spheroids was more attenuated compared to that of HCT116-subALPK2 spheroids. Furthermore, luminal apoptosis and cell aggregation were promoted by wtALPK2, but not by subALPK2 in 3D culture. Conclusion The p.Q1853E variant of ALPK2, which had been accumulating in the Japanese population, induced a metastatic phenotype by disrupting ALPK2 function.

Growth hormone (GH)/insulin-like growth factor-1 (IGF-1)/insulin signaling is one of the most plausible biological pathways regulating aging and longevity. Previous studies have demonstrated that several single nucleotide polymorphisms (SNPs) in the GH/IGF-1/insulin signaling-associated genes influence both longevity and adult height, suggesting the possibility of a shared genetic architecture between longevity and height. We therefore examined the relationship between 30 height-associated SNPs and extreme longevity in a Japanese population consisting of 428 centenarians and 4,026 younger controls. We confirmed that height-increasing genetic scores (HGSs) constructed based on 30 SNPs were significantly associated with height in the controls (p = 6.95 × 10-23). HGS was significantly and inversely associated with extreme longevity in women (p = .011), but not in men, although no SNPs were significantly associated with extreme longevity after Bonferroni correction. The odds ratio for extreme longevity in the lowest HGS group (≤27) and the second lowest HGS group (28-30) relative to the highest HGS group (≥37) was 1.71 (p = .056) and 1.69 (p = .034), respectively, for women. In conclusion, the present study demonstrated an inverse association between height-increasing alleles with extreme longevity in Japanese women, providing novel insight into the genetic architecture of longevity and aging.

Background Abdominal aortic aneurysm (AAA) is a multifactorial disease with strong genetic components. Various genetic loci have been associated with clinical AAA, but few studies have investigated pathological AAA, an intermediate phenotype of the disease. Methods We examined 2263 consecutive autopsies of older Japanese subjects from a study on geriatric diseases in Japanese individuals (The JG-SNP study). The presence of AAA was determined with a pathological diagnosis during autopsy. Single nucleotide variants (SNVs) associated with AAA were determined with an Illumina HumanExome Beadchip array. Logistic regression analyses were performed to determine genetic associations. Age, gender, and other risk factors of AAA were analyzed as covariates. Results 118 subjects with AAA and 2145 subjects without AAA were analyzed in a case-control setting. No variants reached significance after applying the Bonferroni correction (P < 2.05×10−6). The strongest associations were found with rs3750092 (p.E321G, OR: 0.36, 95% CI: 0.24–0.56, P = 6.09 × 10−6), a variant in the WAS/WASL interacting protein family 3 (WIPF3), and with rs1051338 (p.T16P, OR: 2.50, 95% CI: 1.70–3.66, P = 2.79 × 10−6) and rs2246942 (intronic, OR: 2.32, 95% CI: 1.58–3.41, P = 1.61 × 10−5), variants in the lysosomal acid lipase A (LIPA). LIPA is essential for macrophage cholesterol metabolism. Immunohistological analyses of WIPF3 protein in AAA samples from three subjects revealed that WIPF3 was expressed in macrophages of atheromatous plaques. Conclusions This study suggests that WIPF3 and LIPA, both of which are expressed in the macrophages are involved in pathological AAA. These results should be regarded as hypothesis-generating; thus, replication study is warranted.

// Yoshiji Yamada 1, 2 , Jun Sakuma 2, 3, 4 , Ichiro Takeuchi 2, 4, 5 , Yoshiki Yasukochi 1, 2 , Kimihiko Kato 1, 6 , Mitsutoshi Oguri 1, 7 , Tetsuo Fujimaki 8 , Hideki Horibe 9 , Masaaki Muramatsu 10 , Motoji Sawabe 11 , Yoshinori Fujiwara 12 , Yu Taniguchi 12 , Shuichi Obuchi 13 , Hisashi Kawai 13 , Shoji Shinkai 14 , Seijiro Mori 15 , Tomio Arai 16 , Masashi Tanaka 17 1 Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Japan 2 CREST, Japan Science and Technology Agency, Kawaguchi, Japan 3 Computer Science Department, College of Information Science, University of Tsukuba, Tsukuba, Japan 4 RIKEN Center for Advanced Intelligence Project, Tokyo, Japan 5 Department of Computer Science, Nagoya Institute of Technology, Nagoya, Japan 6 Department of Internal Medicine, Meitoh Hospital, Nagoya, Japan 7 Department of Cardiology, Kasugai Municipal Hospital, Kasugai, Japan 8 Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Japan 9 Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi, Japan 10 Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan 11 Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan 12 Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 13 Research Team for Promoting Support System for Home Care, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 14 Research Team for Social Participation and Health Promotion, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 15 Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan 16 Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan 17 Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan Correspondence to: Yoshiji Yamada, email: yamada@gene.mie-u.ac.jp Keywords: triglyceride, HDL-cholesterol, LDL-cholesterol, dyslipidemia, exome-wide association study Received: March 03, 2017 Accepted: April 04, 2017 Published: April 17, 2017 ABSTRACT We have performed exome-wide association studies to identify single nucleotide polymorphisms that influence serum concentrations of triglycerides, high density lipoprotein (HDL)–cholesterol, or low density lipoprotein (LDL)–cholesterol or confer susceptibility to hypertriglyceridemia, hypo–HDL-cholesterolemia, or hyper–LDL-cholesterolemia in Japanese. Exome-wide association studies for serum triglycerides (13,414 subjects), HDL-cholesterol (14,119 subjects), LDL-cholesterol (13,577 subjects), hypertriglyceridemia (4742 cases, 8672 controls), hypo–HDL-cholesterolemia (2646 cases, 11,473 controls), and hyper–LDL-cholesterolemia (4489 cases, 9088 controls) were performed with HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. Twenty-four, 69, or 32 loci were significantly ( P < 1.21 × 10 –6 ) associated with serum triglycerides, HDL-cholesterol, or LDL-cholesterol, respectively, with 13, 16, or 9 of these loci having previously been associated with triglyceride-, HDL-cholesterol–, or LDL-cholesterol–related traits, respectively. Two single nucleotide polymorphisms (rs10790162, rs7350481) were significantly related to both serum triglycerides and hypertriglyceridemia; three polymorphisms (rs146515657, rs147317864, rs12229654) were significantly related to both serum HDL-cholesterol and hypo–HDL-cholesterolemia; and six polymorphisms (rs2853969, rs7771335, rs2071653, rs2269704, rs2269703, rs2269702) were significantly related to both serum LDL-cholesterol and hyper–LDL-cholesterolemia. Among polymorphisms identified in the present study, two polymorphisms (rs146515657, rs147317864) may be novel determinants of hypo–HDL-cholesterolemia, and six polymorphisms (rs2853969, rs7771335, rs2071653, rs2269704, rs2269703, rs2269702) may be new determinants of hyper–LDL-cholesterolemia. In addition, 12, 61, 23, or 3 polymorphisms may be new determinants of the serum triglyceride, HDL-cholesterol, or LDL-cholesterol concentrations or of hyper–LDL-cholesterolemia, respectively.

Background ATP10D belongs to a subfamily of P-type ATPases implicated in phospholipids translocation from the exoplasmic to the cytoplasmic leaflet of cellular biological membrane. Previous genome-wide association study (GWAS) identified that a variant in Atp10d gene (rs2351791) associates with serum lipid profile and myocardial infarction. The objective of this study is to assess the effect of this variant on atherosclerosis in Japanese elderly population. Method Consecutive autopsy cases registered in JG-SNP study were recruited (n = 1536). The samples were pathologically assessed for atherosclerosis using macroscopic examination of the formalin-fixed arteries, and coronary stenotic index (CSI), intracranial atherosclerotic index (ICAI) and pathological atherosclerotic index (PAI), which represent systemic arteries were calculated. The variant rs2351791 (G/T) in Atp10d gene was genotyped by Taqman genotyping assay and association determined. Result Both CSI and ICAI were significantly higher in GG genotype than GT genotype and TT genotype (p = 0.003 and p = 0.001, respectively). Both associations remained significant in minor allele dominant model after adjusting for age, hypertension, diabetes, HDL, smoking and drinking (p = 0.001 and p = 0.001, respectively). PAI was not associated with this variant. Consistent with the previous report, plasma HDL cholesterol level was lower in GG genotype compared to GT + TT genotypes (p = 0.001). Conclusion The rs2351791 SNP in the Atp10d gene affects the susceptibility for cardiac and intracranial vascular stenosis in the elderly Japanese population.

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.

Background: Macrophage capping protein (CAPG), an actin filament end-capping protein, plays an important role in regulation of cellular motility and structural rearrangement within cells and has been implicated with development of various types of cancer. Recent study demonstrated that a CAPG variant was associated with a rare fallopian tube tumor, albeit with a small sample size. The present study aimed to determine the association of CAPG variants with cancer susceptibility. Methods: Four non-synonymous single nucleotide variations (NSVs), rs2229668 (p.V41I), rs117284777 (p.K227R), rs200233412 (p.A229T) and rs6886 (p.R335H), in CAPG were retrieved from genotyping, by an exome-chip, in 2,317 consecutive autopsy cases (1,284 men and 1,033 women, mean age 80.7 years), in which the presence or absence of cancer was verified pathologically. The association of CAPG variants with presence of cancer and with different types of cancer was determined. Interaction with smoking was also determined. Results: There were 1,446 cancer-bearing and 897 cancer-free subjects. Among four SNVs, only p.R335H (c.1004C>T) was associated with the presence of cancer (adjusted OR=1.49, 95% CI=1.23-1.81, P=5.08 × 10-5). The association was found in men (adjusted OR=1.64, 95% CI=1.26-2.14, P=2.25 × 10-4), but not in women. Investigation with different types of cancer revealed that gastric cancer showed a positive association (adjusted OR=1.61, 95% CI=1.16-2.24, P=0.005) in men. The effect size of CAPG variants showed no difference between smokers and nonsmokers. Conclusions: Our study suggests that a non-synonymous SNV of CAPG, p.R335H, affects cancer susceptibility in men without interaction with smoking habit and that the SNV is associated with gastric cancer in men.

A growing body of evidence shows that the presence of single nucleotide polymorphisms (SNPs) influences individual predisposition to pancreatic cancer. In the present study, we comparatively analyzed serially autopsied, elderly Japanese patients (n = 2,205) with pancreatic intraepithelial neoplasias (PanINs) and pancreatic ductal adenocarcinomas (PDACs) on the basis of their pancreatic lesions, clinical information, and SNPs. The incidence of PanIN-1, -2, -3, and PDACs in these patients was 55%, 12%, 1.4%, and 2.4%, respectively. The occurrence of PanINs was associated with female sex, increasing age, and lower body mass index. We did not identify any common SNPs between PanINs and PDACs. There were no common SNPs associated with PanINs and PDACs between men and women. In previously reported pancreatic cancer-associated SNPs, rs3790844 (NR5A2) showed a significant correlation with PDAC in our cohort. Six SNPs (rs7016880, rs10096633, rs10503669, rs12678919, rs17482753, rs328) that were correlated with blood lipid levels were associated with the risk for PDACs. Our data suggest that different clinicopathological characteristics and predispositions may affect pancreatic carcinogenesis in elderly Japanese patients. This article is protected by copyright. All rights reserved.

Aim We aimed to study a single nucleotide polymorphism (SNP), rs2106261, in the transcription factor gene, ZFHX3 , in atrial fibrillation (AF) and other related phenotypes by phenome scanning in a Japanese population. Method We retrieved consecutive autopsy data ( n = 2433, mean age = 80 years) from the Japanese SNP database for geriatric diseases (JG-SNP). Clinical data, including an AF diagnosis, were collected from medical charts. Genotyping was performed with the DNA chip method. We also analyzed 42 pathological and 26 clinical phenotypes, including cerebral infarctions (CIs) and lung thromboembolisms (LTs), diagnosed by macroscopic inspection during the autopsy. Result Among the 2433 patients with available data, 18.6% had AF, 29.4% had CI, and 4.9% had LT phenotypes. The A allele of the rs2106261 SNP was significantly associated with AF, after adjusting for age, sex, diabetes, hypertension, and smoking (AA + AG/GG, OR = 1.51, 95%CI: 1.16–1.97, p = 0.002). In the entire cohort, CI was not associated with rs2106261 ( p = 0.14). However, among patients under 80 years old, rs2106261 was significantly associated with CI (AA + AG/GG, OR = 1.57, 95%CI: 1.09–2.26, p = 0.01). LT was also associated with rs2106261 (AA + AG/GG, OR = 1.99, 95%CI: 1.31–3.01, p = 0.001). Associations between rs2106261 and CI and LT remained positive after adjusting for the presence of AF, which indicated that this SNP variant might serve as an independent risk marker. Conclusion We showed that the ZFHX3 polymorphism, rs2106261 (A allele), was a risk marker for AF and AF-related phenotypes. The roles of this variant in the development of AF and its related phenotypes warrant further investigation.

GLUT4 is a major mediator of glucose removal from the circulation and a key regulator of whole-body glucose homeostasis. Recent studies in south Indian populations revealed that haplotypes of the GLUT4 gene associated with type 2 diabetes. A total of 734 middle aged apparently healthy Japanese men were recruited from two separate occupational cohorts from Kanagawa and Kyoto. Participants were genotyped for GLUT4 variants, rs5418 (A/G) and rs2654185 (C/A), and association with HbA1c level was analyzed. The HbA1c value was determined by JDS method which is 0.4% lower than NGSP value. The G allele carrier of rs5418 and A allele carrier of rs2654185 associated with significantly higher HbA1c level (AG + GG vs. AA carriers; 5.2 ± 0.8 vs. 4.9 ± 0.4, P < 0.002, and AA + AC vs. CC; 5.2 ± 0.9, vs. 4.9 ± 0.4, P < 0.002, respectively). G allele, AG + GG genotype of rs5418 and A allele, AA + AC genotype of rs2654185 showed a significant association with higher HbA1c (β = 0.215, P = 0.026; β = 0.215, P = 0.026; β = 0.190, P = 0.042; β = 0.190, P = 0.042, respectively). These two SNPs are in high linkage disequilibrium (LD) of r(2) = 0.67. In haplotype analysis, four haplotypes were estimated. HbA1c is significantly higher in the most frequent GA haplotype compared with the second frequent AC haplotype (5.2% vs. 5.1%, P = 0.004). Genetic variations, rs5418 and rs2654185 in GLUT4 gene are associated with HbA1c level in Japanese men.

Aim: Atherosclerotic disease is a major health problem among the elderly, which arises from a complex interaction between genetic and environmental factors. The catechol-O-methyltransferase (COMT) gene encodes an enzyme that degrades catecholamines and estrogens to less active metabolites. The objective of this study was to examine whether polymorphisms of the COMT gene affected the severity of atherosclerotic disease in a Japanese elderly population.Method: A total of 1536 autopsy cases of hospital deaths were assessed for the degree of pathological atherosclerotic index (PAI), coronary stenotic index (CSI) and intracranial stenotic index (ICAI), which were obtained by macroscopic examination of the luminal surface of formalin-fixed arteries. Two single nucleotide polymorphisms (SNPs) in the COMT gene, rs4633 (C/T) and rs4680 (G/A) were genotyped. The rs4680 (G/A) corresponds to a functional SNP with the substitution of valine to methionine.Result: The CC genotype of rs4633 (C/T) and the GG genotype of rs4680 (G/A) showed a significantly higher degree of PAI and the association remained positive after adjustment for age, hypertension, diabetes, smoking and drinking (p=0.035 and p=0.031, respectively). There were no significant associations between COMT genotypes and CSI or ICAI. When male and female subjects were analyzed separately, the association was observed only in female subjects (p=0.012 and p=0.027) after adjustment for age, hypertension, diabetes, smoking and drinking.Conclusion: The functional SNP in the COMT gene associated with the severity of atherosclerosis in a Japanese elderly population, whereby the influence of the genotype appears to be stronger in females than in males.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe, cutaneous adverse drug reactions that are rare but life threatening. Genetic biomarkers for allopurinol-related SJS/TEN in Japanese were examined in a genome-wide association study in which Japanese patients (n=14) were compared with ethnically matched healthy controls (n=991). Associations between 890 321 single nucleotide polymorphisms and allopurinol-related SJS/TEN were analyzed by the Fisher's exact test (dominant genotype mode). A total of 21 polymorphisms on chromosome 6 were significantly associated with allopurinol-related SJS/TEN. The strongest association was found at rs2734583 in BAT1, rs3094011 in HCP5 and GA005234 in MICC (P=2.44 × 10(-8); odds ratio=66.8; 95% confidence interval, 19.8-225.0). rs9263726 in PSORS1C1, also significantly associated with allopurinol-related SJS/TEN, is in absolute linkage disequilibrium with human leukocyte antigen-B*5801, which is in strong association with allopurinol-induced SJS/TEN. The ease of typing rs9263726 makes it a useful biomarker for allopurinol-related SJS/TEN in Japanese.

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