Publications by authors named "Katsushi Tokunaga"

369 Publications

Clinical Characteristics of Patients with Coronavirus Disease (COVID-19): Preliminary Baseline Report of Japan COVID-19 Task Force, a Nation-wide Consortium to Investigate Host Genetics of COVID-19.

Int J Infect Dis 2021 Sep 30. Epub 2021 Sep 30.

Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.

Background And Design: The coronavirus disease (COVID-19) pandemic is having a devastating effect worldwide. Host genome differences between populations may influence the severity of COVID-19. The Japan COVID-19 Task Force is conducting host genome analysis of hospitalized patients with COVID-19 from more than 70 institutions nationwide in Japan. This report describes the clinical characteristics of patients enrolled to date.

Results: The median (interquartile range) age of the 1674 patients included in the analysis was 59 (45-71) years, and more than half of the patients (66.2%) were male. Less than half of the patients (41.2%) had severe disease. The case fatality rate was 3.2%.

Conclusions: Since this is a hospital-based study, the number of severe cases was relatively high, but the case fatality rate was relatively low, when compared to that of other countries. In the future, we will continue to enroll patients and conduct genome analyses of patients with COVID-19.
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http://dx.doi.org/10.1016/j.ijid.2021.09.070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482546PMC
September 2021

Genome-wide copy number variation analysis of hepatitis B infection in a Japanese population.

Hum Genome Var 2021 Jun 8;8(1):22. Epub 2021 Jun 8.

Department of Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan.

Genome-wide association studies have been performed to identify common genetic variants associated with hepatitis B (HB). However, little is known about copy number variations (CNVs) in HB. In this study, we performed a genome-wide CNV analysis between 1830 healthy controls and 1031 patients with HB infection after quality control. Using signal calling by the Axiom Analysis Suite and CNV detection by PennCNV software, we obtained a total of 4494 CNVs across all individuals. The genes with CNVs that were found only in the HB patients were associated with the immune system, such as antigen processing. A gene-level CNV association test revealed statistically significant CNVs in the contactin 6 (CNTN6) gene. Moreover, we also performed gene-level CNV association tests in disease subgroups, including hepatocellular carcinoma patients, liver cirrhosis patients, and HBV carriers, including asymptomatic carriers and patients with HBV-derived chronic hepatitis. Our findings from germline cells suggested that patient-specific CNVs may be inherent genetic risk factors for HB.
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http://dx.doi.org/10.1038/s41439-021-00154-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187437PMC
June 2021

An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs.

J Hepatol 2021 Sep 23;75(3):572-581. Epub 2021 May 23.

Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.

Backgrounds & Aims: Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening.

Methods: We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts.

Results: We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57 genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (T)1 and T17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders.

Conclusions: This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders.

Lay Summary: Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these 'candidate genes' to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC.
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http://dx.doi.org/10.1016/j.jhep.2021.04.055DOI Listing
September 2021

Characterization of intermediate-sized insertions using whole-genome sequencing data and analysis of their functional impact on gene expression.

Hum Genet 2021 Aug 12;140(8):1201-1216. Epub 2021 May 12.

Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Intermediate-sized insertions are one of the structural variants contributing to genome diversity. However, due to technical difficulties in identifying them, their importance in disease pathogenicity and gene expression regulation remains unclear. We used whole-genome sequencing data of 174 Japanese samples to characterize intermediate-sized insertions using a highly-accurate insertion calling method (IMSindel software and joint-call recovery) and obtained a catalogue of 4254 insertions. We constructed an imputation panel comprising of insertions and SNVs from all samples, and conducted imputation of intermediate-sized insertions for 82 publicly-available Japanese samples. Positive Predictive Value of imputation, evaluated using Nanopore long-read sequencing data, was 97%. Subsequent eQTL analysis predicted 128 (~ 3.0%) insertions as causative for gene expression level changes. Enrichment analysis of causal insertions for genome regulatory elements showed significant associations with CTCF-binding sites, super-enhancers, and promoters. Among 17 causal insertions found in the same causal set with GWAS hits, there were insertions associated with changes in expression of cancer-related genes such as BRCA1, ZNF222, and ABCB10. Analysis of insertions sequences revealed that 461 insertions were short tandem duplications frequently found in early-replicating regions of genome. Furthermore, comparison of functional importance of intermediate-sized insertions with that of intermediate-sized deletions detected in the same sample set in our previous study showed that insertions were more frequent in genic regions, and proportion of functional candidates was smaller in insertions. Here, we characterize a high-confidence set of intermediate-sized insertions and indicate their importance in gene expression regulation. Our results emphasize the importance of considering intermediate-sized insertions in trait association studies.
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http://dx.doi.org/10.1007/s00439-021-02291-2DOI Listing
August 2021

HLA-A*11:01:01:01, HLA-C*12:02:02:01-HLA-B*52:01:02:02, Age and Sex Are Associated With Severity of Japanese COVID-19 With Respiratory Failure.

Front Immunol 2021 22;12:658570. Epub 2021 Apr 22.

Genome Medical Science Project, National Center for Global Health and Medicine Hospital, Tokyo, Japan.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19) was announced as an outbreak by the World Health Organization (WHO) in January 2020 and as a pandemic in March 2020. The majority of infected individuals have experienced no or only mild symptoms, ranging from fully asymptomatic cases to mild pneumonic disease. However, a minority of infected individuals develop severe respiratory symptoms. The objective of this study was to identify susceptible HLA alleles and clinical markers that can be used in risk prediction model for the early identification of severe COVID-19 among hospitalized COVID-19 patients. A total of 137 patients with mild COVID-19 (mCOVID-19) and 53 patients with severe COVID-19 (sCOVID-19) were recruited from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan for the period of February-August 2020. High-resolution sequencing-based typing for eight HLA genes was performed using next-generation sequencing. In the HLA association studies, HLA-A*11:01:01:01 [P = 0.013, OR = 2.26 (1.27-3.91)] and HLA-C*12:02:02:01-HLA-B*52:01:01:02 [P = 0.020, OR = 2.25 (1.24-3.92)] were found to be significantly associated with the severity of COVID-19. After multivariate analysis controlling for other confounding factors and comorbidities, HLA-A*11:01:01:01 [P = 3.34E-03, OR = 3.41 (1.50-7.73)], age at diagnosis [P = 1.29E-02, OR = 1.04 (1.01-1.07)] and sex at birth [P = 8.88E-03, OR = 2.92 (1.31-6.54)] remained significant. The area under the curve of the risk prediction model utilizing HLA-A*11:01:01:01, age at diagnosis, and sex at birth was 0.772, with sensitivity of 0.715 and specificity of 0.717. To the best of our knowledge, this is the first article that describes associations of HLA alleles with COVID-19 at the 4-field (highest) resolution level. Early identification of potential sCOVID-19 could help clinicians prioritize medical utility and significantly decrease mortality from COVID-19.
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http://dx.doi.org/10.3389/fimmu.2021.658570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100314PMC
May 2021

Regional heritability mapping identifies several novel loci (STAT4, ULK4, and KCNH5) for primary biliary cholangitis in the Japanese population.

Eur J Hum Genet 2021 Aug 9;29(8):1282-1291. Epub 2021 Apr 9.

Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Sakyo-ku, Kyoto, Japan.

While the advent of GWAS more than a decade ago has ushered in remarkable advances in our understanding of complex traits, the limitations of single-SNP analysis have also led to the development of several other approaches. Simulation studies have shown that the regional heritability mapping (RHM) method, which makes use of multiple adjacent SNPs jointly to estimate the genetic effect of a given region of the genome, generally has higher detection power than single-SNP GWAS. However, thus far its use has been mostly limited to agricultural settings, and its potential for the discovery of new genes in human diseases is yet to be fully exploited. In this study, by applying the RHM method to primary biliary cholangitis (PBC) in the Japanese population, we identified three novel loci (STAT4, ULK4, and KCNH5) at the genome-wide significance level, two of which (ULK4 and KCNH5) have not been found associated with PBC in any population previously. Notably, these genes could not be detected by using conventional single-SNP GWAS, highlighting the potential of the RHM method for the detection of new susceptibility loci in human diseases. These findings thereby provide strong empirical evidence that RHM is an effective and practical complementary approach to GWAS in this context. Also, liver tissue mRNA microarray analysis revealed higher gene expression levels in ULK4 in PBC patients (P < 0.01). Lastly, we estimated the common SNP heritability of PBC in the Japanese population (0.210 ± 0.026).
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http://dx.doi.org/10.1038/s41431-021-00854-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385030PMC
August 2021

X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis.

Gastroenterology 2021 Jun 4;160(7):2483-2495.e26. Epub 2021 Mar 4.

University of California-Davis, Davis, California.

Background & Aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease.

Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals).

Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively).

Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.
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http://dx.doi.org/10.1053/j.gastro.2021.02.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169555PMC
June 2021

Importance of HBsAg recognition by HLA molecules as revealed by responsiveness to different hepatitis B vaccines.

Sci Rep 2021 Mar 2;11(1):3703. Epub 2021 Mar 2.

Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, 272-8516, Japan.

Hepatitis B (HB) vaccines (Heptavax-II and Bimmugen) designed based on HBV genotypes A and C are mainly used for vaccination against HB in Japan. To determine whether there are differences in the genetic background associated with vaccine responsiveness, genome-wide association studies were performed on 555 Heptavax-II and 1193 Bimmugen recipients. Further HLA imputation and detailed analysis of the association with HLA genes showed that two haplotypes, DRB1*13:02-DQB1*06:04 and DRB1*04:05-DQB1*04:01, were significantly associated in comparison with high-responders (HBsAb > 100 mIU/mL) for the two HB vaccines. In particular, HLA-DRB1*13:02-DQB1*06:04 haplotype is of great interest in the sense that it could only be detected by direct analysis of the high-responders in vaccination with Heptavax-II or Bimmugen. Compared with healthy controls, DRB1*13:02-DQB1*06:04 was significantly less frequent in high-responders when vaccinated with Heptavax-II, indicating that high antibody titers were less likely to be obtained with Heptavax-II. As Bimmugen and Heptavax-II tended to have high and low vaccine responses to DRB1*13:02, 15 residues were found in the Heptavax-II-derived antigenic peptide predicted to have the most unstable HLA-peptide binding. Further functional analysis of selected hepatitis B patients with HLA haplotypes identified in this study is expected to lead to an understanding of the mechanisms underlying liver disease.
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http://dx.doi.org/10.1038/s41598-021-82986-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925550PMC
March 2021

rs1944919 on chromosome 11q23.1 and its effector genes COLCA1/COLCA2 confer susceptibility to primary biliary cholangitis.

Sci Rep 2021 Feb 25;11(1):4557. Epub 2021 Feb 25.

Department of Microbiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.

Primary biliary cholangitis (PBC) is a chronic, progressive cholestatic liver disease in which intrahepatic bile ducts are destroyed by an autoimmune reaction. Our previous genome-wide association study (GWAS) identified chromosome 11q23.1 as a susceptibility gene locus for PBC in the Japanese population. Here, high-density association mapping based on single nucleotide polymorphism (SNP) imputation and in silico/in vitro functional analyses identified rs1944919 as the primary functional variant. Expression-quantitative trait loci analyses showed that the PBC susceptibility allele of rs1944919 was significantly associated with increased COLCA1/COLCA2 expression levels. Additionally, the effects of rs1944919 on COLCA1/COLCA2 expression levels were confirmed using genotype knock-in versions of cell lines constructed using the CRISPR/Cas9 system and differed between rs1944919-G/G clones and -T/T clones. To our knowledge, this is the first study to demonstrate the contribution of COLCA1/COLCA2 to PBC susceptibility.
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http://dx.doi.org/10.1038/s41598-021-84042-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907150PMC
February 2021

Mapping of susceptible variants for cold medicine-related Stevens-Johnson syndrome by whole-genome resequencing.

NPJ Genom Med 2021 Feb 11;6(1). Epub 2021 Feb 11.

Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Stevens-Johnson syndrome (SJS) and its severe condition with extensive skin detachment and a poor prognosis, toxic epidermal necrolysis (TEN), are immunologically mediated severe cutaneous reactions of the skin and mucous membranes such as the ocular surface. Genetic variations on the HLA-A and other autosomal genes have been identified as risk factors for cold medicine-related SJS/TEN with severe ocular complications (CM-SJS/TEN with SOC). Using a whole-genome sequencing (WGS) approach, we explored other susceptible variants of CM-SJS/TEN with SOC, especially among rare variants and structural variants (SVs). WGS was performed on samples from 133 patients with CM-SJS/TEN with SOC and 418 healthy controls to obtain single nucleotide polymorphisms (SNPs) and SVs. Genome-wide association tests were performed with these variants. Our genome-wide association test reproduced the associations of the common variants of HLA-A and loci on chromosome 16q12.1. We also identified novel associations of SVs on these loci and an aggregation of rare coding variants on the TPRM8 gene. In silico gene expression analysis on the HLA-A locus revealed that the SNP (rs12202296), which was significantly associated with susceptibility to CM-SJS/TEN with SOC, was correlated to an increase in HLA-A expression levels in the whole blood (P = 2.9 × 10), from the GTEx database. The majority of variants that were significantly associated with CM-SJS/TEN with SOC were found in non-coding regions, indicating the regulatory role of genetic variations in the pathogenesis of CM-SJS/TEN with SOC.
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http://dx.doi.org/10.1038/s41525-021-00171-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878485PMC
February 2021

Genome-wide association study in patients with pulmonary complex disease.

Eur Respir J 2021 08 12;58(2). Epub 2021 Aug 12.

Respiratory Disease Center, Fukujuji Hospital, Japan Anti-Tuberculosis Association, Tokyo, Japan.

Rationale: Nontuberculous mycobacteria (NTM) are environmental mycobacteria that can cause a chronic progressive lung disease. Although epidemiological data indicate potential genetic predisposition, its nature remains unclear.

Objectives: We aimed to identify host susceptibility loci for complex (MAC), the most common NTM pathogen.

Methods: This genome-wide association study (GWAS) was conducted in Japanese patients with pulmonary MAC and healthy controls, followed by genotyping of candidate single-nucleotide polymorphisms (SNPs) in another Japanese cohort. For verification by Korean and European ancestry, we performed SNP genotyping.

Results: The GWAS discovery set included 475 pulmonary MAC cases and 417 controls. Both GWAS and replication analysis of 591 pulmonary MAC cases and 718 controls revealed the strongest association with chromosome 16p21, particularly with rs109592 (p=1.64×10, OR 0.54), which is in an intronic region of the calcineurin-like EF-hand protein 2 (). Expression quantitative trait loci analysis demonstrated an association with lung CHP2 expression. CHP2 was expressed in the lung tissue in pulmonary MAC disease. This SNP was associated with the nodular bronchiectasis subtype. Additionally, this SNP was significantly associated with the disease in patients of Korean (p=2.18×10, OR 0.54) and European (p=5.12×10, OR 0.63) ancestry.

Conclusions: We identified rs109592 in the locus as a susceptibility marker for pulmonary MAC disease.
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http://dx.doi.org/10.1183/13993003.02269-2019DOI Listing
August 2021

Characterization of LILRB3 and LILRA6 allelic variants in the Japanese population.

J Hum Genet 2021 Jul 1;66(7):739-748. Epub 2021 Feb 1.

Advanced Preventive Medical Sciences Research Center, Kanazawa University, Ishikawa, Japan.

Leukocyte immunoglobulin (Ig)-like receptors (LILRs) are encoded by members of a human multigene family, comprising 11 protein-coding genes and two pseudogenes. Among the LILRs, LILRB3 and LILRA6 show the highest homology with each other, along with high allelic and copy number variations. Therefore, it has been difficult to discriminate between them, both genetically and functionally, precluding disease association studies of LILRB3 and LILRA6. In this study, we carefully performed variant screening of LILRB3 and LILRA6 by cDNA cloning from Japanese individuals and identified four allelic lineages showing significantly high non-synonymous-to-synonymous ratios in pairwise comparisons. Furthermore, the extracellular domains of the LILRB3*JP6 and LILRA6*JP1 alleles were identical at the DNA level, suggesting that gene conversion-like events diversified LILRB3 and LILRA6. To determine the four allelic lineages from genomic DNA, we established a lineage typing method that accurately estimated the four allelic lineages in addition to specific common alleles from genomic DNA. Analysis of LILRA6 copy number variation revealed one, two, and three copies of LILRA6 in the Japanese-in-Tokyo (JPT) population. Flow cytometric analysis showed that an anti-LILRB3 antibody did not recognize the second most common lineage in the Japanese population, indicating significant amino acid differences across the allelic lineages. Taken together, our findings indicate that our lineage typing is useful for classifying the lineage-specific functions of LILRB3 and LILRA6, serving as the basis for disease association studies.
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http://dx.doi.org/10.1038/s10038-021-00906-0DOI Listing
July 2021

Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease.

Inflamm Bowel Dis 2021 Jan 27. Epub 2021 Jan 27.

Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Mitaka, Japan.

Background: Some patients with inflammatory bowel disease (IBD) who were under mesalamine treatment develop adverse reactions called "mesalamine allergy," which includes high fever and worsening diarrhea. Currently, there is no method to predict mesalamine allergy. Pharmacogenomic approaches may help identify these patients. Here we analyzed the genetic background of mesalamine intolerance in the first genome-wide association study of Japanese patients with IBD.

Methods: Two independent pharmacogenetic IBD cohorts were analyzed: the MENDEL (n = 1523; as a discovery set) and the Tohoku (n = 788; as a replication set) cohorts. Genome-wide association studies were performed in each population, followed by a meta-analysis. In addition, we constructed a polygenic risk score model and combined genetic and clinical factors to model mesalamine intolerance.

Results: In the combined cohort, mesalamine-induced fever and/or diarrhea was significantly more frequent in ulcerative colitis vs Crohn's disease. The genome-wide association studies and meta-analysis identified one significant association between rs144384547 (upstream of RGS17) and mesalamine-induced fever and diarrhea (P = 7.21e-09; odds ratio = 11.2). The estimated heritability of mesalamine allergy was 25.4%, suggesting a significant correlation with the genetic background. Furthermore, a polygenic risk score model was built to predict mesalamine allergy (P = 2.95e-2). The combined genetic/clinical prediction model yielded a higher area under the curve than did the polygenic risk score or clinical model alone (area under the curve, 0.89; sensitivity, 71.4%; specificity, 90.8%).

Conclusions: Mesalamine allergy was more common in ulcerative colitis than in Crohn's disease. We identified a novel genetic association with and developed a combined clinical/genetic model for this adverse event.
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http://dx.doi.org/10.1093/ibd/izab004DOI Listing
January 2021

Genome-wide SNP data of Izumo and Makurazaki populations support inner-dual structure model for origin of Yamato people.

J Hum Genet 2021 Jul 25;66(7):681-687. Epub 2021 Jan 25.

Population Genetics Laboratory, National Institute of Genetics, Yata 1111, Mishima, 411-8540, Japan.

The "Dual Structure" model on the formation of the modern Japanese population assumes that the indigenous hunter-gathering population (symbolized as Jomon people) admixed with rice-farming population (symbolized as Yayoi people) who migrated from the Asian continent after the Yayoi period started. The Jomon component remained high both in Ainu and Okinawa people who mainly reside in northern and southern Japan, respectively, while the Yayoi component is higher in the mainland Japanese (Yamato people). The model has been well supported by genetic data, but the Yamato population was mostly represented by people from Tokyo area. We generated new genome-wide SNP data using Japonica Array for 45 individuals in Izumo City of Shimane Prefecture and for 72 individuals in Makurazaki City of Kagoshima Prefecture in Southern Kyushu, and compared these data with those of other human populations in East Asia, including BioBank Japan data. Using principal component analysis, phylogenetic network, and f4 tests, we found that Izumo, Makurazaki, and Tohoku populations are slightly differentiated from Kanto (including Tokyo), Tokai, and Kinki regions. These results suggest the substructure within Mainland Japanese maybe caused by multiple migration events from the Asian continent following the Jomon period, and we propose a modified version of "Dual Structure" model called the "Inner-Dual Structure" model.
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http://dx.doi.org/10.1038/s10038-020-00898-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225512PMC
July 2021

Human leucocyte antigen association of patients with Stevens-Johnson syndrome/toxic epidermal necrolysis with severe ocular complications in Han Chinese.

Br J Ophthalmol 2021 Jan 13. Epub 2021 Jan 13.

Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan

Background/aims: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) induced by cold medicine (CM) may result in severe ocular complications (SOCs). The purpose of this study was to investigate the human leucocyte antigen (HLA) polymorphism pattern in CM-induced patients with SJS/TEN developing SOCs.

Methods: All participants, including patients with SJS/TEN (n=33) and control patients (n=98), were enrolled through visits to the clinic from 2016 to 2017. SOCs were diagnosed (n=26) via a chart review or eye examination. Patient saliva was collected with commercialised kits and genotyped with PCR assays followed by hybridisation with sequence-specific oligonucleotide (SSO) probes (PCR-SSO) using commercial bead-based typing kits.

Results: In all patients with SJS/TEN with SOCs, the HLA-A*02:07 carrier frequency was significantly higher than that in controls (OR=3.24, 95% CI=1.09 to 9.60, p=0.049), as was the genotype frequency (OR=3.89, 95% CI=1.49 to 10.16, p=0.007). In patients with CM-SJS/TEN with SOCs, the HLA-A*02:07 carrier frequency was higher than that in controls (OR=5.56, 95% CI=1.52 to 20.00, p=0.016), as was the allele frequency (OR=6.67, 95% CI=2.33 to 20.00, p=0.001). In patients with CM-SJS/TEN with SOCs, the HLA-B*46:01 allele frequency was significantly higher than that in controls (OR=3.85, 95% CI=1.52 to 10.00, p=0.008).

Conclusions: The HLA-A*02:07 and HLA-B*46:01 alleles were significantly associated with SOCs among Han Chinese patients with CM-SJS/TEN. These findings demonstrate the genetic diversity in SJS pathogenesis among different ethnic groups.
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http://dx.doi.org/10.1136/bjophthalmol-2020-317105DOI Listing
January 2021

Genetic characterization of -acetyltransferase 2 variants in acquired multidrug-resistant tuberculosis in Indonesia.

Pharmacogenomics 2021 02 5;22(3):157-163. Epub 2021 Jan 5.

Genome Medical Science Project (Toyama), National Center for Global Health & Medicine, Tokyo, Japan.

Owing to the high resistance rate of tuberculosis (TB) to isoniazid, which is metabolized by -acetyltransferase 2 (NAT2), we investigated the associations between variants and multidrug-resistant (MDR)-TB. The acetylator status based on haplotypes of 128 patients with MDR-TB in Indonesia were compared with our published data from patients with anti-TB drug-induced liver injury (AT-DILI), TB and the general population. was more frequent in the MDR-TB group than in the AT-DILI group, TB controls and general controls. was significantly more frequent in patients with MDR-TB than in those with AT-DILI.  and were detected at lower frequencies in patients with AT-DILI. Rapid acetylators were significantly more frequent in patients with MDR-TB than in those with AT-DILI. These results provide an initial data for optimizing TB treatment in the Indonesian population, and suggest that genotyping may help to select appropriate treatment by predicting TB-treatment effect.
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http://dx.doi.org/10.2217/pgs-2020-0163DOI Listing
February 2021

Identification and functional prediction of lineage-specific SNPs distributed in DosR-related proteins and resuscitation-promoting factor proteins of .

Heliyon 2020 Dec 18;6(12):e05744. Epub 2020 Dec 18.

Pornchai Matangkasombut Center for Microbial Genomics, Department of Microbiology, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok, Thailand.

One-third of the world population is infected by which may persist in the latent or dormant state. Bacteria can shift to dormancy when encountering harsh conditions such as low oxygen, nutrient starvation, high acidity and host immune defenses Genes related to the dormancy survival regulator (DosR) regulon are responsible for the inhibition of aerobic respiration and replication, which is required to enter dormancy. Conversely, resuscitation-promoting factor (rpf) proteins participate in reactivation from dormancy and the development of active tuberculosis (TB). Many DosR regulon and rpf proteins are immunodominant T cell antigens that are highly expressed in latent TB infection. They could serve as TB vaccine candidates and be used for diagnostic development. We explored the genetic polymorphisms of 50 DosR-related genes and 5 genes among 1,170 previously sequenced clinical genomes. Forty-three lineage- or sublineage-specific nonsynonymous single nucleotide polymorphisms (nsSNPs) were identified. Ten nsSNPs were specific to all Mtb isolates belonging to lineage 1 (L1). Two common sublineages, the Beijing family (L2.2) and EAI2 (L1.2.1), differed at as many as 26 lineage- or sublineage-specific SNPs. DosR regulon genes related to membrane proteins and the family possessed mean dN/dS ratios greater than one, suggesting that they are under positive selection. Although the T cell epitope regions of DosR-related and rpf antigens were quite conserved, we found that the epitopes in L1 had higher rates of genetic polymorphisms than the other lineages. Some mutations in immunogenic epitopes of the antigens were specific to particular lineages. Therefore, the genetic diversity of the DosR regulon and rpf proteins might impact the adaptation of to the dormant state and the immunogenicity of latency antigens, which warrants further investigation.
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http://dx.doi.org/10.1016/j.heliyon.2020.e05744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753917PMC
December 2020

Digenic mutations in and impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome.

Sci Adv 2020 Dec 18;6(51). Epub 2020 Dec 18.

Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.

Rs671 in the aldehyde dehydrogenase 2 gene () is the cause of Asian alcohol flushing response after drinking. ALDH2 detoxifies endogenous aldehydes, which are the major source of DNA damage repaired by the Fanconi anemia pathway. Here, we show that the rs671 defective allele in combination with mutations in the alcohol dehydrogenase 5 gene, which encodes formaldehyde dehydrogenase ( ), causes a previously unidentified disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome. Cellular studies revealed that a decrease in the formaldehyde tolerance underlies a loss of differentiation and proliferation capacity of hematopoietic stem cells. Moreover, double-deficient mice recapitulated key clinical features of AMeDS, showing short life span, dwarfism, and hematopoietic failure. Collectively, our results suggest that the combined deficiency of formaldehyde clearance mechanisms leads to the complex clinical features due to overload of formaldehyde-induced DNA damage, thereby saturation of DNA repair processes.
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http://dx.doi.org/10.1126/sciadv.abd7197DOI Listing
December 2020

Association of disease severity with toll-like receptor polymorphisms in multidrug-resistant tuberculosis patients.

Int J Mycobacteriol 2020 Oct-Dec;9(4):380-390

Department of Clinical Microbiology, Faculty of Medicine, Airlangga University, Surabaya, Indonesia.

Background: The disease severity in pulmonary Multidrug-resistant tuberculosis (MDR-TB) varies from mild to severe, which is determined by host and pathogen virulence factors. The difference of symptoms felt by TB patients were interesting to investigate in discovering whether its the human immune response or bacteria's virulence gene that plays the role. The aim of this research was to analyze association between disease severity degree of pulmonary MDR-TB patients with Single nucleotide polymorphisms (SNPs) found in toll-like receptors (TLRs) gene.

Method: Blood samples were obtained from pulmonary MDR-TB patients in Dr. Soetomo Hospital, Surabaya, Indonesia. Polymerase chain reaction (PCR) multiplex and target SNPs were analyze using DigiTag2 assay. The variant of esxA gene was determined using PCR and sequencing. Severity degree was determined by chest X-ray, the lesions were scored according to their severity, score of =2.5 ranking as mild, 2.5-6 as moderate and =6 as severe. Association level between SNP in TLRs gene degree of pulmonary MDR-TB was analyzed using Chi-square test. Bonferroni correction for multiple comparison was used to anticipate genotyping error.

Results: A total of 22 MDR-TB patients were classified into severe degree group, while 16 patients were moderate/mild degree. SNPs in encoding gene of TLRs were mostly found in intron, specifically in TLR-1, TLR-2, and TLR-6. HWE P value in rs5743572 was 0.841; in rs3804100 was 0.0176; and in rs5743808 was 0.562. Association analysis between SNP in TLRs genes and degree of disease revealed significant association in rs5743572, SNP of TLR-1, with P < 0.05; odds ratio [OR] = 11.67 (95% confidence interval [CI]: 3.94-34.52); rs3804100, SNP of TLR-2 had P < 0.05; OR = 37.59 (95% CI: 9.30-151.88); and rs5743808, the SNP of TLR-6 had P < 0.05; OR = 31.5 (95% CI: 8.60-115.34).

Conclusions: We concluded that SNPs in TLR-1, TLR-2, and TLR-6 of pulmonary MDR-TB patients was found to have an association with disease severity. TLRs polymorphism had significant association was present in TLR-1 rs5743572 in intron, TLR-2 rs3804100 in exon, and TLR-6 rs5743808 in exon and among MDR-TB isolates from patients with pulmonary MDR-TB of severe and moderate/mild degree.
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http://dx.doi.org/10.4103/ijmy.ijmy_175_20DOI Listing
September 2021

Verifying nomenclature of DNA variants in submitted manuscripts: Guidance for journals.

Hum Mutat 2021 Jan 10;42(1):3-7. Epub 2020 Dec 10.

Department of Genetic Medicine, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Documenting variation in our genomes is important for research and clinical care. Accuracy in the description of DNA variants is therefore essential. To address this issue, the Human Variome Project convened a committee to evaluate the feasibility of requiring authors to verify that all variants submitted for publication complied with a widely accepted standard for description. After a pilot study of two journals, the committee agreed that requiring authors to verify that variants complied with Human Genome Variation Society nomenclature is a reasonable step toward standardizing the worldwide inventory of human variation.
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http://dx.doi.org/10.1002/humu.24144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961887PMC
January 2021

Practical guide for managing large-scale human genome data in research.

J Hum Genet 2021 Jan 23;66(1):39-52. Epub 2020 Oct 23.

Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan.

Studies in human genetics deal with a plethora of human genome sequencing data that are generated from specimens as well as available on public domains. With the development of various bioinformatics applications, maintaining the productivity of research, managing human genome data, and analyzing downstream data is essential. This review aims to guide struggling researchers to process and analyze these large-scale genomic data to extract relevant information for improved downstream analyses. Here, we discuss worldwide human genome projects that could be integrated into any data for improved analysis. Obtaining human whole-genome sequencing data from both data stores and processes is costly; therefore, we focus on the development of data format and software that manipulate whole-genome sequencing. Once the sequencing is complete and its format and data processing tools are selected, a computational platform is required. For the platform, we describe a multi-cloud strategy that balances between cost, performance, and customizability. A good quality published research relies on data reproducibility to ensure quality results, reusability for applications to other datasets, as well as scalability for the future increase of datasets. To solve these, we describe several key technologies developed in computer science, including workflow engine. We also discuss the ethical guidelines inevitable for human genomic data analysis that differ from model organisms. Finally, the future ideal perspective of data processing and analysis is summarized.
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http://dx.doi.org/10.1038/s10038-020-00862-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728600PMC
January 2021

Risk factors associated with large clusters of tuberculosis patients determined by whole-genome sequencing in a high-tuberculosis-burden country.

Tuberculosis (Edinb) 2020 12 11;125:101991. Epub 2020 Sep 11.

National Centre for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathumthani, Thailand; Pornchai Matangkasombut Centre of Microbial Genomics, Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand. Electronic address:

Whole-genome sequencing (WGS) analysis has great discriminative power for detecting similar molecular fingerprints of suspected tuberculosis (TB) clusters. The proportion of TB cases within clusters and the associated risk factors are important epidemiological parameters guiding appropriate outbreak control strategies in endemic settings. We conducted a hospital-based TB case-cohort study between 2003 and 2011 in the northernmost province of Thailand. We identified TB clusters by Mycobacterium tuberculosis WGS and analysed the risks of TB clustering and the characteristics of large clusters compared with small clusters. Among 1146 TB isolates, we identified 77 clusters with 251 isolates defined by a 5-single-nucleotide variant (SNV) cutoff and 112 clusters with 431 isolates defined by a 12-SNV cutoff. Twelve large clusters with 6 isolates or more in each cluster were identified by a 12-SNV cutoff. Sublineage 2.2.1 (both Ancestral and Modern) strains and imprisonment were independently associated with large clusters. Furthermore, although large clusters of Lineage 2.2.1/Ancestral strains included a high number of prisoners, Lineage 2.2.1/Modern strain clusters were only associated with treatment failures and drug resistance. Heterogeneity among lineage strains was observed with respect to large-cluster characteristics. Patients with an increased TB-transmission tendency should be priority targets for contact investigations and outbreak interventions to prevent ongoing transmission.
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http://dx.doi.org/10.1016/j.tube.2020.101991DOI Listing
December 2020

Genome-Wide Association Study of Lean Nonalcoholic Fatty Liver Disease Suggests Human Leukocyte Antigen as a Novel Candidate Locus.

Hepatol Commun 2020 Aug 19;4(8):1124-1135. Epub 2020 May 19.

Division of Human Genetics Center for Molecular Medicine Jichi Medical University Shimotsuke Japan.

Nonalcoholic fatty liver disease (NAFLD) is supposed to manifest its metabolic phenotype in the liver, but it is common to have lean individuals diagnosed with NAFLD, known as lean NAFLD. We conducted a two-stage analysis to identify NAFLD-associated loci in Japanese patients. In stage I, 275 metabolically healthy normal-weight patients with NAFLD were compared with 1,411 non-NAFLD controls adjusted for age, sex, and alcohol consumption by a genome-wide association study (GWAS). In stage II, human leukocyte antigen () in chromosome 6 (chr6) ( = 6.73E-08), microRNA (MIR) in chr7 ( = 4.25E-07), myosin light chain 2 () in chr12 ( = 4.39E-07), and glycoprotein precursor () in chr13 ( = 5.43E-07), as suggested by the GWAS, were assessed by single nucleotide polymorphism (SNP) association analysis of whole NAFLD against non-NAFLD in 9,726 members of the general population. A minor allele of the secondary lead SNP in chr6, rs2076529, was significantly associated (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.11-1.28;  = 2.10E-06) and the lead SNP in chr7 was weakly associated (OR 1.15; 95% CI, 1.04-1.27;  = 6.19E-03) with increased NAFLD risk. Imputation-based typing of showed a significant difference in the distribution of DR-beta chain 1 (), and DQ-beta chain 1 () alleles in lean NAFLD GWAS. Next-generation sequence-based typing of in 5,649 members of the general population replicated the significant difference of allele distribution and the significant increase of the allele in whole NAFLD. Fecal metagenomic analysis of 3,420 members of the general population showed significant dissimilarity in beta-diversity analysis of rs2076529 and allele carriers from noncarriers. Veillonellaceae was increased but Verrucomicrobia was decreased in rs2076529 minor allele and allele carriers as in NAFLD. : was identified as a novel locus associated with NAFLD susceptibility, which might be affected by the alteration of gut microbiota.
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http://dx.doi.org/10.1002/hep4.1529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395061PMC
August 2020

An Integrated Genomic and Transcriptomic Analysis Reveals Candidates of Susceptibility Genes for Crohn's Disease in Japanese Populations.

Sci Rep 2020 06 24;10(1):10236. Epub 2020 Jun 24.

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Expression quantitative trait locus (eQTL) analyses have enabled us to predict the function of disease susceptibility SNPs. However, eQTL for the effector memory T cells (TEM) located in the lamina propria mononuclear cells (LPMCs), which play an important role in Crohn's disease (CD), are not yet available. Thus, we conducted RNA sequencing and eQTL analyses of TEM cells located in the LPMCs from IBD patients (n = 20). Genome-wide association study (GWAS) was performed using genotyping data of 713 Japanese CD patients and 2,063 controls. We compared the results of GWAS and eQTL of TEM, and also performed a transcriptome-wide association study using eQTL from Genotype Tissue Expression project. By eQTL analyses of TEM, correlations of possible candidates were confirmed in 22,632 pairs and 2,463 genes. Among these candidates, 19 SNPs which showed significant correlation with tenascin-XA (TNXA) expression were significantly associated with CD in GWAS. By TWAS, TNFSF15 (FDR = 1.35e-13) in whole blood, ERV3-1 (FDR = 2.18e-2) in lymphocytes, and ZNF713 (FDR = 3.04e-2) in the sigmoid colon was significantly associated with CD. By conducting integration analyses using GWAS and eQTL data, we confirmed multiple gene transcripts are involved in the development of CD.
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http://dx.doi.org/10.1038/s41598-020-66951-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314801PMC
June 2020

Large-scale genome-wide association study identifies HLA class II variants associated with chronic HBV infection: a study from Taiwan Biobank.

Aliment Pharmacol Ther 2020 08 23;52(4):682-691. Epub 2020 Jun 23.

Taipei, Taiwan.

Background: Chronic hepatitis B virus (HBV) infection is a great health burden with geographical variations.

Aims: To explore genetic variants associated with chronic HBV infection.

Methods: The study included 15 352 participants seropositive for HBV core antibodies in Taiwan Biobank. Among them, 2591 (16.9%) seropositive for HBV surface antigen (HBsAg) were defined as having chronic HBV infection. All participants were examined for whole-genome genotyping by Axiom-Taiwan Biobank Array. The human leucocyte antigen (HLA) imputation was performed after identification of the variants within the region. Logistic regressions were used to estimate odds ratios (ORs) with 95% confidence intervals. Correlations of different HLA allele frequencies with HBsAg seroprevalence were evaluated across worldwide populations by Pearson correlation coefficients. Epitope prediction was performed for HLA alleles using NetMHCIIpan method.

Results: Located within a cluster of 450 single nucleotide polymorphisms in HLA class II, rs7770370 (P = 2.73 × 10 ) was significantly associated with HBV chronicity (P  < 8.6 × 10 ). Imputation analyses showed that HLA-DPA1*02:02 and HLA-DPB1*05:01 were associated with chronic HBV, with adjusted ORs of 1.43 (1.09-1.89) and 1.61 (1.29-2.01). These allele frequencies were positively correlated with global HBsAg seroprevalence, with R of 0.75 and 0.62 respectively (P < 0.05). HLA-DRB1*13:02, HLA-DQA1* 01:02 and HLA-DQB1*06:09 associated with HBV chronicity negatively, with adjusted ORs of 0.31 (0.17-0.58), 0.70 (0.56-0.87) and 0.33 (0.18-0.63). These HLA alleles had various binding affinities to the predicted epitopes derived from HBV nucleocapsid protein.

Conclusions: HLA class II variants are relevant for chronicity after HBV acquisition.
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http://dx.doi.org/10.1111/apt.15887DOI Listing
August 2020

Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome.

Kidney Int 2020 11 14;98(5):1308-1322. Epub 2020 Jun 14.

Department of Pediatrics, Chonnam National University Children's Hospital, Gwangju, Korea.

To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (P=6.71E-28, OR=1.88) and TNFSF15 (P=5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4). Because rare pathogenic variants in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF), the present study provides further evidence that variation along the allele frequency spectrum in the same gene can cause or contribute to both a rare monogenic disease (CNSF) and a more complex, polygenic disease (SSNS).
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http://dx.doi.org/10.1016/j.kint.2020.05.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101291PMC
November 2020

Polo-like kinase 4 and Stromal antigen 3 are not associated with recurrent pregnancy loss caused by embryonic aneuploidy.

Hum Genome Var 2020 29;7:18. Epub 2020 May 29.

Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

No genetic association with recurrent pregnancy loss (RPL) caused by embryonic aneuploidy has been found. Recent studies have indicated that the common genetic variant rs2305957, surrounding the gene, contributes to mitotic-origin aneuploidy risk during human early embryo development. The decrease in meiosis-specific cohesin causes predivision of sister chromatids in the centromere and chromosome segregation errors. is a component of cohesin and is a meiosis-specific gene. Our case-control study included 184 patients with RPL whose previous products of conception (POC) exhibited aneuploidy and 190 fertile control women without a history of miscarriage. We performed a genetic association study to examine the genotype distribution at (rs2305957) and in patients with RPL caused by aneuploidy compared with controls. Regarding , SNPs with a minor allele frequency (MAF) threshold > 0.05 that were predicted to be binding sites of transcription factors and that showed significant associations in expression quantitative trait locus (e-QTL) analysis were selected. No significant differences in the MAF or distribution in any model of (rs2305957) and 5 selected tag SNPs in were found between the patients and controls. A further genome-wide association study is needed since a combination of genetic risk alleles might be useful in predicting future age-dependent RPL caused by aneuploidy.
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http://dx.doi.org/10.1038/s41439-020-0106-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260232PMC
May 2020

Homoplastic single nucleotide polymorphisms contributed to phenotypic diversity in Mycobacterium tuberculosis.

Sci Rep 2020 05 15;10(1):8024. Epub 2020 May 15.

Pornchai Matangkasombut Center for Microbial Genomics, Department of Microbiology, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok, Thailand.

Homoplastic mutations are mutations independently occurring in different clades of an organism. The homoplastic changes may be a result of convergence evolution due to selective pressures. Reports on the analysis of homoplastic mutations in Mycobacterium tuberculosis have been limited. Here we characterized the distribution of homoplastic single nucleotide polymorphisms (SNPs) among genomes of 1,170 clinical M. tuberculosis isolates. They were present in all functional categories of genes, with pe/ppe gene family having the highest ratio of homoplastic SNPs compared to the total SNPs identified in the same functional category. Among the pe/ppe genes, the homoplastic SNPs were common in a relatively small number of homologous genes, including ppe18, the protein of which is a component of a promising candidate vaccine, M72/AS01E. The homoplastic SNPs in ppe18 were particularly common among M. tuberculosis Lineage 1 isolates, suggesting the need for caution in extrapolating the results of the vaccine trial to the population where L1 is endemic in Asia. As expected, homoplastic SNPs strongly associated with drug resistance. Most of these mutations are already well known. However, a number of novel mutations associated with streptomycin resistance were identified, which warrants further investigation. A SNP in the intergenic region upstream of Rv0079 (DATIN) was experimentally shown to increase transcriptional activity of the downstream gene, suggesting that intergenic homoplastic SNPs should have effects on the physiology of the bacterial cells. Our study highlights the potential of homoplastic mutations to produce phenotypic changes. Under selective pressure and during interaction with the host, homoplastic mutations may confer advantages to M. tuberculosis and deserve further characterization.
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http://dx.doi.org/10.1038/s41598-020-64895-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229016PMC
May 2020

Metabolome analysis using cerebrospinal fluid from narcolepsy type 1 patients.

Sleep 2020 11;43(11)

Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Narcolepsy type 1 (NT1) is a hypersomnia characterized by excessive daytime sleepiness and cataplexy. Inappropriate regulation of fatty acid metabolism has been suggested to be involved in the pathophysiology of NT1, but the detailed mechanisms remain uncertain. Here we performed a metabolomic analysis of cerebrospinal fluid samples from 14 NT1 and 17 control subjects using a novel capillary electrophoresis coupled with Fourier transform mass spectrometry. A total of 268 metabolites were identified and the amount of histidine was the most significantly increased in NT1 patients (p = 4.0 × 10-4). Validation analysis using high-performance liquid chromatography (HPLC) including independent replication samples also identified the association of histidine (p = 2.02 × 10-3). Further, levels of histamine, which is synthesized from histidine, were also examined using HPLC and were found to be significantly decreased in NT1 patients (p = 6.12 × 10-4). Pathway analysis with nominally significant metabolites identified several pathways related to the metabolism of glycogenic amino acids, suggesting that glycogenesis is enhanced in NT1 as a compensatory mechanism for fatty acid metabolism. We performed further exploratory analysis, searching for metabolites associated with sleep variables from polysomnography and the multiple sleep latency test. As a result, 5'-deoxy-5'-methylthioadenosine showed a significant association with apnea-hypopnea index (p = 2.66 ×10-6). Moreover, gamma aminobutyric acid displayed a negative correlation with rapid eye movement sleep latency (REML), and thus might represent an intriguing target for future studies to elucidate how the controlling circuit of REM sleep is associated with abnormally short REML in NT1.
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http://dx.doi.org/10.1093/sleep/zsaa095DOI Listing
November 2020

Haplotype-specific PCR for diplotyping.

Hum Genome Var 2020 11;7:13. Epub 2020 May 11.

1Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand.

N-acetyltransferase 2 (NAT2) is an enzyme that acetylates many kinds of drugs, including the antituberculosis drug isoniazid. The gene is highly diverse across populations. An individual can be classified as having a slow acetylator (SA), an intermediate acetylator (IA), or a rapid acetylator (RA) phenotype based on its two haplotypes (diplotype) of . SA individuals are at a higher risk for isoniazid-induced hepatitis, while the RA phenotype contributes to failure in tuberculosis treatment. Being able to predict individual NAT2 phenotypes is important for dose adjustment of isoniazid. 2 haplotypes are commonly determined via an indirect method of statistical haplotype inference from SNP genotyping. Here, we report a direct haplotyping method using haplotype-specific PCR (HS-PCR) for the 6 most commonly found 2 haplotypes: 2*42*52*62*72*12, and 2*13. Validation of this HS-PCR method via comparison with a sequencing method in 650 Thai DNA samples (107 RA, 279 IA, and 264 SA samples) showed a concordance rate for diplotype calls of 99.23% (645/650 samples). The discordant results in 5 samples were due to 3 rare haplotypes: *5 ( = 3), 2*7 ( = 1), and 2*11 ( = 1). This novel HS-PCR method allows direct 2 diplotyping, enabling the implementation of NAT2 acetylator phenotypes in clinical pharmacogenetic testing.
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http://dx.doi.org/10.1038/s41439-020-0101-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214404PMC
May 2020
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