Biomedical subjects

Susumu Saito

Publications and source records attributed to Susumu Saito.

At least 19 recordsLinked to original sources

PubMed2025

Multivariate Effects of SNPs on Environmental Streptococcal Mastitis Evaluated With an NGS-Based Association Study Using Targeted Resequencing in the Bovine MHC Region.

Mastitis is an inflammatory reaction caused by bacterial infection of the teat, and a relationship between its onset and cattle major histocompatibility complex (BoLA) region has been reported. However, no comprehensive genetic analysis of mastitis caused by environmental streptococci has been reported. Here, we resequenced the BoLA region using a hybridisation capture target next-generation sequencing (NGS) method to identify disease susceptibility markers mapped to the BoLA region in environmental streptococcal mastitis. This study examined 75 cows with mastitis caused by environmental streptococci selected from 1641 cows with mastitis and 222 healthy cows without mastitis in Japan. Targeted sequences obtained from MiSeq NGS were aligned to the bovine reference genome (ARS-UCD1.2/bosTau9), and 2,920,355 variants were detected within the BoLA region of the 297 Holstein cattle. In an association study using 2264 variants after quality control, the top 20 variants with the lowest P values were selected and assigned to the 18 surrounding candidate genes, and a gene network analysis of these genes resulted in the narrowing down of five candidate genes POU5F1, IER3, GNL1, ABCF1, and PRR3. Multivariate effect analysis of all 6 SNPs associated with these 5 genes revealed that they were significantly correlated with mastitis, indicating that they were useful for classification of mastitis-resistant and mastitis-susceptible cattle. This is the first report to identify SNPs associated with environmental streptococcal mastitis with an NGS-based association study using targeted resequencing in the BoLA region, and understanding host factors may provide important clues for mastitis control.

Animals↗

PubMed2007

A functional SNP in ITIH3 is associated with susceptibility to myocardial infarction.

Myocardial infarction (MI) results from complex interactions of multiple genetic and environmental factors. To disclose genetic backgrounds of MI, we performed a large-scale, case-control association study using 52,608 gene-based single-nucleotide polymorphism (SNP) markers, and identified a candidate SNP located on chromosome 3p21.2-p21.1. Subsequent linkage-disequilibrium mapping indicated very significant association between MI and a SNP in exon 2 of the inter-alpha (globulin) inhibitor 3 gene (ITIH3; chi(2) = 24.88, P = 6.1 x 10(-7), 3,353 affected individuals versus 3,807 controls). In vitro functional analyses showed that this SNP enhanced the transcriptional level of the ITIH3 gene. Furthermore, we found expression of the ITIH3 protein in the vascular smooth muscle cells and macrophages in the human atherosclerotic lesions, suggesting ITIH3 SNP to be a novel genetic risk factor of MI.

Alpha-Globulins↗

PubMed2007

A nonsynonymous SNP in PRKCH (protein kinase C eta) increases the risk of cerebral infarction.

Cerebral infarction is the most common type of stroke and often causes long-term disability. To investigate the genetic contribution to cerebral infarction, we conducted a case-control study using 52,608 gene-based tag SNPs selected from the JSNP database. Here we report that a nonsynonymous SNP in a member of protein kinase C (PKC) family, PRKCH, was significantly associated with lacunar infarction in two independent Japanese samples (P = 5.1 x 10(-7), crude odds ratio of 1.40). This SNP is likely to affect PKC activity. Furthermore, a 14-year follow-up cohort study in Hisayama (Fukuoka, Japan) supported involvement of this SNP in the development of cerebral infarction (P = 0.03, age- and sex-adjusted hazard ratio of 2.83). We also found that PKCeta was expressed mainly in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions, and its expression increased as the lesion type progressed. Our results support a role for PRKCH in the pathogenesis of cerebral infarction.

Case-Control Studies↗

PubMed2007

Functional single-nucleotide polymorphisms in the secretogranin III (SCG3) gene that form secretory granules with appetite-related neuropeptides are associated with obesity.

CONTEXT: Genetic factors are important for the development of obesity. However, the genetic background of obesity still remains unclear. OBJECTIVE: Our objective was to search for obesity-related genes using a large number of gene-based single-nucleotide polymorphisms (SNPs). DESIGN AND SETTING: We conducted case-control association analyses using 94 obese patients and 658 controls with 62,663 SNPs selected from the SNP database. SNPs that possessed P < or = 0.02 were further analyzed using 796 obese and 711 control subjects. One SNP (rs3764220) in the secretogranin III (SCG3) gene showed the lowest P value (P = 0.0000019). We sequenced an approximately 300-kb genomic region around rs3764220 and discovered SNPs for haplotype analyses. SCG3 was the only gene within a haplotype block that contained rs3764220. The functions of SCG3 were studied. PATIENTS: Obese subjects (body mass index > or = 30 kg/m(2), n = 890) and control subjects (general population; n = 658, body mass index < or = 25 kg/m(2); n = 711) were recruited for this study. RESULTS: Twelve SNPs in the SCG3 gene including rs3764220 were in almost complete linkage disequilibrium and significantly associated with an obesity phenotype. Two SNPs (rs16964465, rs16964476) affected the transcriptional activity of SCG3, and subjects with the minor allele seemed to be resistant to obesity (odds ratio, 9.23; 95% confidence interval, 2.77-30.80; chi(2) = 19.2; P = 0.0000067). SCG3 mRNA and immunoreactivity were detected in the paraventricular nucleus, lateral hypothalamic area, and arcuate nucleus, and the protein coexisted with orexin, melanin-concentrating hormone, neuropeptide Y, and proopiomelanocortin. SCG3 formed a granule-like structure together with these neuropeptides. CONCLUSIONS: Genetic variations in the SCG3 gene may influence the risk of obesity through possible regulation of hypothalamic neuropeptide secretion.

Adult↗

PubMed2006

Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction.

Through a large-scale case-control association study using 52,608 haplotype-based single nucleotide polymorphism (SNP) markers, we identified a susceptible locus for myocardial infarction (MI) on chromosome 22q12.1. Following linkage disequilibrium (LD) mapping, haplotype analyses revealed that six SNPs in this locus, all of which were in complete LD, showed markedly significant association with MI (chi2=25.27, P=0.0000005; comparison of allele frequency, 3,435 affected individuals versus 3,774 controls, in the case of intron 1 5,338 C>T; rs2331291). Within this locus, we isolated a complete cDNA of a novel gene, designated myocardial infarction associated transcript (MIAT). MIAT has five exons, and in vitro translation assay showed that MIAT did not encode any translational product, indicating that this is likely to be a functional RNA. In vitro functional analyses revealed that the minor variant of one SNP in exon 5 increased transcriptional level of the novel gene. Moreover, unidentified nuclear protein(s) bound more intensely to risk allele than non-risk allele. These results indicate that the altered expression of MIAT by the SNP may play some role in the pathogenesis of MI.

Alleles↗

PubMed2006

Highly anti-selective catalytic aldol reactions of amides with aldehydes.

Barium phenoxide-catalyzed, highly anti-selective direct-type aldol reactions of amides with aldehydes have been developed. In the presence of a slight excess amount of an amide, the desired reactions proceeded smoothly under mild conditions, and a wide range of aromatic, heterocyclic, alpha,beta-unsaturated aldehydes were applicable to afford the desired adducts in high yields with high anti-selectivities. A catalytic, enantioselective reaction of an amide with an aldehyde using a chiral ligand is also described.

Aldehydes↗

PubMed2006

A SNP in the ABCC11 gene is the determinant of human earwax type.

Human earwax consists of wet and dry types. Dry earwax is frequent in East Asians, whereas wet earwax is common in other populations. Here we show that a SNP, 538G --> A (rs17822931), in the ABCC11 gene is responsible for determination of earwax type. The AA genotype corresponds to dry earwax, and GA and GG to wet type. A 27-bp deletion in ABCC11 exon 29 was also found in a few individuals of Asian ancestry. A functional assay demonstrated that cells with allele A show a lower excretory activity for cGMP than those with allele G. The allele A frequency shows a north-south and east-west downward geographical gradient; worldwide, it is highest in Chinese and Koreans, and a common dry-type haplotype is retained among various ethnic populations. These suggest that the allele A arose in northeast Asia and thereafter spread through the world. The 538G --> A SNP is the first example of DNA polymorphism determining a visible genetic trait.

ATP-Binding Cassette Transporters↗

PubMed2006

Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in Japanese patients.

Warfarin is the most commonly used oral anticoagulant for treatment of thromboembolism, but adjustment of the dose appropriate to each patient is not so easy because of the large inter-individual variation in dose requirement. We analyzed single nucleotide polymorphism (SNP) genotypes of the VKORC1 and CYP2C9 genes using DNA from 828 Japanese patients treated with warfarin, and investigated association between SNP genotype and warfarin-maintenance dose. Five SNPs in VKORC1, 5' flanking-1413A > G, intron 1-136T > C, intron 2+124C > G, intron 2+837T > C and exon 3 343G > A, were in absolute linkage disequilibrium, and showed a significant association with daily warfarin dose of these patients. The median warfarin dose of patients with homozygosity for the minor allele was 4.0 mg/day, which is significantly higher than those heterozygous for the minor allele (3.5 mg/day) or those homozygous for the major allele (2.5 mg/day; P = 5.1 x 10(-11) in the case of intron 1-136T > C SNP). We then genotyped the CYP2C9 gene for the Japanese common genetic variant, CYP2C9*3 and, based on the genotype of these two genes, classified patients into three categories, which we call "warfarin-responsive index." The median warfarin daily dose varied significantly in this classification according to the warfarin-responsive index (2.0 mg/day for index 0 group, 2.5 mg/day for index 1 group, and 3.5 mg/day for index 2 group; P = 4.4 x 10(-13)). Thus, analysis of the combination of VKORC1 and CYP2C9 genotypes should identify warfarin-sensitive patients who require a lower dose of drug, allowing personalized warfarin treatment.

Anticoagulants↗

PubMed2006

Japanese single nucleotide polymorphism database for 267 possible drug-related genes.

To establish 'personalized medicines' that can provide the right drug at the appropriate dose for each individual patient on the basis of genetic background, we have been building the infrastructure for a Japanese single nucleotide polymorphism (SNP) database of the genes encoding various enzymes, transporters and receptors that are involved in the metabolism, transportation and action of drugs. We have so far screened a genomic region of 4,068.3 kb, and identified a total of 7,552 genetic variations, including 6,733 SNP and 819 genetic variations of other types among 267 genes in Japanese populations. Interestingly, among the 212 non-synonymous substitutions we found, six would be considered to be nonsense mutations. In this review, we focused on the molecular features of the non-synonymous substitutions and insertion/deletion polymorphisms within coding regions detected in drug-related gene loci. The database established in this study makes us confident of achieving one of our goals, which is establishment of personalized medicine.

Asian People↗

PubMed2006

[VDT worker's posture and workload in free-address office system].

A free-address system is a new office layout in which a worker can freely sit in their favorite place with a computer and materials. Since this layout has recently been introduced in offices, we conducted a questionnaire survey which aimed to clarify the effects of the free-address system on visual display terminals (VDT) workers' posture and workload. A total of 203 male VDT workers who were system engineers aged 20 to 59 using a notebook computer were evaluated, of whom 150 used the free-address layout, and 53 used the fixed-address layout. The free-address layout was effective in the improvement of individual work space compared with the fixed-address layout. Also, in this layout the worker did not feel dissatisfaction with communication or support between workers. However, workers using the free-address layout assumed an unsuitable work posture, without adjusting the height of their chairs. Furthermore, this layout might have risk factors which increase neck/shoulder and low back stiffness and/or pain. Therefore, the free-address layout may have incipient problems, and it will be necessary to examine further the effects of this layout on VDT worker's health.

Adult↗

PubMed2005

Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease.

The inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis, are chronic inflammatory disorders of the digestive tract. The pathogenesis of IBD is complicated, and it is widely accepted that immunologic, environmental and genetic components contribute to its etiology. To identify genetic susceptibility factors in CD, we performed a genome-wide association study in Japanese patients and controls using nearly 80,000 gene-based single nucleotide polymorphism (SNP) markers and investigated the haplotype structure of the candidate locus in Japanese and European patients. We identified highly significant associations (P = 1.71 x 10(-14) with odds ratio of 2.17) of SNPs and haplotypes within the TNFSF15 (the gene encoding tumor necrosis factor superfamily, member 15) genes in Japanese CD patients. The association was confirmed in the study of two European IBD cohorts. Interestingly, a core TNFSF15 haplotype showing association with increased risk to the disease was common in the two ethnic groups. Our results suggest that the genetic variations in the TNFSF15 gene contribute to the susceptibility to IBD in the Japanese and European populations.

Adult↗

PubMed2005

A model of prediction system for adverse cardiovascular reactions by calcineurin inhibitors among patients with renal transplants using gene-based single-nucleotide polymorphisms.

The application of pharmacogenomic information to diagnostic assays is expected to improve the prediction of drug efficacy and toxicity, leading to appropriate therapeutic regimens for individual patients. Cardiovascular events are common and severe adverse drug reactions (ADRs) among transplant patients treated with calcineurin inhibitors (CNIs). We conducted case-control association studies using 50,947 gene-based single-nucleotide polymorphisms (SNPs) to identify genetic variations that might be associated with cardiovascular risk factors in 72 renal transplant recipients with CNI therapy. The overall incidence of cardiovascular events was 13.9% (10/72) among patients receiving cyclosporine or tacrolimus; arrhythmias in six patients (8.3%), ischemic heart diseases in two patients (2.8%), and heart failure in two patients (2.8%). On the basis of results of the genome-wide association studies, we attempted to establish a scoring system to predict individual risks for cardiovascular toxicity of cyclosporine and tacrolimus. Estimation of the predictive performance was carried out by the use of internal leave-one-out cross-validation test. When we combined arrhythmia, ischemic heart disease and heart failure cases as subjects with a cardiotoxicity phenotype, nine of ten ADR patients and 50 of 62 non-ADR patients were correctly classified into the respective categories using the top eight SNPs. In addition, the proportion of individuals in the control population (n=246) with scores over the cut-off (11.0%) was close to the cardiovascular ADR frequency (8.3%) among renal transplant patients in the previous clinical study. Our results open the possibility that prediction of CNI-induced cardiovascular complications can lead to better prognosis and quality of life among kidney-transplant patients, and to improved immunosuppressive regimens.

Calcineurin Inhibitors↗

PubMed2005

A functional single nucleotide polymorphism in the core promoter region of CALM1 is associated with hip osteoarthritis in Japanese.

Osteoarthritis (OA), a common skeletal disease, is a leading cause of disability among the elderly populations. OA is characterized by gradual loss of articular cartilage, but the etiology and pathogenesis of OA are largely unknown. Epidemiological and genetic studies have demonstrated that genetic factors play an important role in OA. To identify susceptibility genes for OA, we performed a large-scale, case-control association study using gene-based single nucleotide polymorphisms (SNPs). In two independent case-control populations, we found significant association (P=9.8x10(-7)) between hip OA and a SNP (IVS3-293C>T) located in intron 3 of the calmodulin (CaM) 1 gene (CALM1). CALM1 was expressed in cultured chondrocytes and articular cartilage, and its expression was increased in OA. Subsequent linkage-disequilibrium mapping identified five SNPs showing significant association equivalent to IVS3-293C>T. One of these (-16C>T) is located in the core promoter region of CALM1. Functional analyses indicate that the susceptibility -16T allele decreases CALM1 transcription in vitro and in vivo. Inhibition of CaM in chondrogenic cells reduced the expression of the major cartilage matrix genes Col2a1 and Agc1. These results suggest that the transcriptional level of CALM1 is associated with susceptibility for hip OA through modulation of chondrogenic activity. Our findings reveal the CALM1-mediated signaling pathway in chondrocytes as a novel potential target for treatment of OA.

Alleles↗

PubMed2005

Genetic variations in the gene encoding ELMO1 are associated with susceptibility to diabetic nephropathy.

To search for a gene(s) conferring susceptibility to diabetic nephropathy (DN), we genotyped over 80,000 gene-based single nucleotide polymorphisms (SNPs) in Japanese patients and identified that the engulfment and cell motility 1 gene (ELMO1) was a likely candidate for conferring susceptibility to DN, in view of the significant association of an SNP in this gene with the disease (intron 18+9170, GG vs. GA+AA, chi(2) = 19.9, P = 0.000008; odds ratio 2.67, 95% CI 1.71-4.16). In situ hybridization (ISH) using the kidney of normal and diabetic mice revealed that ELMO1 expression was weakly detectable mainly in tubular and glomerular epithelial cells in normal mouse kidney and was clearly elevated in the kidney of diabetic mice. Subsequent in vitro analysis revealed that ELMO1 expression was elevated in cells cultured under high glucose conditions (25 mmol/l) compared with cells cultured under normal glucose conditions (5.5 mmol/l). Furthermore, we identified that the expression of extracellular matrix protein genes, such as type 1 collagen and fibronectin, were increased in cells that overexpress ELMO1, whereas the expression of matrix metalloproteinases was decreased. These results indicate that ELMO1 is a novel candidate gene that both confers susceptibility to DN and plays an important role in the development and progression of this disease.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Association analysis of SLC22A4, SLC22A5 and DLG5 in Japanese patients with Crohn disease.

Crohn disease (CD) is an inflammatory bowel disease characterized by chronic transmural, segmental, and typically granulomatous inflammation of the gut. Recently, two novel candidate gene loci associated with CD, SLC22A4 and SLC22A5 on chromosome 5 known as IBD5 and DLG5 on chromosome 10, were identified through association analysis of Caucasian CD patients. We validated these candidate genes in Japanese patients with CD and found a weak but possible association with both SLC22A4 (P=0.028) and DLG5 (P=0.023). However, the reported genetic variants that were indicated to be causative in the Caucasian population were completely absent in or were not associated with Japanese CD patients. These findings imply significant differences in genetic background with CD susceptibility among different ethnic groups and further indicate some difficulty of population-based studies.

Case-Control Studies↗

PubMed2004

Identification of 20 novel SNPs in the guanine nucleotide binding protein alpha 12 gene locus.

Heterotrimeric guanine nucleotide binding proteins (G proteins) regulate various signals from transmembrane receptors to intracellular effectors thereby mediating cell growth, differentiation, and apoptosis. We have been publishing a series of genetic variations detected in the genomic regions corresponding to the potential drug target genes. As an addition to genetic information reported earlier, we provide here 20 novel single nucleotide polymorphisms (SNPs) in the region corresponding to a gene encoding alpha subunits of G(12) protein, GNA12, in the Japanese population: 16 in introns, two in the coding region, and two in the 3' flanking region. We also identified 12 genetic variations of other types from this locus. The collection of genetic variations reported here will serve as a useful resource for analyzing potential associations between genotypes and susceptibility to common diseases as well as efficacy and/or adverse reactions to drugs.

Asian People↗

PubMed2004

Large-scale single-nucleotide polymorphism (SNP) and haplotype analyses, using dense SNP Maps, of 199 drug-related genes in 752 subjects: the analysis of the association between uncommon SNPs within haplotype blocks and the haplotypes constructed with haplotype-tagging SNPs.

To optimize the strategies for population-based pharmacogenetic studies, we extensively analyzed single-nucleotide polymorphisms (SNPs) and haplotypes in 199 drug-related genes, through use of 4,190 SNPs in 752 control subjects. Drug-related genes, like other genes, have a haplotype-block structure, and a few haplotype-tagging SNPs (htSNPs) could represent most of the major haplotypes constructed with common SNPs in a block. Because our data included 860 uncommon (frequency <0.1) SNPs with frequencies that were accurately estimated, we analyzed the relationship between haplotypes and uncommon SNPs within the blocks (549 SNPs). We inferred haplotype frequencies through use of the data from all htSNPs and one of the uncommon SNPs within a block and calculated four joint probabilities for the haplotypes. We show that, irrespective of the minor-allele frequency of an uncommon SNP, the majority (mean +/- SD frequency 0.943+/-0.117) of the minor alleles were assigned to a single haplotype tagged by htSNPs if the uncommon SNP was within the block. These results support the hypothesis that recombinations occur only infrequently within blocks. The proportion of a single haplotype tagged by htSNPs to which the minor alleles of an uncommon SNP were assigned was positively correlated with the minor-allele frequency when the frequency was <0.03 (P<.000001; n=233 [Spearman's rank correlation coefficient]). The results of simulation studies suggested that haplotype analysis using htSNPs may be useful in the detection of uncommon SNPs associated with phenotypes if the frequencies of the SNPs are higher in affected than in control populations, the SNPs are within the blocks, and the frequencies of the SNPs are >0.03.

Computational Biology↗

PubMed2004

O-nitroso aldol synthesis: Catalytic enantioselective route to alpha-aminooxy carbonyl compounds via enamine intermediate.

The approach using pyrrolidine enamine as substrate has been studied for this synthesis, and an important catalyst structural feature has been developed. After survey of pyrrolidine-based Brønsted acid catalyst, tetrazole catalyst (3f) was found to be optimal in synthesis of aminooxy carbonyl compounds in high yields, with complete enantioselectivity not only for aldehydes but also for ketones.

Aldehydes↗