Evaluation of pathophysiology of cancer based on HLA and APRs.
Ontology highlight
ABSTRACT: Interventions: Examination of HLA and APR
Primary outcome(s): The association between HLA and the cancer risk.
Study Design: Single arm Non-randomized
DISEASE(S): Esophageal Cancer Gastric Cancer Colorectal Cancer Liver Cancer Pancreatic Cancer Gallbladder And Bili Duct Cancer Breast Cancer Lung Cancer
Project description:The presence of the HLA-B35 allele has emerged as an important risk factor for the development of isolated pulmonary hypertension (iPHT) in patients with Scleroderma (SSc), however the mechanisms underlying this association have not been fully elucidated. The goal of our study was to determine the molecular mechanisms that mediate the biological effects of HLA-B35 in endothelial cells (ECs). Our data demonstrate that HLA-B35 expression at the physiological levels using via adenoviral vector resulted in a significantly increased endothelin-1 (ET-1) and a significantly decreased endothelial nitric oxide synthase (eNOS) mRNA and protein levels. Furthermore, HLA-B35 greatly upregulated expression of cytoplasmic chaperones, including heat shock proteins (HSPs) HSP70 (HSPA1A and HSPA1B) and HSP40 (DNAJB1 and DNAJB9), suggesting that HLA-B35 induced the ER stress and unfolded protein response (UPR) in ECs. Examination of selected mediators of the UPR response, including BiP (GRP78), CHOP (GADD153), ERO1 (endoplasmic reticulum oxidase) and PDI (protein disulfide isomerase) has revealed a consistent increase of BiP expression levels. Accordingly, Thapsigargin (TG), a known ER stress inducer, stimulated ET-1 mRNA and protein levels in ECs. This study suggests that HLA-B35 could contribute to endothelial cell dysfunction via ER stress mediated induction of ET-1 in patients with PHT.
Project description:Leprosy is a chronic granulomatous disease caused by infection with Mycobacterium leprae. Genetic association studies indicated that leprosy risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but the full number of variants in this region has yet to be elucidated. To identify further susceptibility loci or loss of function variants for this disease, we performed fine-mapping analysis of the MHC region using a Han Chinese reference panel (n= 10,689 patients, 29,948 genetic markers) in the data sets from our previous leprosy studies. Then, a fixed-effect meta-analysis was carried out separately for Chinese (case=2,901, control=3,801) and North Chinese (case=1,983, control=2,635) participants. The meta-analysis of Chinese participants identified 10 HLA-type or amino acid variants with lower than the genome-wide significant susceptibility signal. Next, gene-by-gene step-wise conditional analysis was performed in the combined dataset of these cohorts. Finally, we identified four new independent susceptibility loci (HLA-DQA1, HLA-C, rs3129063, and rs58327373) and confirmed one previously reported locus (HLA-DRB1) that significantly associated with leprosy in the Chinese Han population. Thus the results of this study increase knowledge about leprosy risk variants and illustrate the value of HLA imputation for fine mapping of causal variants in the MHC.
Project description:Background. Assessment of non-HLA variants alongside standard HLA testing was previously shown to improve the identification of potential coeliac disease (CD) patients. We intended to identify new genetic variants associated with CD in the Polish population that would improve CD risk prediction when used alongside HLA haplotype analysis. Results. Association analysis using four HLA-tagging SNPs showed that, as was found in other populations, positive predicting genotypes (HLA-DQ2.5/DQ2.5, HLA-DQ2.5/DQ2.2, and HLA-DQ2.5/DQ8) were found at higher frequencies in CD patients than in healthy control individuals in the Polish population. Both CD-associated SNPs discovered by GWAS were found in the CD susceptibility region, confirming the previously-determined association of the major histocompatibility (MHC) region with CD pathogenesis. The two most significant SNPs from the GWAS were rs9272346 (HLA-dependent; localized within 1 Kb of DQA1) and rs3130484 (HLA-independent; mapped to MSH5). Specificity of CD prediction using the four HLA-tagging SNPs achieved 92.9%, but sensitivity was only 45.5%. However, when a testing combination of the HLA-tagging SNPs and the MSH5 SNP was used, specificity decreased to 80%, and sensitivity increased to 74%.
Project description:The Human leukocyte antigen (HLA) -region, especially HLA class I and II genes, plays a major role in the predisposition to autoimmune disorders. Particularly three HLA haplotypes, DRB1*03-DQA1*05-DQB1*02 (DR3-DQ2), DRB1*04:01-DQA1*03-DQB1*03:02 (DR4-DQ8) and DRB1*15-DQA1*01-DQB1*06:02 (DR2-DQ6), have an important role in many autoimmune diseases: for example, in type 1 diabetes (T1D) the DR2-DQ6 is associated with a strongly decreased T1D risk and the DR3-DQ2 and DR4-DQ8 are associated with a moderately increased T1D risk. To clarify the mechanisms behind this association, we examined genome-wide DNA methylation in CD4+ T cells and CD19+ B cells of healthy subjects homozygous either for DR3-DQ2 (n = 19), DR4-DQ8 (n = 17) or DR2-DQ6 (n = 14), and compared methylation between the genotypes. For the study, CD4+ T cells and CD19+ B cells were isolated consecutively from PBMC samples using magnetic bead separation. DNA was extracted from the cell lysates with AllPrep DNA/RNA/miRNA Universal Kit (Qiagen, Germany). Then the individual DNA samples were pooled into 11 pooled samples with 4–5 samples per pooled sample. The original 50 samples were designated pools based on age and sex to ensure that the age and sex distributions would be as similar as possible between the pooled samples. The mean age (±SD) in the three HLA-groups (DR2-DQ6, DR3-DQ2 and DR4-DQ8) were 15.0 (±8.3), 11.1 (±5.6) and 11.8 (±7.9) and their male to female ratios were 8/6, 9/10 and 11/6. Similar pooled samples were created for both the CD4+ T cell and the CD19+ B cell samples. Then DNA methylation was examined in the pooled CD4+ T cell and CD19+ B cell samples using Illumina Infinium HumanMethylation EPIC beadchip.
Project description:HLA-DPA1-related SNP rs9277336 is linked to increased PAH risk and binds ACTN4 in an allele-specific fashion. HLA-DPA1 transcript is decreased in PAH lung endothelial cells and controlled by ACTN4. ACTN4 differential binding may cause HLA-DPA1-mediated immune dysfunction. The purpose of this specific experiment is to determine the downstream effects of ACTN4 and HLA-DPA1 downregulation, specifically looking at overlaps between the two conditions.
Project description:The endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 trim peptides to be loaded onto HLA molecules, including the main risk factor for Behçet’s disease HLA-B*51. ERAP1 is also a risk factor among HLA-B*51-positive individuals, whereas no association is known with ERAP2. This study addressed the mutual relationships between both enzymes in the processing of an HLA-bound peptidome, interrogating their differential association with Behçet’s disease. CRISPR/Cas9 was used to generate knock outs of ERAP1, ERAP2 or both from transfectant 721.221-HLA-B*51:01 cells. The surface expression of HLA-B*51 was reduced in all cases. The effects of depleting each or both enzymes on the B*51:01 peptidome were analyzed by quantitative label-free mass spectrometry. Substantial quantitative alterations of peptide length, subpeptidome balance, N-terminal residue usage, affinity and presentation of non-canonical ligands were observed. These effects were often different in the presence or absence of the other enzyme, revealing their mutual dependency. In the absence of ERAP1, ERAP2 showed similar and significant processing of B*51:01 ligands, indicating functional redundancy. The high overlap between the peptidomes of wildtype and double KO cells indicates that a large majority of B*51:01 ligands are present in the ER even in the absence of ERAP1/ERAP2. These results indicate that both enzymes have distinct, but complementary and partially redundant effects on the B*51:01 peptidome, leading to its optimization and maximal surface expression. The distinct effects of both enzymes on the HLA-B*51 peptidome provide a basis for their differential association with Behçet’s disease and suggest a pathogenetic role of the B*51:01 peptidome.
Project description:The aim of this study was to construct and validate a prognostic risk model to predict the overall survival (OS) of patients with cervical cancer, providing a reference for individualized clinical treatment that may lead to better clinical outcomes. HLA-G-driven DEG signature consisting of the eight most important prognostic genes CD46, LGALS9, PGM1, SPRY4, CACNB3, PLIN2, MSMO1, and DAGLB was identified as a key predictor of cervical cancer. To summarize, we developed and validated a novel prognostic risk model for cervical cancer based on HLA-G-driven DEGs, and the prognostic signature showed great ability in predicting the overall survival of patients with cervical cancer.
Project description:The aim of this study was to construct and validate a prognostic risk model to predict the overall survival (OS) of patients with cervical cancer, providing a reference for individualized clinical treatment that may lead to better clinical outcomes. HLA-G-driven DEG signature consisting of the eight most important prognostic genes CD46, LGALS9, PGM1, SPRY4, CACNB3, PLIN2, MSMO1, and DAGLB was identified as a key predictor of cervical cancer. To summarize, we developed and validated a novel prognostic risk model for cervical cancer based on HLA-G-driven DEGs, and the prognostic signature showed great ability in predicting the overall survival of patients with cervical cancer.
Project description:HLA-DRB1 alleles have been associated with several autoimmune diseases. In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), HLA-DRB1 shared epitope (SE) alleles are the major genetic risk factors. In order to investigate whether expression of different alleles of major histocompatibility complex (MHC) Class II genes influence functions of immune cells, we investigated transcriptomic profiles of a variety of immune cells from healthy individuals carrying different HLA-DRB1 alleles. Sequencing libraries from peripheral blood mononuclear cells, CD4+ T cells, CD8+ T cells, and CD14+ monocytes of 32 genetically pre-selected healthy female individuals were generated, sequenced and reads were aligned to the standard reference. For the MHC region, reads were mapped to available MHC reference haplotypes and AltHapAlignR was used to estimate gene expression. Using this method, HLA-DRB and HLA-DQ were found to be differentially expressed in different immune cells of healthy individuals as well as in whole blood samples of RA patients carrying HLA-DRB1 SE-positive versus SE-negative alleles. In contrast, no genes outside the MHC region were differentially expressed between individuals carrying HLA-DRB1 SE-positive and SE-negative alleles. Existing methods for HLA-DR allele-specific protein expression were evaluated but were not mature enough to provide appropriate complementary information at the protein level. Altogether, our findings suggest that immune effects associated with different allelic forms of HLA-DR and HLA-DQ may be associated not only with differences in the structure of these proteins, but also with differences in their expression levels.