HLA-DQB1

Gene Summary

Gene:HLA-DQB1; major histocompatibility complex, class II, DQ beta 1
Aliases: IDDM1, CELIAC1, HLA-DQB
Location:6p21.32
Summary:HLA-DQB1 belongs to the HLA class II beta chain paralogs. This class II molecule is a heterodimer consisting of an alpha (DQA) and a beta chain (DQB), both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. Class II molecules are expressed in antigen presenting cells (APC: B lymphocytes, dendritic cells, macrophages). The beta chain is approximately 26-28 kDa and it contains six exons. Exon 1 encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and exon 5 encodes the cytoplasmic tail. Within the DQ molecule both the alpha chain and the beta chain contain the polymorphisms specifying the peptide binding specificities, resulting in up to four different molecules. Typing for these polymorphisms is routinely done for bone marrow transplantation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:HLA class II histocompatibility antigen, DQ beta 1 chain
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: HLA-DQB1 (cancer-related)

Lee C, An D, Park J
Hyperglycemic memory in metabolism and cancer.
Horm Mol Biol Clin Investig. 2016; 26(2):77-85 [PubMed] Related Publications
Hyperglycemia is a hallmark of both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Recent evidence strongly suggests that prolonged exposure to hyperglycemia can epigenetically modify gene expression profiles in human cells and that this effect is sustained even after hyperglycemic control is therapeutically achieved; this phenomenon is called hyperglycemic memory. This metabolic memory effect contributes substantially to the pathology of various diabetic complications, such as diabetic retinopathy, hypertension, and diabetic nephropathy. Due to the metabolic memory in cells, diabetic patients suffer from various complications, even after hyperglycemia is controlled. With regard to this strong association between diabetes and cancer risk, cancer cells have emerged as key target cells of hyperglycemic memory in diabetic cancer patients. In this review, we will discuss the recent understandings of the molecular mechanisms underlying hyperglycemic memory in metabolism and cancer.

El Khatib MM, Ohmine S, Jacobus EJ, et al.
Tumor-Free Transplantation of Patient-Derived Induced Pluripotent Stem Cell Progeny for Customized Islet Regeneration.
Stem Cells Transl Med. 2016; 5(5):694-702 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Human induced pluripotent stem cells (iPSCs) and derived progeny provide invaluable regenerative platforms, yet their clinical translation has been compromised by their biosafety concern. Here, we assessed the safety of transplanting patient-derived iPSC-generated pancreatic endoderm/progenitor cells. Transplantation of progenitors from iPSCs reprogrammed by lentiviral vectors (LV-iPSCs) led to the formation of invasive teratocarcinoma-like tumors in more than 90% of immunodeficient mice. Moreover, removal of primary tumors from LV-iPSC progeny-transplanted hosts generated secondary and metastatic tumors. Combined transgene-free (TGF) reprogramming and elimination of residual pluripotent cells by enzymatic dissociation ensured tumor-free transplantation, ultimately enabling regeneration of type 1 diabetes-specific human islet structures in vivo. The incidence of tumor formation in TGF-iPSCs was titratable, depending on the oncogenic load, with reintegration of the cMYC expressing vector abolishing tumor-free transplantation. Thus, transgene-free cMYC-independent reprogramming and elimination of residual pluripotent cells are mandatory steps in achieving transplantation of iPSC progeny for customized and safe islet regeneration in vivo.
SIGNIFICANCE: Pluripotent stem cell therapy for diabetes relies on the safety as well as the quality of derived insulin-producing cells. Data from this study highlight prominent tumorigenic risks of induced pluripotent stem cell (iPSC) products, especially when reprogrammed with integrating vectors. Two major underlying mechanisms in iPSC tumorigenicity are residual pluripotent cells and cMYC overload by vector integration. This study also demonstrated that combined transgene-free reprogramming and enzymatic dissociation allows teratoma-free transplantation of iPSC progeny in the mouse model in testing the tumorigenicity of iPSC products. Further safety assessment and improvement in iPSC specification into a mature β cell phenotype would lead to safe islet replacement therapy for diabetes.

Lehmann-Werman R, Neiman D, Zemmour H, et al.
Identification of tissue-specific cell death using methylation patterns of circulating DNA.
Proc Natl Acad Sci U S A. 2016; 113(13):E1826-34 [PubMed] Free Access to Full Article Related Publications
Minimally invasive detection of cell death could prove an invaluable resource in many physiologic and pathologic situations. Cell-free circulating DNA (cfDNA) released from dying cells is emerging as a diagnostic tool for monitoring cancer dynamics and graft failure. However, existing methods rely on differences in DNA sequences in source tissues, so that cell death cannot be identified in tissues with a normal genome. We developed a method of detecting tissue-specific cell death in humans based on tissue-specific methylation patterns in cfDNA. We interrogated tissue-specific methylome databases to identify cell type-specific DNA methylation signatures and developed a method to detect these signatures in mixed DNA samples. We isolated cfDNA from plasma or serum of donors, treated the cfDNA with bisulfite, PCR-amplified the cfDNA, and sequenced it to quantify cfDNA carrying the methylation markers of the cell type of interest. Pancreatic β-cell DNA was identified in the circulation of patients with recently diagnosed type-1 diabetes and islet-graft recipients; oligodendrocyte DNA was identified in patients with relapsing multiple sclerosis; neuronal/glial DNA was identified in patients after traumatic brain injury or cardiac arrest; and exocrine pancreas DNA was identified in patients with pancreatic cancer or pancreatitis. This proof-of-concept study demonstrates that the tissue origins of cfDNA and thus the rate of death of specific cell types can be determined in humans. The approach can be adapted to identify cfDNA derived from any cell type in the body, offering a minimally invasive window for diagnosing and monitoring a broad spectrum of human pathologies as well as providing a better understanding of normal tissue dynamics.

Han L, Husaiyin S, Wang L, et al.
Analysis of HLA-DQB1 allele polymorphisms in Uyghur women with cervical cancer.
Genet Mol Res. 2015; 14(4):17252-61 [PubMed] Related Publications
In Uyghur women, mortality rates from cervical cancer are amongst the highest in the nation, and genetic susceptibility probably plays a role in the pathogenesis of the disease. We investigated the correlation between polymorphisms of the HLA-DQB1 allele and cervical cancer in Xinjiang Uyghur women. Cervix tissue samples from 80 cases of cervical cancer and 80 cases of cervicitis were genotyped using polymerase chain reaction-sequence-based typing (PCR-SBT) for HLA-DQB1. Two hundred and ninety-six alleles were identified among the 160 cases. One hundred and thirty-six alleles were heterozygous and 24 were homozygous. Using frequency calculations and statistical analysis, we found that HLA-DQB1*0325 (OR: 10.60, 1.341-83.81) and HLA-DQB1*0332 (OR: 12.59, 2.909-54.526) were more frequently identified in the cervical cancer group compared with the cervicitis group (P < 0.05). However, HLA-DQB1*0317 (OR: 0.49, 0.304-0.798) and HLA-DQB1*040302 (OR: 0.40, 0.243-0.658) were present less frequently in the cervical cancer group (P < 0.05). The frequency of the HLA-DQB1 genotype in Uyghur was different from that reported previously in other areas. HLA-DQB1*0325 and HLA-DQB1*0332 probably act as cervical cancer susceptibility genes in Uyghur women from Xinjiang. In contrast, HLA-DQB1*0317 and HLA-DQB1*040302 may be protective genes.

Hayakawa S, Okada S, Tsumura M, et al.
A Patient with CTLA-4 Haploinsufficiency Presenting Gastric Cancer.
J Clin Immunol. 2016; 36(1):28-32 [PubMed] Related Publications
Cytotoxic T-lymphocyte-antigen 4 (CTLA-4) is an essential negative regulator expressed on regulatory T cells (Tregs) and activated T cells. Germline heterozygous mutations in CTLA4 lead to haploinsufficiency of CTLA-4, resulting in the development of an autosomal dominant immune dysregulation syndrome with incomplete penetrance. We report here a Japanese patient with this disorder who has a novel heterozygous single nucleotide insertion, 76_77insT (p. L28SfsX40), in the CTLA4 gene. Peripheral blood mononuclear cells from the patient showed decreased frequency of CTLA-4(high) cells in CD4(+)FOXP3(+) cells following CD3/CD28 stimulation. The patient experienced hypogammaglobulinemia, recurrent pneumonia, esophageal candidiasis, cytomegalovirus-positive chronic gastritis, chronic and severe diarrhea, and type 1 diabetes mellitus. Moreover, the patient developed multifocal gastric cancer, histologically poorly and well-differentiated adenocarcinomas, associated with chronic atrophic gastritis and intestinal metaplasia. Previously, 23 symptomatic cases with heterozygous CTLA4 mutations have been reported. Including the case presented here, 3 of the 24 cases (12.5%) developed gastric cancer. Notably, 2 of 3 patients presented similarly multifocal adenocarcinomas associated with atrophic gastritis and intestinal metaplasia. Predisposition to gastric cancer has been also reported in CVID patients. These clinical observations suggest that gastric cancer is a disease commonly associated with autosomal dominant immune dysregulation syndrome due to CTLA4 mutation.

Yamagishi S, Nakamura N, Suematsu M, et al.
Advanced Glycation End Products: A Molecular Target for Vascular Complications in Diabetes.
Mol Med. 2015; 21 Suppl 1:S32-40 [PubMed] Free Access to Full Article Related Publications
A nonenzymatic reaction between reducing sugars and amino groups of proteins, lipids and nucleic acids contributes to the aging of macromolecules and subsequently alters their structural integrity and function. This process has been known to progress at an accelerated rate under hyperglycemic and/or oxidative stress conditions. Over a course of days to weeks, early glycation products undergo further reactions such as rearrangements and dehydration to become irreversibly cross-linked, fluorescent and senescent macroprotein derivatives termed advanced glycation end products (AGEs). There is a growing body of evidence indicating that interaction of AGEs with their receptor (RAGE) elicits oxidative stress generation and as a result evokes proliferative, inflammatory, thrombotic and fibrotic reactions in a variety of cells. This evidence supports AGEs' involvement in diabetes- and aging-associated disorders such as diabetic vascular complications, cancer, Alzheimer's disease and osteoporosis. Therefore, inhibition of AGE formation could be a novel molecular target for organ protection in diabetes. This report summarizes the pathophysiological role of AGEs in vascular complications in diabetes and discusses the potential clinical utility of measurement of serum levels of AGEs for evaluating organ damage in diabetes.

Hirabayashi K, Kurata T, Horiuchi K, et al.
Loss of Mismatched HLA on the Leukemic Blasts of Patients With Relapsed Lymphoid Malignancies Following Bone Marrow Transplantation From Related Donors With HLA Class II Mismatches in the Graft Versus Host Direction.
Pediatr Blood Cancer. 2016; 63(4):709-11 [PubMed] Related Publications
Mechanisms of relapse of acute lymphoblastic leukemia (ALL) after human leukocyte antigen (HLA) class II mismatched hematopoietic stem cell transplantation (HSCT) remain unclear. We report two children with relapsed ALL after HSCT from related donors with HLA-DRB1 and -DQB1 mismatches in the graft versus host direction. One lost HLA-DRB1, DQB1, and DPB1 alleles, and the other lost one HLA haplotype of the leukemic blasts at relapse. HLA class II loss may be a triggering event for ALL relapse after partially HLA-mismatched-related HSCT. In addition, HLA typing of relapsed leukemic blasts could be vital in the selection of retransplant donors.

Galleze A, Raache R, Amroun H, et al.
HLA Polymorphism in Algerian Children With Lymphomas.
J Pediatr Hematol Oncol. 2015; 37(8):e458-61 [PubMed] Related Publications
BACKGROUND: Non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) are the 2 types of lymphoma that represent the third most common childhood malignancy. Multiple etiological factors are involved in lymphoma pathogenesis, including viral infection, immune deficiencies, environmental agents, and genetic factors. Strong arguments supporting a genetic linkage between the susceptibility to lymphomas and human leukocyte antigens (HLA) are reported and give an idea about susceptibility or protection from the disease.
METHODS: Seventy-one cases were included in this study: 36 cases of non-Hodgkin lymphoma and 35 patients with Hodgkin lymphoma. Their ages ranged from 4 to 18 years. The control group consisted of 70 unrelated healthy individuals, with a mean age of 5 to 17 years. The genotype of HLA-A, HLA-B, HLA-DR, and HLA-DQ alleles was typed by means of PCR sequence-specific priming.
RESULTS: HLA-B*18, HLA-DRB1*03, *07, and HLA-DQB1*02 were significantly increased in patients with lymphomas when compared with controls, whereas HLA-DRB1*13 and DQB1*03 were significantly decreased when compared with controls.
CONCLUSIONS: These results indicate that HLA-B*18, DRB1*03, *07, and DQB1*02 may contribute to lymphoma susceptibility, whereas HLA-DRB1*13 and DQB1*03 may confer protection to lymphoma in the Algerian population.

Zhang X, Lv Z, Yu H, et al.
The HLA-DQB1 gene polymorphisms associated with cervical cancer risk: A meta-analysis.
Biomed Pharmacother. 2015; 73:58-64 [PubMed] Related Publications
Human leukocyte antigens (HLA) alleles may affect the development of cervical cancer through immunologic control of human papillomavirus (HPV). The association between HLA-DQB1 alleles and risk of cervical cancer has been extensively studied, but the results obtained remain inconsistent. To explore a more extensive role of HLA-DQB1 alleles on cervical cancer risk, we carried out a meta-analysis including 4862 cases and 8988 controls from 22 published studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. The overall results suggested that HLA-DQB1*02 (OR=0.91, 95% CI=0.82-0.99), *03 (OR=0.85, 95% CI=0.74-0.97) and *0603 (OR=0.62, 95% CI=0.53-0.72) had a significantly association with decreased cervical cancer risk. In contrast, DQB1*05 (OR=1.18, 95% CI=1.01-1.38), *0301 (OR=1.14, 95% CI=1.06-1.23) and *0402 (OR=1.31, 95% CI=1.04-1.64) conferred a significantly higher risk to cervical cancer. Moreover, a significantly association with increased or decreased cervical cancer risk was found among Europeans and Asians after stratification of the HLA-DQB1 alleles by ethnicity. These findings supported that the HLA-DQB1 alleles may contribute to genetic susceptibility of cervical cancer. Further studies with a greater number of cases are expected to confirm our results.

Wang XJ, Sun HY, Li QH, Ru K
Identification of a novel HLA-DQB1 allele, HLA-DQB1*06:148, by sequence-based typing in a Chinese individual.
Tissue Antigens. 2015; 85(6):514-5 [PubMed] Related Publications
One nucleotide replacement in codon 13 (GGC>GCC) of HLA-DQB1*06: 03:01 results in a novel allele formation, HLA-DQB1*06:148.

Kim LH, Cheong HS, Namgoong S, et al.
Replication of genome wide association studies on hepatocellular carcinoma susceptibility loci of STAT4 and HLA-DQ in a Korean population.
Infect Genet Evol. 2015; 33:72-6 [PubMed] Related Publications
A recent genome-wide association study (GWAS) for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) identified two loci (rs7574865 in STAT4 and rs9275319 in HLA-DQ) in a Chinese population. We attempted to replicate the associations between the two SNP loci and the risk of HCC in a Korean population. The rs7574865 in STAT4 and rs9275319 in HLA-DQ were genotyped in a total of 3838 Korean subjects composed of 287 HBV-related hepatocellular carcinoma patients, 671 chronic hepatitis B virus (CHB) patients, and 2880 population controls using TaqMan genotyping assay. Gene expression was measured by microarray. A logistic regression analysis revealed that rs7574865 in STAT4 and rs9275319 in HLA-DQ were associated with the risk of CHB (OR = 1.25, P = 0.0002 and OR = 1.57, P= 1.44 × 10(-10), respectively). However, these loci were no association with the risk of HBV-related HCC among CHB patients. In the gene expression analyses, although no significant differences in mRNA expression of nearby genes according to genotypes were detected, a significantly decreased mRNA expression in HCC subjects was observed in STAT4, HLA-DQA1, and HLA-DQB1. Although the genetic effects of two HCC susceptibility loci were not replicated, the two loci were found to exert susceptibility effects on the risk of CHB in a Korean population. In addition, the decreased mRNA expression of STAT4, HLA-DQA1, and HLA-DQB1 in HCC tissue might provide a clue to understanding their role in the progression to HCC.

Wang L, Wei B, Hu G, et al.
Screening of differentially expressed genes associated with human glioblastoma and functional analysis using a DNA microarray.
Mol Med Rep. 2015; 12(2):1991-6 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is the most malignant type of human glioma, and has a poor prognosis. Screening differentially expressed genes (DEGs) in brain tumor samples and normal brain samples is of importance for identifying GBM and to design specific-targeting drugs. The transcriptional profile of GSE30563, containing three genechips of brain tumor samples and three genechips of normal brain samples, was downloaded from Gene Expression Omnibus to identify the DEGs. The differences in the expression of the DEGs in the two different samples were compared through hierarchical biclustering. The co-expression coefficient of the DEGs was calculated using the information from COXPRESdb, the network of the DEGs was constructed and functional enrichment and pathway analysis were performed. Finally, the transcription factors of important DEGs were predicted. A total of 1,006 DEGs, including 368 upregulated and 638 downregulated DEGs, were identified. A close correlation was demonstrated between six important genes, associated with immune response, HLA-DQB1, HLA-DRB1, HLA-DPA1, HLA-B, HLA-DMA and HLA-DRA, and the immune response. Allograft rejection was selected as the most significant pathway. A total of 17 transcription factors, including nuclear factor (NF)-κB and NF-κB1, and their binding sites containing these six DEGs, were also identified. The DEGs, including major histocompatibility complex (MHC) class II, DQβ1, MHC class II, DRβ1, MHC class IB, MHC class II, DMα, MHC class II, DPα1, MHC class II, DRα, may provide novel targets for the diagnosis and treatment of GBM. The transcription factors of these six genes and their binding sites may also provide evidence and direction for identifying target-specific drugs.

Kumar A, Hussain S, Yadav IS, et al.
Identification of human papillomavirus-16 E6 variation in cervical cancer and their impact on T and B cell epitopes.
J Virol Methods. 2015; 218:51-8 [PubMed] Related Publications
The infection with high-risk human papillomavirus (HR-HPV) is the most important risk factor for development of cervical cancer. The intra-type variations of HPV have different biological and pathological consequences with respect to disease progression. In the present study, six major Indian variants were experimentally identified in E6 gene of HPV-16 and showed their impact on immunogenicity by in silico methods. Four different phylogenetic lineages were observed in sequences including European (E) prototype, European variant, Asian and American Asian variant classes and complete absence of African phylogenetic lineages. On the prediction of B- and T-cell epitopes, 18 and 23 potent epitopes for MHC-II alleles, 10 potent MHC-I and 15 B-cell epitopes in each reference and variant sequence were identified. Interestingly, the presence of variation H78Y and L83V result in creation of four new epitopes for the HLA-DQA1*0101/DQB1*0501. Out of 15 B-cell predicted epitopes, three most potent epitopes were identified in both reference and variant sequence. Notably the amino acid stretch from amino acid 16-60 and 76-94 are very important for the immunological properties of E6 protein because these regions contain majority of the predicted epitopes. In future, this could control the cervical cancer by targeting these amino acid stretches for the development of HPV-16 vaccine.

Shu X, Purdue MP, Ye Y, et al.
Multilevel-analysis identify a cis-expression quantitative trait locus associated with risk of renal cell carcinoma.
Oncotarget. 2015; 6(6):4097-109 [PubMed] Free Access to Full Article Related Publications
We conducted multilevel analyses to identify potential susceptibility loci for renal cell carcinoma (RCC), which may be overlooked in traditional genome-wide association studies (GWAS). A gene set enrichment analysis was performed utilizing a GWAS dataset comprised of 894 RCC cases and 1,516 controls using GenGen, SNP ratio test, and ALIGATOR. The antigen processing and presentation pathway was consistently significant (P = 0.001, = 0.004, and < 0.001, respectively). Versatile gene-based association study approach was applied to the top-ranked pathway and identified the driven genes. By comparing the expression of the genes in RCC tumor and adjacent normal tissues, we observed significant overexpression of HLA genes in tumor tissues, which was also supported by public databases. We sought to validate genetic variants in antigen processing and presentation pathway in an independent GWAS dataset comprised of 1,311 RCC cases and 3,424 control subjects from the National Cancer Institute; one SNP, rs1063355, was significant in both populations (P(meta-analysis) = 9.15 × 10⁻⁴, P(heterogeneity) = 0.427). Strong correlation indicated that rs1063355 was a cis-expression quantitative trait loci which associated with HLA-DQB1 expression (Spearman's rank r = -0.59, p = 5.61 × 10⁻⁶). The correlation was further validated using a public dataset. Our results highlighted the role of immune-related pathway and genes in the etiology of RCC.

Brazzelli V, Rivetti N, Badulli C, et al.
Mycosis fungoides: association of KIR ligands and HLA-DQB1*05 with bad prognosis of the disease.
J Eur Acad Dermatol Venereol. 2016; 30(2):266-9 [PubMed] Related Publications
BACKGROUND: Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma. We previously reported that the prognosis of MF patients is not only related on clinical variables but it is also associated with peculiar HLA alleles. Until today, the association of HLA ligands for KIR with the prognosis of the disease has not yet been analysed.
OBJECTIVE: We investigated the frequency of HLA ligands for killer cell Immunoglobulin-like receptors (KIRs) in MF patients, evaluating if the presence of particular HLA alleles that are ligands for KIR may have prognostic value.
METHODS: The study includes 46 Caucasian MF patients that, between 1993 and 1997, underwent HLA genomic typing. All patients were diagnosed and followed up from 1977 to 2012 (mean follow-up of 11 years).
RESULTS: MF patients have been divided into two groups (long survivors and dead patients). We noticed that the HLA-Bw6/Bw6 specificity increased among the group of seven dead patients compared to the group of 39 long survivors (71.4% vs. 41.0%, P = ns, OR = 3.59), while in the long survivors group the HLA- Bw4/Bw4 specificity increased when compared to dead patients (23.0% vs. 0%, P = ns). Moreover, we observed that six of the seven dead patients had HLA-DQB1*05; the phenotypic frequency of this HLA allele, in dead and long survivors patients, was 85.7% and 23.0% respectively (P = 0.004; OR = 20).
CONCLUSION: Our observations suggest that the presence of the HLA-DQB1*05 alleles characterizes the patients with the poorest prognosis in MF. In addition, absence of the KIR-ligand epitope HLA-B Bw4 showed a trend of being more prominent in MF patients with the poorest prognosis.

Ślusarz A, Pulakat L
The two faces of miR-29.
J Cardiovasc Med (Hagerstown). 2015; 16(7):480-90 [PubMed] Free Access to Full Article Related Publications
Diabetes mellitus is a metabolic homeostasis disease that contributes to additional comorbidities such as cardiovascular disease (CVD) and cancer. It has a long undiagnosed latent period during which there can be irreparable damage to the pancreas and cardiovascular tissues. Recent studies have highlighted the roles of several microRNAs in CVD. Determining the microRNAs that link diabetes mellitus and CVD is an important topic to be explored. In the present review, we discuss the microRNAs that contribute to the progression of diabetes mellitus and CVD and focus on the miR-29 family microRNAs whose expression is upregulated by hyperglycemia and proinflammatory cytokines, the hallmarks of diabetes mellitus. Upregulation of miR-29 expression is a key factor in the loss of pancreatic β cells and development of the first stage of type 1 diabetes mellitus (T1DM). Additionally, miR-29-mediated suppression of myeloid cell leukemia 1 (MCL-1), an important prosurvival protein, underlies Marfan's syndrome, abdominal aortic aneurysm, and diabetes mellitus-associated cardiomyocyte disorganization. Suppression of miR-29 expression and subsequent increase in the prosurvival MCL-1, however, promotes tumor development. Therefore, miR-29 mimics that suppress MCL-1 are hailed as tumor suppressors. The critical question is whether an increase in miR-29 levels is well tolerated in conditions of comorbidities in which insulin resistance is an underlying disease. In light of increasing awareness of the interconnection of diabetes mellitus, CVD, and cancer, it is of utmost importance to understand the mechanism of action of current treatment options on all of the comorbidities and careful evaluation of cardiovascular toxicity must accompany any treatment paradigm that increases miR-29 levels.

Morishima Y, Kashiwase K, Matsuo K, et al.
Biological significance of HLA locus matching in unrelated donor bone marrow transplantation.
Blood. 2015; 125(7):1189-97 [PubMed] Free Access to Full Article Related Publications
We hypothesized that the compatibility of each HLA loci between donor and patient induced divergent transplant-related immunologic responses, which attributed to the individualized manifestation of clinical outcomes. Here, we analyzed 7898 Japanese pairs transplanted with T-cell-replete marrow from an unrelated donor with complete HLA allele typing data. Multivariable competing risk regression analyses were conducted to evaluate the relative risk (RR) of clinical outcomes after transplantation. A significant RR of HLA allele mismatch compared with match was seen with HLA-A, -B, -C, and -DPB1 for grade III-IV acute graft-versus-host disease (GVHD), and HLA-C for chronic GVHD. Of note, only HLA-C and HLA-DPB1 mismatch reduced leukemia relapse, and this graft-versus-leukemia effect of HLA-DPB1 was independent of chronic GVHD. HLA-DRB1 and HLA-DQB1 double (DRB1_DQB1) mismatch was revealed to be a significant RR for acute GVHD and mortality, whereas single mismatch was not. Thus, the number of HLA-A, -B, -C, -DPB1, and DRB1_DQB1 mismatches showed a clear-cut risk difference for acute GVHD, whereas the number of mismatches for HLA-A, -B, -C, and DRB1_DQB1 showed the same for mortality. In conclusion, we determined the biological response to HLA locus mismatch in transplant-related immunologic events, and provide a rationale for use of a personalized algorithm for unrelated donor selection.

Hu JM, Li L, Chen YZ, et al.
HLA-DRB1 and HLA-DQB1 methylation changes promote the occurrence and progression of Kazakh ESCC.
Epigenetics. 2014; 9(10):1366-73 [PubMed] Free Access to Full Article Related Publications
Human leukocyte antigen II (HLA-II) plays an important role in host immune responses to cancer cells. Changes in gene methylation may result in aberrant expression of HLA-II, serving a key role in the pathogenesis of Kazakh esophageal squamous cell carcinoma (ESCC). We analyzed the expression level of HLA-II (HLA-DP, -DQ, and -DR) by immunohistochemistry, as well as the methylation status of HLA-DRB1 and HLA-DQB1 by MassARRAY spectrometry in Xinjiang Kazakh ESCC. Expression of HLA-II in ESCC was significantly higher than that in cancer adjacent normal (ACN) samples (P < 0.05). Decreased HLA-II expression was closely associated with later clinical stages of ESCC (P < 0.05). Hypomethylation of HLA-DRB1 and hypermethylation of HLA-DQB1 was significantly correlated with occurrence of Kazakh ESCC (P < 0.01), and mainly manifested as hypomethylation of CpG9, CpG10-11, and CpG16 in HLA-DRB1 and hypermethylation of CpG6-7 and CpG16-17 in HLA-DQB1 (P < 0.01). Moreover, hypomethylation of HLA-DQB1 CpG6-7 correlated with poor differentiation in ESCCs, whereas hypermethylation of HLA-DRB1 CpG16 and hypomethylation of HLA-DQB1 CpG16-17 were significantly associated with later stages of ESCC (P < 0.05). A significant inverse association between HLA-DRB1 CpG9 methylation and HLA-II expression was found in ESCC (P < 0.05). These findings suggest aberrant HLA-DRB1 and HLA-DQB1 methylation contributes to the aberrant expression of HLA-II. These molecular changes may influence the immune response to specific tumor epitopes, promoting the occurrence and progression of Kazakh ESCC.

Hu JM, Sun Q, Li L, et al.
Human leukocyte antigen-DRB1*1501 and DQB1*0602 alleles are cervical cancer protective factors among Uighur and Han people in Xinjiang, China.
Int J Clin Exp Pathol. 2014; 7(9):6165-71 [PubMed] Free Access to Full Article Related Publications
Human papillomavirus (HPV) infection is a major risk factor for cervical cancer. However, only some high risk human papillomavirus (HR-HPV)-infected women progress to cervical cancer, host immunogenetic factors human leukocyte antigen (HLA) may account for viral antigens presenting individually or together in the progression to cervical cancer. This study examined the association between the development of invasive cervical cancer (ICC) and the determinant factors including HLA-DRB1*1501 and DQB1*0602, HR-HPV infection among Chinese Uighur and Han populations. Blood samples, cervical swabs and biopsies were obtained from 287 patients with ICC (192 Uighurs and 95 Hans) and 312 healthy controls (218 Uighurs and 94 Hans). HPV DNA was detected by PCR and HLA-DRB1*1501 and DQB1*0602 alleles were performed using PCR-SSP method. HPV16 infection rates was significantly higher among Uighur and Han with ICC as compared to healthy controls (OR = 58.317; 95% CI: 39.663-85.744; OR = 33.778; 95% CI: 12.581-90.691; P < 0.05 for all). HLA-DRB1*1501 (OR = 0.305; 95% CI: 0.115-0.813; P < 0.05) and HLA-DRB1*1501-DQB1*0602 haplotype frequencies (OR = 0.274; 95% CI: 0.086-0.874; P < 0.05) were significantly reduced in Han ICC. The HLA-DQB1*0602 frequency significantly decreased among Uighur women with ICC (OR = 0.482; 95% CI: 0.325-0.716; P < 0.05). Similar tendencies were observed for DQB1*0602 with HPV16-positive ICC (OR = 0.550; 95% CI: 0.362-0.837; P < 0.05). This study suggests that HLA-DRB1*1501 and DQB1*0602 alleles may influence the immune response to HPV16 infection and decrease the risk of ICC among Uighurs and Hans in Xinjiang, China.

An WX, Fan YX, Liang XH, Liu H
Changes in median ages at death from selected cancer types in relation to HLA-DRB1/DQB1.
Asian Pac J Cancer Prev. 2014; 15(10):4125-8 [PubMed] Related Publications
The median ages at death from cancers between 1985 and 2005 were calculated to demonstrate that inherent anticancer mechanisms may be a common pathway for different cancers. Seventy-eight patients with gastric, liver and lung cancers, were recruited in the solid cancer group. The leukemia group consisted of 31 patients with three main types of leukemia. The controls were 100 healthy individuals. The samples were typed using an HLA-DR/DQ PCR-SSP typing kit. The results showed that the median ages at death from all causes were 64.7 years in 1985 and 70.1 years in 2005. The range of the median ages at death from all cancers was similar to the corresponding value for deaths attributed to all causes. The frequency of DRB1*03 was 9.6% in the solid cancer group and 3.0% in the control group (p<0.05). The frequency of DRB1*04 in the leukemia group were significantly lower than that of the control (p<0.05). DRB1*13 and DQB1*06 frequencies in the leukemia group were significantly higher than those of the controls (p<0.05). It is suggested that inherent anti-cancer mechanisms may be a common pathway for different cancers and are associated with the immune system and HLA.

Arons E, Adams S, Venzon DJ, et al.
Class II human leucocyte antigen DRB1*11 in hairy cell leukaemia patients with and without haemolytic uraemic syndrome.
Br J Haematol. 2014; 166(5):729-38 [PubMed] Free Access to Full Article Related Publications
Frequencies of human leucocyte antigens (HLA) were determined in 287 classic hairy cell leukaemia (HCL) patients. With respect to both population (n = 287) and allele (2n = 574) frequency respectively, the most common HLA class I and II antigens expressed were HLA-A*02 (49·1% and 28·6%), HLA-B*07 (21·3% and 11·1%), HLA-C*07 (46·7 and 28·2%), HLA-DQB1*03 (62·7% and 37·3%), HLA-DRB1*11 (30·0% and 16·0%) and HLA-DRB4*01 (45·3% and 29·6%). In comparing 6-14 databases of control Caucasians to 267 Caucasian HCL patients, only HLA-DRB1*11 was consistently over-represented in HCL, 31·1% of patients vs. 17-19·9% of controls (P = 0·0055 to <0·0001) and 16·5% of alleles vs. 6·5-12·3% of control alleles (P = 0·022 to <0·0001). HLA-DRB1*11 is a known risk factor for acquired thrombotic microangiopathy. Anti-CD22 recombinant immunotoxin BL22 in HCL was associated with a 12% incidence of completely reversible grade 3-4 haemolytic uraemic syndrome (HUS), mainly during the second or third retreatment cycle. Of 49 HCL patients receiving ≥2 cycles of BL22, 7 (14%) had HUS and HLA-DRB1*11 was expressed in 71% of 7 with HUS compared with only 21% of 42 without (P = 0·015). These data suggest that DBR1*11 may be a marker for increased susceptibility to HCL and, among HCL patients, could be a risk factor for BL22-induced HUS.

Wang C, Cicek MS, Charbonneau B, et al.
Tumor hypomethylation at 6p21.3 associates with longer time to recurrence of high-grade serous epithelial ovarian cancer.
Cancer Res. 2014; 74(11):3084-91 [PubMed] Free Access to Full Article Related Publications
To reveal biologic mechanisms underlying clinical outcome of high-grade serous (HGS) epithelial ovarian carcinomas (EOC), we evaluated the association between tumor epigenetic changes and time to recurrence (TTR). We assessed methylation at approximately 450,000 genome-wide CpGs in tumors of 337 Mayo Clinic (Rochester, MN) patients. Semi-supervised clustering of discovery (n=168) and validation (n=169) sets was used to determine clinically relevant methylation classes. Clustering identified two methylation classes based on 60 informative CpGs, which differed in TTR in the validation set [R vs. L class, P=2.9×10(-3), HR=0.52; 95% confidence interval (CI), 0.34-0.80]. Follow-up analyses considered genome-wide tumor mRNA expression (n=104) and CD8 T-cell infiltration (n=89) in patient subsets. Hypomethylation of CpGs located in 6p21.3 in the R class associated with cis upregulation of genes enriched in immune response processes (TAP1, PSMB8, PSMB9, HLA-DQB1, HLA-DQB2, HLA-DMA, and HLA-DOA), increased CD8 T-cell tumor infiltration (P=7.6×10(-5)), and trans-regulation of genes in immune-related pathways (P=1.6×10(-32)). This is the most comprehensive assessment of clinical outcomes with regard to epithelial ovarian carcinoma tumor methylation to date. Collectively, these results suggest that an epigenetically mediated immune response is a predictor of recurrence and, possibly, treatment response for HGS EOC.

Zhang X, Zhang L, Tian C, et al.
Genetic variants and risk of cervical cancer: epidemiological evidence, meta-analysis and research review.
BJOG. 2014; 121(6):664-74 [PubMed] Related Publications
BACKGROUND: More than 200 articles have been published in the past 20 years on associations between genetic variants and risk of cervical cancer but the results have generally been inconsistent.
OBJECTIVE: To provide a synopsis of the current understanding of the genetic architecture of the risk of cervical cancer by conducting a systematic review and meta-analysis.
SEARCH STRATEGY: We conducted a systematic literature search by a two-stage strategy using PubMed and other databases on or before 31 March 2012.
SELECTION CRITERIA: Cross-sectional, case-control or cohort studies about the relationship between genetic variants and cervical cancer were included.
DATA COLLECTION AND ANALYSIS: Study outcomes were presented as odds ratios (ORs) with a 95% confidence interval.We did the meta-analysis for genetic variants which had at least three data sources and for which the significant associations were assessed using the Venice criteria.
MAIN RESULTS: A total of 5605 publications were screened, of which 286 were eligible. Meta-analysis was conducted for 58 variants in 25 genes or loci. Fourteen variants in 11 genes or loci could increase the risk of cervical cancer and five variants in three genes or loci could decrease the risk. The epidemiological evidence of the association was graded as strong for four variants in CTLA4 and HLA DQB1, moderate for five variants in IL-1B, IL-10, XRCC3 and HLA DQA1, and weak for 10 variants.
CONCLUSIONS: Many genetic variants were associated with the risk of cervical cancer as supported by the epidemiological evidence in this meta-analysis.

Atoum MF, Tanashat RQ, Mahmoud SA
Negative association of the HLA-DQB1*02 allele with breast cancer development among Jordanians.
Asian Pac J Cancer Prev. 2013; 14(11):7007-10 [PubMed] Related Publications
BACKGROUND: In the literature, data concerning the relationship between breast cancer and HLA class II gene polymorphisms are limited, so the aim of this study was to determine if HLA-DQB1 and HLA-DRB1 MHC class-II alleles may confer susceptibility or resistance to the disease among Jordanian females.
MATERIALS AND METHODS: This case control study enrolled 56 Royal Hospital breast cancer patients and 60 age matched healthy controls, all of whom provided blood samples (2011-2013). A questionnaire was filled after signing a consent form and DNA was extracted, nucleic acids being amplified for assessment of HLA-DQB1 and HLA-DRB1 alleles by muliplex INNO-LiPA and allele typing carried out by reverse hybridization. Comparison of HLA-DQB1 and HLA-DRB1 allele distributions was carried out with paired t-test and chi-square statistics. Risk factors were assessed by odd ratios with 95% confidence intervals.
RESULTS: A significant negative correlation was observed between HLADQB1* 02 alleles and breast cancers (p=0.013). No significant associations were observed among HLADQB1* 03, 04, 05 and 06 or among HLA-DRB1* 01, 03, 04, 07, 08, 10, 11, 13, 14 and 15.
CONCLUSIONS: HLADQB1* 02 alleles may provide positive protection against breast tumor risk among Jordanians, but not HLADQB1* 03, 04, 05 and 06 or HLA-DRB1* 01, 03, 04, 07, 08, 10, 11, 13, 14 and 15 alleles.

Tong FZ, Yu WJ, Liu H
Novel association analysis between HLA-DQB1 polymorphisms and rectal cancer based on a cross-validation design.
Genet Mol Res. 2013; 12(4):5958-63 [PubMed] Related Publications
A new study design based on cross-validation of the age at the onset of rectal cancer and the differences between the frequency distributions of relevant genes in 2 groups was developed for identification of disease-related HLA. Patients with rectal cancer were recruited and their age at the time of the first surgery was recorded. The genetic variants of HLA-DQB1 were genotyped using an HLA-DQB1 PCR-SSP typing kit. Allele frequencies were compared with control population. The mean age of patients with and without the alleles was compared. The frequency values of HLA-DQB1*02 were 12.3% higher in the cancer group than in the control population (P < 0.05). The median ages of the subjects with and without HLA-DQB1*02 were 54.0 and 61.0 years, respectively, with significant difference observed between the ages for these groups (P < 0.05). The median ages of the subjects with and without HLA-DQB1*03 were 62.0 and 58.0 years, respectively, and a significant difference was observed. The cross-validation of the 2 above mentioned analytical results showed that a statistically significant difference was noted for HLA-DQB1*02 (P < 0.05), whereas no such statistically significant difference was observed for HLA-DQB1*03. HLA-DQB1*02 allele was related to cancer susceptibility. The new analysis method may be an efficient and reliable approach for the identification of disease-related HLA.

Cheung SS, Ou D, Metzger DL, et al.
B7-H4 expression in normal and diseased human islet β cells.
Pancreas. 2014; 43(1):128-34 [PubMed] Related Publications
OBJECTIVES: B7-H4 is a negative coregulatory molecule known to be involved in immune response. We study here B7-H4 expression and its possible role in diabetes and cancer development.
METHODS: Formalin-fixed, paraffin-processed pancreas samples from patients with type 1 diabetes (T1D), insulinoma, pancreatic ductal adenocarcinoma (PDAC), and normal organ donors were studied by bright-field and multifluorescence immunohistochemistry to examine B7-H4 expression and its colocalization with islet endocrine hormones. Quantitative RT-PCR and Western blot assay were used to examine B7-H4 mRNA and protein expression in the islet and exocrine tissues from normal donors and pancreatic cancer cell lines.
RESULTS: B7-H4 protein expression in islet β cells is decreased in T1D and PDAC, but increased in insulinoma patients when compared to normal controls; the changes in B7-H4 expression are concomitant with insulin expression on the islet β cells. The insulin/B7-H4 colocalization on the β cells, expressed in colocalization coefficient Pearson r, is also changed in these islets.
CONCLUSIONS: Our observation of altered B7-H4 expression, concomitant with insulin expression, in the pancreatic islets of T1D, PDAC, and insulinoma patients when compared to normal controls suggests that B7-H4 pathway might play an important role in maintenance of β-cell function, but its exact role remains to be explored.

Sillé FC, Conde L, Zhang J, et al.
Follicular lymphoma-protective HLA class II variants correlate with increased HLA-DQB1 protein expression.
Genes Immun. 2014; 15(2):133-6 [PubMed] Related Publications
Multiple follicular lymphoma (FL) susceptibility single-nucleotide polymorphisms in the human leukocyte antigen (HLA) class I and II regions have been identified, including rs6457327, rs3117222, rs2647012, rs10484561, rs9268853 and rs2621416. Here we validated previous expression quantitative trait loci results with real-time reverse transcription quantitative PCR and investigated protein expression in B-lymphoblastoid cell lines and primary dendritic cells using flow cytometry, cell-based enzyme-linked immunosorbent assay and western blotting. We confirmed that FL-protective rs2647012-linked variants, in high linkage disequilibrium with the extended haplotype DRB1*15:01-DQA1*01:02-DQB1*06:02, correlate with increased HLA-DQB1 expression. This association remained significant at the protein level and was reproducible across different cell types. We also found that differences in HLA-DQB1 expression were not related to changes in activation markers or class II, major histocompatibility complex, transactivator expression, suggesting the role of an alternative regulatory mechanism. However, functional analysis using RegulomeDB did not reveal any relevant regulatory candidates. Future studies should focus on the clinical relevance of increased HLA-DQB1 protein expression facilitating tumor cell removal through increased immune surveillance.

Feng B, Awuti I, Deng Y, et al.
Human papillomavirus promotes esophageal squamous cell carcinoma by regulating DNA methylation and expression of HLA-DQB1.
Asia Pac J Clin Oncol. 2014; 10(1):66-74 [PubMed] Related Publications
AIMS: Esophageal cancer (EC) is one of the most prevalent and deadly cancers worldwide. Along with nutrition, smoking and alcohol consumption, human papillomavirus (HPV) infection is one of the major risk factors, which is modulated by host immune response. This study is aimed at elucidating how HPV modifies host immune system in the EC pathogenesis.
METHODS: The HPV and HLA-DQB1 levels in primary esophageal squamous cell (ESC) cancer cells from Han, Khazak and Uygur patients were analyzed by quantitative real-time PCR and immunoblotting. The ability of HPV16 E6/E7 to transform normal primary ESCs was investigated by infecting ESC with pMSCVpuro-carried E6 or E7. The shRNA against HPV16 E6 or E7 was delivered by adenovirus into esophageal squamous cell carcinoma (ESCC) cells with high HPV content. The DNA methylation level of HLA-DQB1 was measured by methylation-specific PCR.
RESULTS: The HLA-DQB1 expression level was correlated with the levels of HPV and inversely related to DNA methylation level of HLA-DQB1. Overexpressing HPV16 E6 or E7 alone was enough to transform normal primary ESCs. However, single knockdown of either E6 or E7 in ESC cancer cells did not reduce HLA-DQB1 expression.
CONCLUSIONS: Oncogenic HPV E6 and E7 genes promoted ESCC pathogenesis by upregulating susceptible HLA-DQB1 via DNA demethylation.

Besic N, Satej N
Insulin glargine versus other types of basal insulin-clinical and tumor characteristics in patients with breast carcinoma.
BMC Res Notes. 2013; 6:416 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recent epidemiological studies have suggested that some insulin analogues could be associated with an increased risk of cancer. The aim of this retrospective study was to examine whether patients with diabetes mellitus (DM) using insulin glargine have a higher tumor stage of breast carcinoma in comparison to patients using other types of insulin.
METHODS: We performed a chart review of 79 surgically treated breast carcinoma patients (mean age of 66.5 years; range 38-86 years) who were on insulin. Insulin glargine was used in 13 patients, while the other 66 patients were on other types of insulin. Clinical and histopathology characteristics of patients on glargine versus other types of insulin were compared using a chi-square test and non-parametric statistical analysis.
RESULTS: DM type 1 and DM type 2 was present in 14 and 65 patients, respectively. The mean tumor size was 2.98 cm. The TNM tumor stage at diagnosis was not higher among patients on glargine compared to patients on other types of insulin (T1/T2 85% vs. 68%, T3/T4 15% vs. 32%, p = 0.32; N1 54% vs. 58%, p = 0.80; M1 8% vs. 6%, respectively). No significant differences between both study groups (glargine vs. other types of insulin) were found in the ages of the patients, their BMI, tumor histology, grade, number of metastatic lymph nodes, hormone receptors or HER-2 status.
CONCLUSION: We could not show that patients with DM using insulin glargine have a higher tumor stage of breast carcinoma in comparison to those using other types of insulin.

Choi SW, Claycombe KJ, Martinez JA, et al.
Nutritional epigenomics: a portal to disease prevention.
Adv Nutr. 2013; 4(5):530-2 [PubMed] Free Access to Full Article Related Publications
Epigenetics can be defined as inheritable and reversible phenomena that affect gene expression without altering the underlying base pair sequence. Epigenomics is the study of genome-wide epigenetic modifications. Because gene expression changes are critical in both normal development and disease progression, epigenetics is widely applicable to many aspects of biological research. The influences of nutrients and bioactive food components on epigenetic phenomena such as DNA methylation and various types of histone modifications have been extensively investigated. Because an individual's epigenetic patterns are established during early gestation and are changed and personalized by environmental factors during our lifetime, epigenetic mechanisms are quite important in the development of transgenerational and adult obesity as well as in the development of diabetes mellitus. Aging and cancer demonstrate profound genome-wide DNA methylation changes, suggesting that nutrition may affect the aging process and cancer development through epigenetic mechanisms.

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