A cis-eQTL of HLA-DPB1 Affects Susceptibility to Type 1 Autoimmune Hepatitis.
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ABSTRACT:
SUBMITTER: Yamazaki T
PROVIDER: S-EPMC6085285 | biostudies-literature | 2018 Aug
REPOSITORIES: biostudies-literature
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A cis-eQTL of HLA-DPB1 Affects Susceptibility to Type 1 Autoimmune Hepatitis.
Yamazaki Tomoo T Umemura Takeji T Joshita Satoru S Yoshizawa Kaname K Tanaka Eiji E Ota Masao M
Scientific reports 20180809 1
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by an autoimmune reaction to hepatocytes. A single nucleotide polymorphism in the 3' untranslated region of HLA-DPB1, rs9277534, is associated with HLA-DPB1 expression. rs9277534 has been linked to hepatitis B virus recovery/persistence and the risk of graft-versus-host disease with HLA-DPB1 mismatching transplantation of hematopoietic cells, but its role along with that of HLA-DP expression in AIH have not been ful ...[more]
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Project description:PURPOSE:The precise etiology of autoimmune hepatitis (AIH) remains unknown, although a number of genetic loci have been implicated in the susceptibility of type 1 AIH. The purpose of this study was to test for association of these loci with type 1 AIH in New Zealand Caucasians. METHODS:77 AIH patients and 485 healthy controls were genotyped for the SNPs rs2187668 (HLA-DRB*03:01), rs660895 (HLA-DRB*04:01), rs3749971 (HLA-A1-B8-DR3), rs231775 (CLTLA4), rs1800629 (TNF), and rs1800682 (FAS) using predesigned TaqMan SNP genotyping assays. Chi square analysis was used to test for association of allele and genotype with overall AIH, and with severe fibrosis and ALT levels at 6 months. RESULTS:Significant risk of AIH was conferred by the minor alleles of rs2187668 (OR?=?2.45, 95% CI 1.65-3.61, p?<?0.0001), rs3749971 (OR?=?1.89, 95% CI 1.21-2.94, p?=?0.004) and rs1800629 (OR?=?2.06, 95% CI 1.41-3.01, p?=?0.0001). Multivariate analysis showed that rs2187668 was independently associated with type 1 AIH susceptibility (OR?=?2.40, 95% CI 1.46-3.93, p?=?0.001). The C allele of FAS SNP rs1800682 was associated with increased risk of severe fibrosis at diagnosis (OR?=?2.03, 95% CI 1.05-3.93, p?=?0.035) and with incomplete normalization of ALT levels at 6 months post-diagnosis (OR?=?3.94, 95% CI 1.62-9.54, p?=?0.0015). CONCLUSIONS:This is the first population-based study to investigate genetic risk loci for type 1 AIH in New Zealand Caucasians. We report significant independent association of HLA-DRB1*03:01 with overall susceptibility to type 1 AIH, as well as FAS with a more aggressive disease phenotype.
| S-EPMC3733077 | biostudies-literature
Project description:Natural killer (NK) cells are key participants in the innate immune response. Killer cell immunoglobulin-like receptors (KIRs) are involved in the activation and inhibition of NK cells through the recognition of human leukocyte antigen (HLA) class I molecules. We investigated the impact of KIR/HLA combinations on susceptibility and long-term clinical outcome in Japanese patients with type 1 autoimmune hepatitis (AIH). Methods:A total of 154 cases of AIH were recruited at Shinshu University Hospital between 1974 and 2018. KIR genes and HLA class I and II alleles were genotyped in all patients along with 201 healthy individuals. Associations between KIR/HLA pairs and clinical outcomes (liver decompensation and liver-related death) were evaluated using the Cox proportional hazards model with stepwise method. Results:After a median follow-up period of 11.1 years, 12% of patients experienced liver decompensation and 8% died from liver disease. KIR3DL1/HLA-B Bw4-80Ile (p = 0.0062) and the HLA-DRB1*04:05-DQB1*04:01 haplotype (p ?0.001) were significantly associated with AIH. Conversely, significant protective associations were found for KIR3DL1/HLA-B Bw4-80Thr (p = 0.0092) and KIR2DL1/HLA-C2 (p = 0.0025). The KIR3DL1/HLA-B Bw4-positive phenotype was strongly associated with a favorable clinical outcome (liver decompensation: hazard ratio [HR] 0.37, p = 0.037; liver-related death: HR 0.26, p = 0.038). Cirrhosis was detected in 16 (10%) patients at diagnosis and was significantly related to poor survival (HR 17.87, p ?0.001) and progression to liver decompensation (HR 9.00, p ?0.001). Conclusions:This study revealed the impact of specific KIR/HLA pairs in AIH susceptibility and progression in Japanese patients. KIR3DL1/HLA-B Bw4-negative patients with AIH and cirrhosis at diagnosis are at high risk of adverse outcomes and require careful surveillance. Lay summary:Autoimmune hepatitis (AIH) is a disease of the liver that can present in acute or chronic hepatitis. We examined whether KIR/HLA pairs were associated with AIH susceptibility or disease progression. KIR3DL1/HLA-B Bw4 was a novel KIR/HLA pair related to a favorable clinical outcome, while cirrhosis at the initial diagnosis was a risk factor for poor prognosis. Thus, frequent and careful surveillance is advised for KIR3DL1/HLA-B Bw4-negative patients with AIH and cirrhosis.
| S-EPMC7005656 | biostudies-literature
Project description:BackgroundThe role of the HLA-DRB1 and HLA-DQB1 genes in the antibody response to hepatitis B (HB) vaccine has been well established; however, the involvement of the HLA-DPB1 allele in the HB vaccine immune response remained to be clarified by a systematic review.MethodsA meta-analysis was performed in which databases were searched for relevant studies published in English or Chinese up until June 1, 2020. Six studies were identified and a total of 10 alleles were processed into statistical processing in this meta-analysis.ResultsThree thousand one hundred forty four subjects (including 2477 responders and 667 non-responders) were included in this research. Alleles HLA-DPB1∗02:02, DPB1∗03:01, DPB1∗04:01, DPB1∗04:02, and DPB1∗14:01 were found to be associated with a significant increase in the antibody response to HB vaccine, and their pooled odds ratios (ORs) were 4.53, 1.57, 3.33, 4.20, and 1.79, respectively; whereas DPB1∗05:01 (OR = 0.73) showed the opposite correlation.ConclusionsThese findings suggested that specific HLA-DPB1 alleles are associated with the antibody response to HB vaccine.
| S-EPMC8036076 | biostudies-literature
Project description:Background & aimsAssociation studies have greatly refined the important role of the major histocompatibility complex (MHC) region in autoimmune hepatitis (AIH). However, the effects of human leucocyte antigen (HLA) polymorphisms on AIH are not well established. The aim of this study is to systematically characterise the association of MHC variants with AIH in our well-defined cohort of patients.MethodsWe performed an imputation-based analysis on the extensive association observed within the MHC region using the Han-MHC reference panel, and tested the comprehensive associations of HLA polymorphisms with AIH in 1622 Chinese AIH type 1 patients and 10,466 population controls.ResultsA total of 588 HLA variants were significantly associated with AIH, with HLA-B∗35:01 (p = 8.17 × 10-304; odds ratio [OR] = 7.32) contributing the strongest signal. Stepwise conditional analysis revealed additional independent signals at HLA-B∗08:01 (p = 1.35 × 10-33; OR = 4.26) and rs7765379 (p = 5.08 × 10-18; OR = 1.66). A strong link between the lead HLA variant and clinical phenotypes of AIH was observed: patients with HLA-B∗35:01 were less frequently positive for ANA and tended to have higher serum AST and ALT levels at diagnosis, but lower serum IgG levels.ConclusionsOur study reveals three novel and independent variants at HLA-B∗35:01, HLA-B∗08:01, and rs7765379 associated with AIH across the whole MHC region in the Han Chinese population. The findings illustrate the value of the MHC region in AIH and provide a new perspective for the immunogenetics of AIH.Impact and implicationsThis study revealed three novel and independent variants associated with autoimmune hepatitis across the whole major histocompatibility complex region in the Han Chinese population. These findings are significant in identifying autoantigens, providing insights into the activation of the autoimmune processes, and further advancing our understanding of the immunogenetic basis underlying autoimmune hepatitis.
| S-EPMC10711477 | biostudies-literature
Project description:HLA-DPB1 T-cell epitope (TCE) mismatching algorithm and rs9277534 SNP at the 3' untranslated region (3'UTR) in the HLA-DPB1 gene are key factors for transplant-related events in unrelated hematopoietic cell transplantation (UR-HCT). However, the association of these 2 mechanisms has not been elucidated. We analyzed 19 frequent HLA-DPB1 alleles derived from Japanese healthy subjects by next-generation sequencing of the entire HLA-DPB1 gene region and multi-SNP data of the HLA region in 1589 UR-HCT pairs. The risk of acute graft-versus-host disease (aGVHD) was analyzed in 1286 patients with single HLA-DPB1 mismatch UR-HCT. The phylogenetic tree constructed using the entire gene region demonstrated that HLA-DPB1 alleles were divided into 2 groups, HLA-DP2 and HLA-DP5. Although a phylogenetic relationship in the genomic region from exon 3 to 3'UTR (Ex3-3'UTR) obviously supported the division of HLA-DP2 and HLA-DP5 groups, which in exon 2 showed intermingling of HLA-DPB1 alleles in a non-HLA-DP2 and non-HLA-DP5-group manner. Multi-SNP data also showed 2 discriminative HLA-DPB1 groups according to Ex3-3'UTR. Risk of grade 2-4 aGVHD was significantly higher in patient HLA-DP5 group mismatch than patient HLA-DP2 group mismatch (hazard ratio, 1.28; P = .005), regardless of donor mismatch HLA-DP group. Regarding TCE mismatch, increasing risk of aGVHD in patient HLA-DP5 group mismatch and TCE-nonpermissive mismatch were observed only in patients with TCE-permissive mismatch and patient HLA-DP2 group mismatch, respectively. Evolutionary analysis revealed that rs9277534 represented a highly conserved HLA-DPB1 Ex3-3'UTR region and may provoke aGVHD differently to TCE mismatching algorithm, reflecting exon 2 polymorphisms. These findings enrich our understanding of the mechanism of aGVHD in HLA-DPB1 mismatch UR-HCT.
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Project description:We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each P ? 4 x 10(-6)). All associations were significant in an independent replication cohort of 2212 cases and 2251 controls (P ? 0.001) and were highly significant in the combined dataset (P ? 6 x 10(-8)). The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD) with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set P = 9 x 10(-9), replication set P = 7 x 10(-4), combined P = 2 x 10(-10)). HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association.
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Project description:ObjectivesTo test the hypothesis that autoimmune hepatitis (AIH type I) in young subjects is due to genetic differences in proinflammatory genes responding to viral triggers in patients and controls.MethodsIntrahepatic gene expression was compared between AIH type I (n = 24, age 9-30 years) patients (hereafter referred to as the AIH group) and controls (n = 21, age 4-25 years). RNA sequencing was performed on complementary DNA (cDNA) libraries made from total RNA extracted from formalin-fixed paraffin-embedded (FFPE) liver biopsy samples. Gene expression levels were quantified, and differentially expressed genes were functionally analyzed. Pathway analysis was performed using the databases Kyoto Encyclopedia of Genes and Genomes (KEGG) and PANTHER. The remaining sequences were mapped to the RefSeq complete set of viral genomes.ResultsDifferential gene analysis identified 181 genes that were significantly differentially expressed (136 upregulated in the AIH group). Autoimmune pathway genes such as CD19 and CD20 which are important in B cell regulation and maturation as well as, CD8 and LY9 , which are T-cell related, were upregulated in our AIH group. Genes implicated in AIH pathogenesis including CXCL10 , which is thought to be associated with AIH severity and progression, complement genes ( C1QA, C1QB , and C1QC ), and human leucocyte antigen ( HLA ) genes ( HLA-DRB1, HLA-DRA, HLA-B , and HLA-C ) were upregulated in samples from the AIH group. Specific viral etiologies were not found.ConclusionsUnbiased next-generation sequencing and differential gene expression analysis of the AIH group has not only added support for the role of B cells in the pathogenesis and treatment of AIH but also has introduced potential new therapeutic targets: CXCL10 (anti- CXCL10 ) and several complement system-related genes.
| S-EPMC9365252 | biostudies-literature
Project description:The major histocompatibility complex region has been suggested to play an important role in the development of autoimmune thyroid disease (AITD). In this study, we investigated the associations of human leukocyte antigen (HLA) alleles and amino acid variants of HLA with early-onset AITD. HLA class I and class II genes were analyzed in 116 Korean children with AITDs (Graves' disease [GD]: 71, Hashimoto's disease [HD]: 45) and 142 healthy controls. HLA-B*46:01 (OR = 3.96, Pc = 0.008), -C*01:02 (OR = 2.51 Pc = 0.04), -DPB1*02:02 (OR = 3.99, Pc = 0.04), and -DPB1*05:01 (OR = 4.6, Pc = 0.003) were significantly associated with GD, and HLA-A*02:07 (OR = 4.68, Pc = 0.045) and -DPB1*02:02 (OR = 6.57, Pc = 0.0001) with HD. The frequency of HLA-DPB1*05:01 was significantly higher in GD patients than in HD patients (Pc = 0.0005). Furthermore, differences were found between patients with Thyroid associated ophthalmopathy (TAO) and those without TAO in the distribution of HLA-B*54:01 (8.6% vs. 30.6%, P = 0.04) and -C*03:03 (37.1% vs. 11.1%, P = 0.02). In the analysis of amino acid variants of HLA molecules, both Leu35 (OR = 23.38, P = 0.0002) and Glu55 (OR = 23.38, P = 0.0002) of HLA-DPB1 were strongly associated with GD and showed different distributions between GD and HD (P = 0.001). Our results suggest that HLA alleles, especially amino-acid signatures of the HLA-DP β chain, might contribute to the molecular pathogenesis of early-onset AITD.
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Project description:Background and aimsDecompensated cirrhosis in autoimmune hepatitis has poor prognosis. Besides liver transplant, treatment for this entity is undefined. We explored the outcomes of autoimmune hepatitis (AIH)-related decompensated cirrhosis with active disease on treatment with steroids.MethodsIn this retrospective analysis, clinical data, laboratory parameters, and prognostic scores, such as baseline model for end-stage liver disease (MELD) scores, were compared among patients of AIH with decompensated cirrhosis with mild/no ascites (n = 38), gross ascites (n = 24), and compensated cirrhosis (n = 32) when administered steroids. The primary outcome was transplant-free survival at 12 months. Biochemical remission rates and other adverse events were also assessed and compared between these groups.ResultsSteroids were initiated at lower doses (25 mg/day-mild/no ascites, 20 mg/day-gross ascites) in patients with decompensated cirrhosis and at 40 mg/day in those with compensated cirrhosis. Transplant-free survival was 25.4%, 74.6%, and 96.9% (P = 0.001), and biochemical remission occurred in 5.1%, 49.0%, and 64.1% (P = 0.001) at 12 months in patients with gross ascites, mild/no ascites, and compensated cirrhosis, respectively. Infections were seen more frequently in decompensated cirrhosis, while other adverse events were comparable. Among decompensated cirrhosis, those with mild/no ascites had better prognostic scores, fewer posttreatment infections, and more frequent biochemical remission than those with gross ascites, achieving rates comparable to compensated cirrhosis. On multivariate analysis, the MELD score (subdistributional hazards ratio [sHR]; 95% confidence interval: 1.153 [1.07-1.24]; P = 0.001) and ascites (sHR: 2.556 [1.565-5.65]; P = 0.020) predicted survival.ConclusionType and severity of decompensation affect outcomes in patients with AIH-related cirrhosis. Those with mild/no ascites have comparable outcomes to those with compensated cirrhosis upon treatment with low-dose steroids.
| S-EPMC7812520 | biostudies-literature
Project description:A genome-wide association study identified single nucleotide polymorphisms (SNPs) rs3077 and rs9277535 located in the 3' untranslated regions of human leukocyte antigen (HLA) class II genes HLA-DPA1 and HLA-DPB1, respectively, as the independent variants most strongly associated with chronic hepatitis B. We examined whether these SNPs are associated with mRNA expression of HLA-DPA1 and HLA-DPB1. We identified gene expression-associated SNPs (eSNPs) in normal liver samples obtained from 651 individuals of European ancestry by integrating genotype (~650?000 SNPs) and gene expression (>39?000 transcripts) data from each sample. We used the Kruskal-Wallis test to determine associations between gene expression and genotype. To confirm findings, we measured allelic expression imbalance (AEI) of complementary DNA compared with DNA in liver specimens from subjects who were heterozygous for rs3077 and rs9277535. On a genome-wide basis, rs3077 was the SNP most strongly associated with HLA-DPA1 expression (p=10(-48)), and rs9277535 was strongly associated with HLA-DPB1 expression (p=10(-15)). Consistent with these gene expression associations, we observed AEI for both rs3077 (p=3.0 × 10(-7); 17 samples) and rs9277535 (p=0.001; 17 samples). We conclude that the variants previously associated with chronic hepatitis B are also strongly associated with mRNA expression of HLA-DPA1 and HLA-DPB1, suggesting that expression of these genes is important in control of HBV.
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