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1.
Eur J Hum Genet ; 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33833419

RESUMO

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).

2.
Gastroenterology ; 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33675743

RESUMO

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 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; 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 × 10-8), 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 × 10-9; 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.

3.
Sci Rep ; 11(1): 3703, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33654122

RESUMO

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.

4.
Eur Respir J ; 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33542050

RESUMO

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 Mycobacterium avium 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=1.64E-13, odds ratio=0.54), which is in an intronic region of the calcineurin like EF-hand protein 2 (CHP2). 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. This SNP was also significantly associated with the disease in patients of Korean (p=2.18E-12, odds ratio=0.54) and European (p=5.12E-03, odds ratio=0.63) ancestry. CONCLUSIONS: We identified rs109592 in the CHP2 locus as a susceptibility marker for pulmonary MAC disease.

5.
Sci Rep ; 11(1): 4557, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33633225

RESUMO

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.

6.
J Hum Genet ; 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526815

RESUMO

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.

7.
Br J Ophthalmol ; 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441319

RESUMO

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.

8.
J Hum Genet ; 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33495571

RESUMO

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.

9.
Inflamm Bowel Dis ; 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33501934

RESUMO

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.

10.
Pharmacogenomics ; 22(3): 157-163, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33399479

RESUMO

Background: Owing to the high resistance rate of tuberculosis (TB) to isoniazid, which is metabolized by N-acetyltransferase 2 (NAT2), we investigated the associations between NAT2 variants and multidrug-resistant (MDR)-TB. Materials & methods: The acetylator status based on NAT2 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. Results: NAT2*4 was more frequent in the MDR-TB group than in the AT-DILI group, TB controls and general controls. NAT2*4/*4 was significantly more frequent in patients with MDR-TB than in those with AT-DILI. NAT2*5B/7B, *6A/6A and *7B/*7B 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. Conclusion: These results provide an initial data for optimizing TB treatment in the Indonesian population, and suggest that NAT2 genotyping may help to select appropriate treatment by predicting TB-treatment effect.

11.
J Hum Genet ; 66(1): 39-52, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33097812

RESUMO

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.

12.
Int J Mycobacteriol ; 9(4): 380-390, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33323653

RESUMO

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.

13.
Sci Adv ; 6(51)2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33355142

RESUMO

Rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) 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 (ADH5FDH ), 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, Adh5-/-Aldh2 E506K/E506K 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.

14.
Hum Mutat ; 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33252176

RESUMO

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.

15.
Tuberculosis (Edinb) ; 125: 101991, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32949880

RESUMO

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.

16.
Hepatol Commun ; 4(8): 1124-1135, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32766473

RESUMO

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 (HLA) in chromosome 6 (chr6) (P = 6.73E-08), microRNA (MIR) MIR548F3 in chr7 (P = 4.25E-07), myosin light chain 2 (MYL2) in chr12 (P = 4.39E-07), and glycoprotein precursor (GPC)6 in chr13 (P = 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; P = 2.10E-06) and the lead SNP in chr7 was weakly associated (OR 1.15; 95% CI, 1.04-1.27; P = 6.19E-03) with increased NAFLD risk. Imputation-based typing of HLA showed a significant difference in the distribution of HLA-B, HLA-DR-beta chain 1 (DRB1), and HLA-DQ-beta chain 1 (DQB1) alleles in lean NAFLD GWAS. Next-generation sequence-based typing of HLA in 5,649 members of the general population replicated the significant difference of HLA-B allele distribution and the significant increase of the HLA-B*54:01 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 HLA-B*54:01 allele carriers from noncarriers. Veillonellaceae was increased but Verrucomicrobia was decreased in rs2076529 minor allele and HLA-B*54:01 allele carriers as in NAFLD. Conclusion: HLA was identified as a novel locus associated with NAFLD susceptibility, which might be affected by the alteration of gut microbiota.

17.
Sci Rep ; 10(1): 10236, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581322

RESUMO

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.

18.
Aliment Pharmacol Ther ; 52(4): 682-691, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32573827

RESUMO

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 × 10-35 ) was significantly associated with HBV chronicity (Pcorrected  < 8.6 × 10-8 ). 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.


Assuntos
Genes MHC da Classe II/genética , Estudo de Associação Genômica Ampla , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Bancos de Espécimes Biológicos/estatística & dados numéricos , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/imunologia , Hepatite B Crônica/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Taiwan/epidemiologia
19.
Kidney Int ; 98(5): 1308-1322, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32554042

RESUMO

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 (Pmeta=6.71E-28, OR=1.88) and TNFSF15 (Pmeta=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).

20.
Hum Genome Var ; 7: 18, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32528715

RESUMO

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 PLK4 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. STAG3 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 PLK4 (rs2305957) and STAG3 in patients with RPL caused by aneuploidy compared with controls. Regarding STAG3, 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 PLK4 (rs2305957) and 5 selected tag SNPs in STAG3 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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