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Kouichi Ozaki

Publications and source records attributed to Kouichi Ozaki.

13 recordsLinked to original sources
PubMed2026

Validation and refinement of a biomarker panel for frailty assessment and prediction of muscle weakness in older adults.

Frailty is a complex geriatric syndrome characterized by age-related declines in physiological function and cognitive reserve. To promote early prevention and intervention, minimally invasive and objective biomarkers that can detect frailty progression are required. We aimed to identify biomarkers associated with frailty progression and to elucidate their relevance to the Japanese version of the Cardiovascular Health Study (J-CHS) criteria, consist of five components (unintentional weight loss, self-reported exhaustion, muscle weakness, slow walking speed, and low physical activity). A total of 168 individuals (61 robust, 25 pre-frail, and 82 frail) enrolled in the NCGG (National Center for Geriatrics and Gerontology) Biobank were analyzed. Clinical information, blood-test data, aging-related factors, and gene-expression data were integrated for the analysis. First, linear regression identified one clinical factor, five aging-related factors, and 251 gene-expression factors associated with frailty. Subsequent logistic regression analyses examining each J-CHS components highlighted six candidate biomarkers. Cross-validation further suggested that three of these biomarkers-SMI, apelin, and GDF15-may represent potential biomarkers. Finally, retrospective and prospective analyses further demonstrated that those biomarkers were predictive of future muscle weakness, yielding a concordance index of 0.70. In conclusion, we validated and refined a biomarker panel consisting of SMI, apelin, and GDF15 that is associated with frailty, particularly muscle weakness (a major J-CHS component). These biomarkers may be useful for frailty assessment. Longitudinal analyses further suggested that they may be associated with the future development of muscle weakness in initially robust older adults, although validation in larger prospective cohorts is warranted.

Journal Article↗
PubMed2025

A genome-wide association study identifies a novel East Asian-specific locus for dementia with Lewy bodies in Japanese subjects.

BACKGROUND: Dementia with Lewy bodies (DLB) is the second most common type of degenerative dementia in older patients. As with other multifactorial diseases, the pathogenesis results from interactions of environmental and genetic factors. The genetic basis of DLB is not yet fully understood. Recent genomic analyses of DLB in Caucasian cohorts identified genetic susceptibility loci for DLB, but the comprehensive genomic analysis in Asians was still not performed. METHODS: We conducted a genome-wide association study (GWAS) in Japanese subjects (211 DLB cases and 6113 controls) to clarify the genetic architecture of DLB pathogenesis. RESULTS: We identified the East Asian-specific DHTKD1 locus (rs138587229) on chromosome 10 with genome-wide significance (GWS; P&#x2009;=&#x2009;3.2710-8) and the ICOS/PARD3B locus on chromosome 2 with suggestive significance (P&#x2009;=&#x2009;3.9510-7) as novel DLB genetic risk loci. We also confirmed the APOE locus (rs429358, P&#x2009;<&#x2009;5.0&#x2009;&#xd7;&#x2009;10-8), a known risk locus for DLB and Alzheimer's disease in Caucasians. The DHTKD1 locus was associated with the gene expression of SEC61A2 and showed a causal relationship with cholinesterase levels. In a trans-ethnic meta-analysis that included Japanese, UK Biobank, and other Caucasian GWAS, we confirmed the risk for DLB at APOE and SNCA loci with GWS. Transcriptome-wide association analysis identified ZNF155 and ZNF284 in the brain cortex and GPRIN3 in the substantia nigra as putative causal genes for DLB. CONCLUSIONS: This is the first GWAS for DLB in East Asians, and our findings provide new biological and clinical insights into the pathogenesis of DLB.

Aged↗
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↗
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

A functional SNP in PSMA6 confers risk of myocardial infarction in the Japanese population.

Inflammation is now considered critical in the pathogenesis of myocardial infarction. One of the mechanisms regulating the inflammatory process is the ubiquitin-proteasome system. We investigated whether variants of the 20S proteasome are associated with susceptibility to myocardial infarction and found a common SNP (minor allele frequency of 0.35) in the proteasome subunit alpha type 6 gene (PSMA6) conferring risk of myocardial infarction in the Japanese population (chi(2) = 21.1, P = 0.0000044, 2,592 affected individuals versus 2,851 controls). We replicated this association in another panel of myocardial infarction and control subjects, although its relevance to other ethnic groups remains to be clarified. The SNP, located in the 5' untranslated region of exon 1 in this gene, enhanced the transcription of PSMA6. Moreover, suppression of PSMA6 expression using short interfering RNA in cultured cells reduced activation of the transcription factor NF-kappaB by stabilizing phosphorylated IkappaB. Our results implicate this PSMA6 SNP as a previously unknown genetic risk factor for myocardial infarction.

Alleles↗
PubMed2006

Inflammation as a risk factor for myocardial infarction.

Myocardial infarction (MI) is one of the common diseases whose pathogenesis includes genetic factors. To reveal genetic backgrounds of this clinically heterogeneous disorder, we started our case-control association study by examining large-scale gene-based single nucleotide polymorphism (SNP) sets for approximately 1,000 patients and controls. As a core genotyping method, a combination of multiplex PCR and Invader method was used, and after genotyping approximately 65,000 SNPs, we found two SNPs located within lymphotoxin-alpha (LTA) gene showing significant association with MI. LTA is one of the cytokines produced in the early stages of vascular inflammatory processes. These SNPs seem to be involved in inflammation by both qualitatively and quantitatively modifying the function of LTA protein, thereby conferring a risk of MI. The genetic association was further confirmed by other researchers using white European trios. To further understand the roles of LTA protein in the pathogenesis of MI, we searched for proteins that interact directly with LTA protein and identified galectin-2 protein as a binding partner of LTA protein. It is a member of galactose-binding lectin family whose function has not been well characterized. Genetic association study again revealed that an SNP in LGALS2 encoding galectin-2 was also associated with susceptibility to MI. This genetic substitution seemed to affect the transcriptional level of galectin-2, which led to altered secretion of LTA, thereby affecting the degree of inflammation. Thus, our findings indicate the importance of inflammation, especially the LTA cascade, in the pathogenesis of MI. Also, combined strategy of genetic and molecular-cellular biological approaches may be useful for clarification of the pathogenesis of common diseases in general.

Case-Control Studies↗
PubMed2006

Genome-wide association study to identify single-nucleotide polymorphisms conferring risk of myocardial infarction.

Myocardial infarction (MI) is characterized by abrupt occlusion of coronary artery resulting in irreversible damage to cardiac muscle. This disease might result from the interactions of multiple genetic and environmental factors, none of which can cause disease solely by themselves. To reveal the genetic bases of MI, we performed a large-scale, case-control association study using 92,788 gene-based single-nucleotide polymorphism (SNP) markers. We have identified functional SNPs within the lymphotoxin-alpha gene located on chromosome 6p21 conferred susceptibility to MI. This chapter describes a detailed protocol for performing a genome-wide association study as used in our MI study.

Case-Control Studies↗
PubMed2005

Impact of atherosclerosis-related gene polymorphisms on mortality and recurrent events after myocardial infarction.

Although previous epidemiologic studies have suggested an association between the onset of myocardial infarction (MI) and some genetic variations, the impact of these variants on recurrent cardiovascular events after MI has not been fully elucidated. We genotyped 87 polymorphisms of 73 atherosclerosis-related genes in consecutive acute MI patients registered in the Osaka Acute Coronary Insufficiency Study and compared the incidence of death and major adverse cardiac events (MACE) among the polymorphisms of each gene. After initial screening in 507 patients, we selected nine polymorphisms for screening in all 1586 patients. Multivariate Cox regression analysis revealed that G allele carriers at the position 252 of the lymphotoxin alpha (LTA) gene were independently associated with an increased risk of death (hazard ratio [HR]: 2.46; 95% CI: 1.24-4.86). In conclusion, a 252G allele of LTA is associated with an increased risk of death after AMI and may be a useful genetic predictor.

Atherosclerosis↗
PubMed2004

Fine-scale SNP map of an 11-kb genomic region at 22q13.1 containing the galectin-1 gene.

Galectins, a family of animal lectins that bind beta-galactoside sugar chains, are thought to have a variety of intra- and extracellular functions. Through a case-control study in the Japanese population and subsequent functional analyses, we previously showed that a functional single nucleotide polymorphism (SNP) in the gene encoding galectin-2 (lectin, galactoside-binding, soluble, 2; LGALS2) is associated with susceptibility to myocardial infarction. As an addition to the genetic information about LGALS2 reported earlier, we provide here a map of polymorphic sites within an 11-kb region containing the gene encoding a closely related molecule, galectin-1 (lectin, galactoside-binding, soluble, 1; LGALS1). The map includes 14 SNPs and two genetic variations of other types detected in a Japanese population sample. Five of the 14 SNPs were not among those deposited in the dbSNP database in the US National Center for Biotechnology Information and appeared to be novel. We also analyzed linkage disequilibrium (LD) using the 12 SNPs in which minor-allele frequencies were >0.20. Investigation of haplotype structure within the LGALS1 locus revealed five common haplotypes covering more than 95% of the test population. One, or a pair, of the SNPs described here might serve as a "tag" for detecting associations between complex diseases and genes in this local segment of chromosome 22q13.1.

Alleles↗
PubMed2004

Functional variation in LGALS2 confers risk of myocardial infarction and regulates lymphotoxin-alpha secretion in vitro.

Myocardial infarction (MI) has become one of the leading causes of death in the world. Its pathogenesis includes chronic formation of plaque inside the vessel wall of the coronary artery and acute rupture of the artery, implicating a number of inflammation-mediating molecules, such as the cytokine lymphotoxin-alpha (LTA). Functional variations in LTA are associated with susceptibility to MI. Here we show that LTA protein binds to galectin-2, a member of the galactose-binding lectin family. Our case-control association study in a Japanese population showed that a single nucleotide polymorphism in LGALS2 encoding galectin-2 is significantly associated with susceptibility to MI. This genetic substitution affects the transcriptional level of galectin-2 in vitro, potentially leading to altered secretion of LTA, which would then affect the degree of inflammation; however, its relevance to other populations remains to be clarified. Smooth muscle cells and macrophages in the human atherosclerotic lesions expressed both galectin-2 and LTA. Our findings thus suggest a link between the LTA cascade and the pathogenesis of MI.

Case-Control Studies↗
PubMed2003

Identification of 46 novel SNPs in the 130-kb region containing a myocardial infarction susceptibility gene on chromosomal band 6p21.

We identified a total of 187 single-nucleotide polymorphisms (SNPs) at 11 gene loci in the 130-kb region on chromosome 6p21 containing a gene strongly associated with myocardial infarction (MI). By comparing our data with SNPs deposited in the dbSNP database at the National Center for Biotechnology Information, 46 of these SNPs (24.6%) were considered to be novel: four were identified in the P5-1 locus, 14 in the MICB locus, nine in the BAT1 locus, one in the ATP6V1G2 locus, six in the NFKBIL1 locus, one in the LTA locus, one in the TNF locus, five in the LST1 locus, four in the LY117a locus, and one in the AIF-1 locus. The SNP map presented here should provide as useful resource not only for examining the relationships between genotypes and susceptibility to the MI phenotype, but also for scanning of complex diseases mapped to this local segment on chromosome 6.

3' Untranslated Regions↗
PubMed2002

Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction.

By means of a large-scale, case-control association study using 92,788 gene-based single-nucleotide polymorphism (SNP) markers, we identified a candidate locus on chromosome 6p21 associated with susceptibility to myocardial infarction. Subsequent linkage-disequilibrium (LD) mapping and analyses of haplotype structure showed significant associations between myocardial infarction and a single 50 kb halpotype comprised of five SNPs in LTA (encoding lymphotoxin-alpha), NFKBIL1 (encoding nuclear factor of kappa light polypeptide gene enhancer in B cells, inhibitor-like 1) and BAT1 (encoding HLA-B associated transcript 1). Homozygosity with respect to each of the two SNPs in LTA was significantly associated with increased risk for myocardial infarction (odds ratio = 1.78, chi(2) = 21.6, P = 0.00000033; 1,133 affected individuals versus 1,006 controls). In vitro functional analyses indicated that one SNP in the coding region of LTA, which changed an amino-acid residue from threonine to asparagine (Thr26Asn), effected a twofold increase in induction of several cell-adhesion molecules, including VCAM1, in vascular smooth-muscle cells of human coronary artery. Moreover, the SNP, in intron 1 of LTA, enhanced the transcriptional level of LTA. These results indicate that variants in the LTA are risk factors for myocardial infraction and implicate LTA in the pathogenesis of the disorder.

Aged↗