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:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:HLA class II histocompatibility antigen, DQ beta 1 chain
Source:NCBIAccessed: 31 August, 2019

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 (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 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)

Bajor J, Szakács Z, Juhász M, et al.
HLA-DQ2 homozygosis increases tTGA levels at diagnosis but does not influence the clinical phenotype of coeliac disease: A multicentre study.
Int J Immunogenet. 2019; 46(2):74-81 [PubMed] Related Publications
BACKGROUND AND PURPOSE: Magnitude of gluten-specific T-cell responses in coeliac disease (CD) might be dependent on HLA-DQ2 gene dose. We aimed to investigate the effects of HLA-DQB1*02 allele dose on clinical outcomes.
METHODS: We reviewed the charts of all coeliac patients attending to three Hungarian university clinics after 1997 and included those patients, who (a) were diagnosed with CD, (b) underwent high-resolution HLA typing and (c) were ≥18 years at the time of data collection. HLA typing was performed to determine DQB1*02 allele dose. Patients were divided into risk groups by DQB1*02 allele dose, as follows: high-, intermediate- and low-risk groups corresponded to a double, single and zero doses, respectively. We used ANOVA and Pearson's chi-squared test to explore association between HLA risk and clinical variables.
RESULTS: A total of 727 coeliac patients attended the clinics but only 105 (14.4%) patients were eligible for inclusion. High, intermediate and low HLA risk patients comprised 35.3%, 52.3% and 12.3% of the study population, respectively. Double dose of HLA-DQB1*02 was more frequent in patient with high tTGA level (>10 times the upper limit of normal; p = 0.045). Gene dose was not associated with younger age at diagnosis (p = 0.549), gender (p = 0.739), more severe diagnostic histology (p = 0.318), more frequent classical presentation (p = 0.846), anaemia (p = 0.611), metabolic bone disease (p = 0.374), dermatitis herpetiformis (p = 0.381) and autoimmune diseases (p = 0.837).
CONCLUSIONS: Our study shows a significant gene dose effect in terms of tTGA level at diagnosis, but no significant association between HLA-DQB1*02 allele dose and the clinical outcomes in CD.

Christopher MJ, Petti AA, Rettig MP, et al.
Immune Escape of Relapsed AML Cells after Allogeneic Transplantation.
N Engl J Med. 2018; 379(24):2330-2341 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: As consolidation therapy for acute myeloid leukemia (AML), allogeneic hematopoietic stem-cell transplantation provides a benefit in part by means of an immune-mediated graft-versus-leukemia effect. We hypothesized that the immune-mediated selective pressure imposed by allogeneic transplantation may cause distinct patterns of tumor evolution in relapsed disease.
METHODS: We performed enhanced exome sequencing on paired samples obtained at initial presentation with AML and at relapse from 15 patients who had a relapse after hematopoietic stem-cell transplantation (with transplants from an HLA-matched sibling, HLA-matched unrelated donor, or HLA-mismatched unrelated donor) and from 20 patients who had a relapse after chemotherapy. We performed RNA sequencing and flow cytometry on a subgroup of these samples and on additional samples for validation.
RESULTS: On exome sequencing, the spectrum of gained and lost mutations observed with relapse after transplantation was similar to the spectrum observed with relapse after chemotherapy. Specifically, relapse after transplantation was not associated with the acquisition of previously unknown AML-specific mutations or structural variations in immune-related genes. In contrast, RNA sequencing of samples obtained at relapse after transplantation revealed dysregulation of pathways involved in adaptive and innate immunity, including down-regulation of major histocompatibility complex (MHC) class II genes ( HLA-DPA1, HLA-DPB1, HLA-DQB1, and HLA-DRB1) to levels that were 3 to 12 times lower than the levels seen in paired samples obtained at presentation. Flow cytometry and immunohistochemical analysis confirmed decreased expression of MHC class II at relapse in 17 of 34 patients who had a relapse after transplantation. Evidence suggested that interferon-γ treatment could rapidly reverse this phenotype in AML blasts in vitro.
CONCLUSIONS: AML relapse after transplantation was not associated with the acquisition of relapse-specific mutations in immune-related genes. However, it was associated with dysregulation of pathways that may influence immune function, including down-regulation of MHC class II genes, which are involved in antigen presentation. These epigenetic changes may be reversible with appropriate therapy. (Funded by the National Cancer Institute and others.).

Shim H, Park B, Shin HJ, et al.
Protective association of HLA-DRB1*13:02, HLA-DRB1*04:06, and HLA-DQB1*06:04 alleles with cervical cancer in a Korean population.
Hum Immunol. 2019; 80(2):107-111 [PubMed] Related Publications
Human leukocyte antigen (HLA) class II alleles have been previously associated with cervical cancer. However, these associations vary widely across racial and ethnic groups. Therefore, we evaluated the effect of HLA class II alleles on cervical cancer in a Korean population. HLA-DRB1, HLA-DQB1, and HLA-DQA1 alleles were analyzed in 457 cervical cancer patients and compared to those of 926 control subjects. The odds ratio (OR) of each allele between the patients and controls was calculated using the logistic regression model. Patients, had significantly lower frequencies of HLA-DRB1 and HLA-DQB1 alleles than control subjects: HLA-DRB1*13:02:01 (4.4% vs 8.8%; OR 0.48, 95% confidence interval (CI) 0.27-0.84; p = 0.001), HLA-DRB1*04:06 (2.1% vs 4.7%; OR 0.44, 95% CI 0.20-0.97; p = 0.033), and HLA-DQB1*06:04:01 (2.3% vs 5.0%; OR 0.46, 95% CI 0.22-0.94; p = 0.021). No significant association was observed for HLA-DQA1. Protective associations between HLA-DRB1*13:02, HLA-DRB1*04:06, and HLA-DQB1*06:04 alleles and cervical cancer were found in the Korean population.

Ferreiro-Iglesias A, Lesseur C, McKay J, et al.
Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity.
Nat Commun. 2018; 9(1):3927 [PubMed] Free Access to Full Article Related Publications
Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

Akturk HK, Alkanani A, Zhao Z, et al.
PD-1 Inhibitor Immune-Related Adverse Events in Patients With Preexisting Endocrine Autoimmunity.
J Clin Endocrinol Metab. 2018; 103(10):3589-3592 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Context: Immune checkpoint inhibitors, including monoclonal antibodies directed against programmed cell death protein 1 (PD-1) and its ligand, have emerged as beneficial cancer immunotherapies. These therapies are known to cause immune-related side effects; however, their role in patients with a preexisting autoimmune disease is not clear.
Case Description: We describe two cases of anti-PD-1 immune-related adverse events. A 52-year-old male with longstanding type 1 diabetes (T1D), long-term stable kidney transplant, and hypothyroidism received two separate anti-PD-1 monoclonal antibodies for metastatic melanoma. The patient developed acute kidney graft rejection requiring hemodialysis and worsening of autoimmune hypothyroidism 3 weeks after starting treatment. He continued anti-PD-1 treatments and remained on hemodialysis and increased levothyroxine dosage. The second case is a 62-year-old male with no previous history of diabetes who received anti-PD-1 treatment and developed severe diabetic ketoacidosis (DKA) 5 days following the start of therapy. Further laboratory testing revealed high titer antibodies directed against glutamic acid decarboxylase. These antibodies, which were of the IgG isotype and involved in memory immune responses, were likely present before anti-PD-1 treatment. He also had human leukocyte antigen genes that confer T1D genetic risk. Despite normal pretreatment blood glucose levels and HbA1c, the patient requires permanent exogenous insulin treatment.
Conclusion: Patients with preexisting endocrine autoimmunity may have more frequent and severe immune-related side effects with anti-PD-1 treatment. Given the morbidity and mortality associated with solid organ transplant rejection and DKA, clinicians caring for patients receiving these state-of-the-art therapies need to be aware of the potential adverse events.

Zhou SK, Yang LL, Chen R, et al.
HLA-DQB1*03 genotype and perioperative blood transfusion are not conducive to the prognosis of patients with gastric cancer.
J Clin Lab Anal. 2018; 32(7):e22443 [PubMed] Related Publications
BACKGROUND: Gastric cancer (GC) is a disease associated with a higher incidence and mortality, and some host genetic polymorphisms have been reported as potential factors contributing to the development of GC. In view of this, the study was conducted to investigate the effects of HLA-DQB1 gene polymorphisms and perioperative blood transfusion on prognosis of patients with gastric cancer (GC).
METHODS: A total of 142 patients with GC (case group) and 150 healthy controls (control group) were enrolled. Relationship between HLA-DQB1 gene polymorphisms, perioperative blood transfusion, and clinical pathological parameters of patients with GC after operation was analyzed. Kaplan-Meier curve was applied for analyzing survival rate of patients with GC, and Cox multivariate regression analysis for prognostic factors of patients with GC.
RESULTS: The frequency of HLA-DQB1*03 gene was increased in patients with GC. Patients with GC with HLA-DQB1*03 genotype had higher number of tumor size >6 cm, deeper depth of infiltration, higher LNM rate, and later stage of disease. Patients with HLA-DQB1*03 genotype had lower survival rate compared with other genotypes. Anemia before operation, depth of infiltration in T3 stage and T4 stage, LNM in N1 stage and N2 stage, and HLA-DQB1*03 genotype were regarded as independent risk factors for patients with GC.
CONCLUSION: These results demonstrate that HLA-DQB1*03 genotype and perioperative blood transfusion are not conducive to the prognosis of patients with GC, which could provide a reference for the treatment of GC.

Moyer AM, Hashmi SK, Kroning C, et al.
Does matching for SNPs in the MHC gamma block in 10/10 HLA-matched unrelated donor-recipient pairs undergoing allogeneic stem cell transplant improve outcomes?
Hum Immunol. 2018; 79(7):532-536 [PubMed] Related Publications
BACKGROUND: Matching at the HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci is important in donor selection for patients undergoing unrelated allogeneic hematopoietic stem cell transplantation (ASCT). Additional matching across the MHC gamma region may further improve outcomes.
METHODS: The MHC gamma region was retrospectively genotyped in 66 adult recipients of ASCT and their 10/10 matched unrelated donors. A chart review was performed to determine whether MHC gamma matching impacted survival, relapse, or graft-versus-host disease.
RESULTS: Of 66 donor-recipient pairs, 26(39.4%) were gamma-type matches, 34(51.5%) were mismatches, and 6(9.1%) were "indeterminate." Matching status was not associated with overall survival (p = 0.43), relapse (p = 0.21), acute GVHD (p = 0.43), severe aGVHD (p = 0.31), or chronic GVHD (p = 0.23) in univariate analyses, nor in multivariate analyses (p = 0.28, 0.13, 0.29, 0.16, and 0.67, respectively), with or without adjusting for HLA-DPB1 matching status.
CONCLUSIONS: In our single institution study, gamma-type matching status was not associated with outcomes of adult ASCT recipients.

Liao S, Vickers MH, Stanley JL, et al.
Human Placental Growth Hormone Variant in Pathological Pregnancies.
Endocrinology. 2018; 159(5):2186-2198 [PubMed] Related Publications
Growth hormone (GH), an endocrine hormone, primarily secreted from the anterior pituitary, stimulates growth, cell reproduction, and regeneration and is a major regulator of postnatal growth. Humans have two GH genes that encode two versions of GH proteins: a pituitary version (GH-N/GH1) and a placental GH-variant (GH-V/GH2), which are expressed in the syncytiotrophoblast and extravillous trophoblast cells of the placenta. During pregnancy, GH-V replaces GH-N in the maternal circulation at mid-late gestation as the major circulating form of GH. This remarkable change in spatial and temporal GH secretion patterns is proposed to play a role in mediating maternal adaptations to pregnancy. GH-V is associated with fetal growth, and its circulating concentrations have been investigated across a range of pregnancy complications. However, progress in this area has been hindered by a lack of readily accessible and reliable assays for measurement of GH-V. This review will discuss the potential roles of GH-V in normal and pathological pregnancies and will touch on the assays used to quantify this hormone.

Angelousi A, Kassi E, Nasiri-Ansari N, et al.
Clock genes alterations and endocrine disorders.
Eur J Clin Invest. 2018; 48(6):e12927 [PubMed] Related Publications
BACKGROUND: Various endocrine signals oscillate over the 24-hour period and so does the responsiveness of target tissues. These daily oscillations do not occur solely in response to external stimuli but are also under the control of an intrinsic circadian clock.
DESIGN: We searched the PubMed database to identify studies describing the associations of clock genes with endocrine diseases.
RESULTS: Various human single nucleotide polymorphisms of brain and muscle ARNT-like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) genes exhibited significant associations with type 2 diabetes mellitus. ARNTL2 gene expression and upregulation of BMAL1 and PER1 were associated with the development of type 1 diabetes mellitus. Thyroid hormones modulated PER2 expression in a tissue-specific way, whereas BMAL1 regulated the expression of type 2 iodothyronine deiodinase in specific tissues. Adrenal gland and adrenal adenoma expressed PER1, PER2, CRY2, CLOCK and BMAL1 genes. Adrenal sensitivity to adrenocorticotrophin was also affected by circadian oscillations. A significant correlation between the expression of propio-melanocorticotrophin and PER 2, as well as between prolactin and CLOCK, was found in corticotroph and lactosomatotroph cells, respectively, in the pituitary. Clock genes and especially BMAL1 showed an important role in fertility, whereas oestradiol and androgens exhibited tissue-specific effects on clock gene expression. Metabolic disorders were also associated with circadian dysregulation according to studies in shift workers.
CONCLUSIONS: Clock genes are associated with various endocrine disorders through complex mechanisms. However, data on humans are scarce. Moreover, clock genes exhibit a tissue-specific expression representing an additional level of regulation. Their specific role in endocrine disorders and their potential implications remain to be further clarified.

Hu JM, Liang WH, Qi CH, et al.
HLA-DQB1*03 and DRB1*07 alleles increase the risk of cervical cancer among Uighur and Han women in Xinjiang, China.
Future Oncol. 2018; 14(20):2005-2011 [PubMed] Related Publications
AIM: To explore the association between the determinant factors including HLA-DQB1*03, DRB1-*07, -*13 and high-risk HPV infection, the cervical squamous cell carcinoma (CSCC) pathogenesis among Chinese Uighur and Han population.
MATERIALS & METHODS: HLA alleles were genotyped by PCR sequence-specific primers.
RESULTS: HPV16 infection rate was significantly higher among the Uighurs and Hans with CSCC as compared with healthy controls, respectively. HLA-DQB1*03 significantly increased among Uighurs with CSCC, while HLA-DRB1*07 significantly increased among Hans with CSCC. Similar tendencies were observed for DQB1*03 with HPV16-positive Uighurs CSCC and DRB1*07 with HPV16-positive Hans CSCC.
CONCLUSION: This study suggests that HLA-DQB1*03 and DRB1*07 alleles may influence the immune response to HPV16 infection and increase the risk of CSCC among the Uighurs and Hans in China.

Huo MR, Pei XY, Li D, et al.
Impact of HLA allele mismatch at HLA-A, -B, -C, -DRB1, and -DQB1 on outcomes in haploidentical stem cell transplantation.
Bone Marrow Transplant. 2018; 53(5):600-608 [PubMed] Related Publications
The impact of human leukocyte antigen (HLA) allele mismatch on transplant outcomes in haploidentical stem cell transplantation (haplo-SCT) has not been established. We retrospectively studied 595 patients with hematologic malignancy who received haplo-SCT. The impact of multiple HLA allele mismatches (HLA-A, -B, -C, -DRB1, and -DQB1) and each HLA allele mismatch on transplant outcomes was analyzed. Greater number of HLA allele disparity does not appear worsen outcome. As for each HLA locus, HLA-A mismatch correlated with decreased rate of platelet engraftment (HR 0.740, P = .003); HLA-B mismatch independently correlated with decreased relapse rate (HR 0.494, P = .032) and improved disease-free survival and overall survival (HR 0.514, P = .003; HR 0.494, P = .002, respectively); HLA-C mismatch appeared to be protective for transplant-related mortality (TRM) (HR 0.567, P = .039); HLA-DRB1 mismatch was associated with increased cumulative incidence of grade II-IV acute graft-vs.-host disease (GVHD) (HR 1.942, P = .002). No associations of any HLA mismatch with delayed neutrophil engraftment or increased cumulative incidence of chronic GVHD were observed. Our data indicated that high degree of HLA allele mismatches did not adversely affect transplant outcomes in haplo-SCT and each HLA allele mismatch had different effect.

Han ZD, Dong LN, Zhao SX, et al.
Identification of the novel HLA-DQB1*03:181 allele in a Chinese leukemia patient.
HLA. 2018; 91(2):142-143 [PubMed] Related Publications
HLA-DQB1*03:181 has one nucleotide change from HLA-DQB1*03:05:01 at position 470C>G.

Qin N, Wang C, Zhu M, et al.
Fine-mapping the MHC region in Asian populations identified novel variants modifying susceptibility to lung cancer.
Lung Cancer. 2017; 112:169-175 [PubMed] Related Publications
OBJECTIVES: The polymorphic major histocompatibility complex (MHC) plays a vital role in the immune system and drives predisposition to multiple cancers. A number of lung cancer-related genetic variants in the MHC have been identified in recent genome-wide association studies; however, the causal variants remain unclear.
MATERIALS AND METHODS: In the present study, we conducted a large-scale fine-mapping study of lung cancer in the MHC region of 13,945 unrelated Asian individuals to search for potential causal variants. We used the recently constructed Pan-Asian panel as the reference and imputed eight HLA genes (HLA-A, HLC-B, HLA-C, HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1) using SNP2HLA software.
RESULTS: We identified one single nucleotide polymorphism, rs12333226 (OR=1.41, P=3.97×10
CONCLUSION: We identified seven novel bi-allelic variants and five polymorphic amino acid positions in HLA-DRβ1, HLA-DQα1, and HLA-A that confer a risk of lung cancer. This finding provides evidence for the substantial contributions of HLA class I and II molecules to lung cancer susceptibility.

Liu XL, Wu H, Zhao LG, et al.
Association between insulin therapy and risk of liver cancer among diabetics: a meta-analysis of epidemiological studies.
Eur J Gastroenterol Hepatol. 2018; 30(1):1-8 [PubMed] Related Publications
As the results of the association between insulin therapy and risk of liver cancer among diabetics have been inconsistent in epidemiological studies, we conducted a meta-analysis to quantify this issue. Data of relevant epidemiological studies were collected by searching articles in PubMed, Web of Science, and Embase till 29 June 2017. Random-effects models were employed to combine study-specific risks. Five cohort studies and nine case-control studies were included in our meta-analysis with 285 008 patients with diabetes mellitus and 4329 liver cancer cases. When we compared insulin-use group with noninsulin use group in patients with diabetes mellitus, we observed a statistically significant association between insulin therapy and liver cancer, with an overall relative risk of 1.90 (95% confidence interval: 1.44-2.50, I=76.1%). We did not find heterogeneity between subgroups stratified by study characteristics and adjusted confounders, except for subgroups related to 'follow-up years' of cohort studies. The combined estimate was robust across sensitivity analysis, and no publication bias was detected. Our results indicated that insulin therapy was associated with elevated incidence of liver cancer among diabetics. Given the high prevalence of diabetes, avoiding excess or unnecessary insulin use to control the blood glucose may offer a potential public health benefit in reducing liver cancer risk. Further studies are warranted to investigate the types, doses, and treatment duration of insulin use in large sample size or cohort of diabetic patients.

Wang H, Bender A, Wang P, et al.
Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas.
Nat Commun. 2017; 8(1):767 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Although diabetes results in part from a deficiency of normal pancreatic beta cells, inducing human beta cells to regenerate is difficult. Reasoning that insulinomas hold the "genomic recipe" for beta cell expansion, we surveyed 38 human insulinomas to obtain insights into therapeutic pathways for beta cell regeneration. An integrative analysis of whole-exome and RNA-sequencing data was employed to extensively characterize the genomic and molecular landscape of insulinomas relative to normal beta cells. Here, we show at the pathway level that the majority of the insulinomas display mutations, copy number variants and/or dysregulation of epigenetic modifying genes, most prominently in the polycomb and trithorax families. Importantly, these processes are coupled to co-expression network modules associated with cell proliferation, revealing candidates for inducing beta cell regeneration. Validation of key computational predictions supports the concept that understanding the molecular complexity of insulinoma may be a valuable approach to diabetes drug discovery.Diabetes results in part from a deficiency of functional pancreatic beta cells. Here, the authors study the genomic and epigenetic landscapes of human insulinomas to gain insight into possible pathways for therapeutic beta cell regeneration, highlighting epigenetic genes and pathways.

Burkitbayev ZK, Abdrakhmanova SA, Turganbekova AA, et al.
Detection of the HLA-DQB1 allele, DQB1*03:82, in a Kazakh patient with acute myeloid leukemia.
HLA. 2017; 90(3):181-182 [PubMed] Related Publications
HLA-DQB1*03:82 differs from DQB1*03:01 at nucleotide 223 in exon 2 from G to A.

Ten LC, Chin YM, Tai MC, et al.
SNP variants associated with non-Hodgkin lymphoma (NHL) correlate with human leukocyte antigen (HLA) class II expression.
Sci Rep. 2017; 7:41400 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Large consortia efforts and genome-wide association studies (GWASs) have linked a number of genetic variants within the 6p21 chromosomal region to non-Hodgkin lymphoma (NHL). Complementing these efforts, we genotyped previously reported SNPs in the human leukocyte antigen (HLA) class I (rs6457327) and class II (rs9271100, rs2647012 and rs10484561) regions in a total of 1,145 subjects (567 NHL cases and 578 healthy controls) from two major ethnic groups in Malaysia, the Malays and the Chinese. We identified a NHL-associated (P

Kim TJ, Lee ST, Moon J, et al.
Anti-LGI1 encephalitis is associated with unique HLA subtypes.
Ann Neurol. 2017; 81(2):183-192 [PubMed] Related Publications
OBJECTIVE: Autoimmune encephalitis (AE), represented by anti-leucine-rich glioma-inactivated 1 (anti-LGI1) and anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, has increasing clinical significance based on recent discoveries of neuronal autoantibodies. However, its immunopathogenesis is not fully understood. Here, we investigated whether AE is associated with the human leukocyte antigen (HLA) subtypes.
METHODS: We compared the HLA genotypes of 11 anti-LGI1 and 17 anti-NMDAR encephalitis patients to the control groups, which consisted of 210 epilepsy patients and 485 healthy Koreans.
RESULTS: Anti-LGI1 encephalitis was associated with the DRB1*07:01-DQB1*02:02 haplotype (10 patients; 91%) in HLA class II genes, as well as with B*44:03 (8 patients; 73%) and C*07:06 (7 patients; 64%) in the HLA class I region. The prevalence of these alleles in anti-LGI1 encephalitis was significantly higher than that in the epilepsy controls or healthy controls. By contrast, anti-NMDAR encephalitis was not associated with HLA genotypes. Additional analysis using HLA-peptide binding prediction algorithms and computational docking underpinned the close relationship.
INTERPRETATION: This finding suggests that most anti-LGI1 encephalitis develops in a population with specific HLA subtypes, providing insight into a novel disease mechanism. Ann Neurol 2017;81:183-192.

Gundala NKV, Naidu VGM, Das UN
Arachidonic acid and lipoxin A4 attenuate alloxan-induced cytotoxicity to RIN5F cells in vitro and type 1 diabetes mellitus in vivo.
Biofactors. 2017; 43(2):251-271 [PubMed] Related Publications
OBJECTIVE: We studied whether polyunsaturated fatty acids (PUFAs) can protect rat insulinoma (RIN5F) cells against alloxan-induced apoptosis in vitro and type 1 diabetes mellitus (type 1 DM) in vivo and if so, mechanism of this beneficial action.
MATERIAL AND METHODS: In vitro study was conducted using RIN5F cells while in vivo study was performed in Wistar rats. The effect of PUFAs, cyclo-oxygenase and lipoxygenase inhibitors, various eicosanoids and PUFAs metabolites: lipoxin A4 (LXA4), resolvin D2 and protectin against alloxan-induced cytotoxicity to RIN5F cells and type 1 DM was studied. Expression of PDX1, P65 NF-kB and IKB in RIN5F cells and Nrf2, GLUT2, COX2, iNOS protein levels in the pancreatic tissue and plasma glucose, insulin and tumor necrosis factor-α and antioxidants, lipid peroxides and nitric oxide were measured.
RESULTS: Of all, arachidonic acid (AA) was found to be the most effective against alloxan-induced cytotoxicity to RIN5F cells and preventing type 1 DM. Both cyclo-oxygenase and lipoxygenase inhibitors did not block the beneficial actions of AA in vitro and in vivo. Alloxan inhibited LXA4 production by RIN5F cells and in alloxan-induced type 1 DM Wistar rats. AA-treatment restored LXA4 levels to normal both in vitro and in vivo. LXA4 protected RIN5F cells against alloxan-induced cytotoxicity and prevented type 1 DM and restored expression of Nrf2, Glut2, COX2, and iNOS genes and abnormal antioxidants to near normal.
DISCUSSION: AA seems to bring about its beneficial actions against alloxan-induced cytotoxicity and type 1 DM by enhancing the production of LXA4. © 2016 BioFactors, 43(2):251-271, 2017.

Isaacs SR, Wang J, Kim KW, et al.
MicroRNAs in Type 1 Diabetes: Complex Interregulation of the Immune System, β Cell Function and Viral Infections.
Curr Diab Rep. 2016; 16(12):133 [PubMed] Related Publications
Since the discovery of the first mammalian microRNA (miRNA) more than two decades ago, a plethora of miRNAs has been identified in humans, now amounting to more than 2500. Essential for post-transcriptional regulation of gene networks integral for developmental pathways and immune response, it is not surprising that dysregulation of miRNAs is often associated with the aetiology of complex diseases including cancer, diabetes and autoimmune disorders. Despite massive expansion of small RNA studies and extensive investigation in diverse disease contexts, the role of miRNAs in type 1 diabetes has only recently been explored. Key studies using human islets have recently implicated virus-induced miRNA dysregulation as a pivotal mechanism of β cell destruction, while the interplay between miRNAs, the immune system and β cell survival has been illustrated in studies using animal and cellular models of disease. The role of specific miRNAs as major players in immune system homeostasis highlights their exciting potential as therapeutics and prognostic biomarkers of type 1 diabetes.

Dong LN, He JJ, Zhang W, et al.
Identification of two novel HLA-DQB1 alleles, HLA-DQB1*03:164 and HLA-DQB1*03:165 in Chinese individuals.
HLA. 2016; 88(6):316-317 [PubMed] Related Publications
HLA-DQB1*03:164 shows 604G>T and HLA-DQB1*03:165 has 611 C>G change compared with HLA-DQB1*03:01:01:01.

Messadi A, Malalla ZH, Al-Madhi SA, et al.
Distribution of HLA DRB1 and DQB1 alleles and DRB1-DQB1 haplotypes among Bahraini women with polycystic ovary syndrome.
J Reprod Immunol. 2016; 117:76-80 [PubMed] Related Publications
OBJECTIVE: This study investigated the association between HLA-DRB1 and -DQB1 alleles and DRB1-DQB1 haplotypes, and polycystic ovary syndrome (PCOS) in Bahraini women.
DESIGN: Case-control, retrospective study.
METHODS: Study subjects comprised 80 women with PCOS, and 169 age- and ethnically-matched control women. DRB1 and DQB1 genotyping was done by PCR-SSP.
RESULTS: Of the 13 DRB1 alleles and 5 DQB1 alleles identified, DRB1*10 (14.3% vs. 4.4%) and DRB1*14 (8.7% vs. 1.1%), along with DQB1*05 (35.0% vs. 23.9%), were the most frequent alleles in cases, while DRB1*11 (15.3% vs. 6.8%) was the frequent allele found in controls. The association of PCOS with DRB1*10 (Pc<0.001), DRB1*14 (Pc<0.001), DQB1*05 (Pc=0.040), but not DRB1*11 (Pc=0.076) persisted after correcting for multiple comparisons. DRB1-DQB1 haplotype analysis identified nine common shared haplotypes in women with PCOS and control women, with a frequency exceeding 1%. Significantly higher frequency of DRB1*10-DQB1*05 (12.4% vs. 3.1%) and DRB1*14-DQB1*03 (5.6% vs. 1.0%), and reduced frequency of DRB1*11-DQB1*03 (4.1% vs. 14.1%) haplotypes were seen in women with PCOS vs. control women, thus assigning PCOS-susceptible and -protective nature to these haplotypes, respectively. This association persisted after controlling for multiple comparisons.
CONCLUSION: Our results confirm an association of HLA-DRB1 and -DQB1 alleles and haplotypes with PCOS susceptibility in Bahraini Arabs, further underscoring the immunological/inflammatory nature of this disorder.

Rajaei B, Shamsara M, Amirabad LM, et al.
Pancreatic Endoderm-Derived From Diabetic Patient-Specific Induced Pluripotent Stem Cell Generates Glucose-Responsive Insulin-Secreting Cells.
J Cell Physiol. 2017; 232(10):2616-2625 [PubMed] Related Publications
Human-induced pluripotent stem cells (hiPSCs) can potentially serve as an invaluable source for cell replacement therapy and allow the creation of patient- and disease-specific stem cells without the controversial use of embryos and avoids any immunological incompatibility. The generation of insulin-producing pancreatic β-cells from pluripotent stem cells in vitro provides an unprecedented cell source for personal drug discovery and cell transplantation therapy in diabetes. A new five-step protocol was introduced in this study, effectively induced hiPSCs to differentiate into glucose-responsive insulin-producing cells. This process mimics in vivo pancreatic organogenesis by directing cells through stages resembling definitive endoderm, primitive gut-tube endoderm, posterior foregut, pancreatic endoderm, and endocrine precursor. Each stage of differentiation were characterized by stage-specific markers. The produced cells exhibited many properties of functional β-cells, including expression of critical β-cells transcription factors, the potency to secrete C-peptide in response to high levels of glucose and the presence of mature endocrine secretory granules. This high efficient differentiation protocol, established in this study, yielded 79.18% insulin-secreting cells which were responsive to glucose five times higher than the basal level. These hiPSCs-derived glucose-responsive insulin-secreting cells might provide a promising approach for the treatment of type I diabetes mellitus. J. Cell. Physiol. 232: 2616-2625, 2017. © 2016 Wiley Periodicals, Inc.

Liu X, Yu L, Han C, et al.
Polymorphisms of HLA-DQB1 predict survival of hepatitis B virus-related hepatocellular carcinoma patients receiving hepatic resection.
Clin Res Hepatol Gastroenterol. 2016; 40(6):739-747 [PubMed] Related Publications
OBJECTIVE: Human leukocyte antigen (HLA)-DQB1 genetic polymorphisms are associated with an increased risk of hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC). We aimed to evaluate the influence of genetic polymorphisms in HLA-DQB1 exon region and neighboring single nucleotide polymorphisms (SNPs rs9275572 and rs2244546) on survival of HBV-related HCC patients undergoing hepatic resection.
METHODOLOGY: All SNPs were genotyped by sequencing DNA isolated from tumor samples of 483 patients with HBV-related HCC.
RESULTS: We identified rs9275572 and HLA-DQB1 haplotype CCCCC (constituted by rs1130375C, rs12722107C, rs12722106C, rs36222416C and rs3189152C) were significantly associated with overall survival (OS) of HBV-related HCC patients (P=0.015 and 0.049, respectively), after adjusting for serum AFP level, the Barcelona Clinic Liver Cancer (BCLC) stages, Child-Pugh score, regional invasion, radical hepatic resection and adjuvant antiviral treatment. In stratified analyses, the AG/GG genotype of rs9275572 significantly decreased risk of death among patients with younger age, serum AFP levels ≥400ng/mL, tumor size ≥10cm, BCLC stage A and radical hepatic resection. HLA-DQB1 haplotype CCCCC was significantly protective for male patients, patients with serum AFP levels <400ng/mL, tumor size ≥10cm, BCLC stage B/C, postoperative adjuvant TACE/TAC/TAE, radical hepatic resection and patients with adjuvant antiviral treatment. Moreover, gene-dosage effects were also observed, patients with SNP rs9275572 AG/GG genotypes and Block2 CCCCC haplotype had a decreased risk of death compared to others after adjusting for serum AFP level, BCLC stages, Child-Pugh score, regional invasion, radical hepatic resection and adjuvant antiviral treatment (adjusted HR=0.38, 95% CI=0.20-0.73, P=0.004).
CONCLUSIONS: The AG/GG genotype of rs9275572 and HLA-DQB1 Block2 CCCCC haplotype may have protective effects in HBV-related HCC patients receiving hepatic resection.

Chen D, Enroth S, Liu H, et al.
Pooled analysis of genome-wide association studies of cervical intraepithelial neoplasia 3 (CIN3) identifies a new susceptibility locus.
Oncotarget. 2016; 7(27):42216-42224 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Recent genome-wide association studies (GWASs) in subjects of European descent have identified associations between cervical cancer risk and three independent loci as well as multiple classical human leukocyte antigen (HLA) alleles at 6p21.3. To search for novel loci associated with development of cervical cancer, we performed a pooled analysis of data from two GWASs by imputing over 10 million genetic variants and 424 classical HLA alleles, for 1,553 intraepithelial neoplasia 3 (CIN3), 81 cervical cancer and 4,442 controls from the Swedish population. Notable findings were validated in an independent study of 961 patients (827 with CIN3 and 123 with cervical cancer) and 1,725 controls. Our data provided increased support for previously identified loci at 6p21.3 (rs9271898, P = 1.2 × 10-24; rs2516448, 1.1 × 10-15; and rs3130196, 2.3 × 10-9, respectively) and also confirmed associations with reported classical HLA alleles including HLA-B*07:02, -B*15:01, -DRB1*13:01, -DRB1*15:01, -DQA1*01:03, -DQB1*06:03 and -DQB1*06:02. In addition, we identified and subsequently replicated an independent signal at rs73730372 at 6p21.3 (odds ratio = 0.60, 95% confidence interval = 0.54-0.67, P = 3.0 × 10-19), which was found to be an expression quantitative trait locus (eQTL) of both HLA-DQA1 and HLA-DQB1. This is one of the strongest common genetic protective variants identified so far for CIN3. We also found HLA-C*07:02 to be associated with risk of CIN3. The present study provides new insights into pathogenesis of CIN3.

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] Article available free on PMC after 01/10/2019 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] Article available free on PMC after 01/10/2019 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.

Deniger DC, Pasetto A, Tran E, et al.
Stable, Nonviral Expression of Mutated Tumor Neoantigen-specific T-cell Receptors Using the Sleeping Beauty Transposon/Transposase System.
Mol Ther. 2016; 24(6):1078-1089 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Neoantigens unique to each patient's tumor can be recognized by autologous T cells through their T-cell receptor (TCR) but the low frequency and/or terminal differentiation of mutation-specific T cells in tumors can limit their utility as adoptive T-cell therapies. Transfer of TCR genes into younger T cells from peripheral blood with a high proliferative potential could obviate this problem. We generated a rapid, cost-effective strategy to genetically engineer cancer patient T cells with TCRs using the clinical Sleeping Beauty transposon/transposase system. Patient-specific TCRs reactive against HLA-A*0201-restriced neoantigens AHNAK(S2580F) or ERBB2(H473Y) or the HLA-DQB*0601-restricted neoantigen ERBB2IP(E805G) were assembled with murine constant chains and cloned into Sleeping Beauty transposons. Patient peripheral blood lymphocytes were coelectroporated with SB11 transposase and Sleeping Beauty transposon, and transposed T cells were enriched by sorting on murine TCRβ (mTCRβ) expression. Rapid expansion of mTCRβ(+) T cells with irradiated allogeneic peripheral blood lymphocytes feeders, OKT3, interleukin-2 (IL-2), IL-15, and IL-21 resulted in a preponderance of effector (CD27(-)CD45RA(-)) and less-differentiated (CD27(+)CD45RA(+)) T cells. Transposed T cells specifically mounted a polyfunctional response against cognate mutated neoantigens and tumor cell lines. Thus, Sleeping Beauty transposition of mutation-specific TCRs can facilitate the use of personalized T-cell therapy targeting unique neoantigens.

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.

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