Gene Summary

Gene:HLA-DQB1; major histocompatibility complex, class II, DQ beta 1
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, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:HLA class II histocompatibility antigen, DQ beta 1 chain
Source:NCBIAccessed: 11 August, 2015


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 (1990-2015)
Graph generated 11 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 August, 2015 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)

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] 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] Article available free on PMC after 01/09/2015 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] Article available free on PMC after 01/09/2015 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.

Smith MA, Tellier PP, Roger M, et al.
Determinants of human papillomavirus coinfections among Montreal university students: the influence of behavioral and biologic factors.
Cancer Epidemiol Biomarkers Prev. 2014; 23(5):812-22 [PubMed] Related Publications
BACKGROUND: Human papillomavirus (HPV) coinfections are common among HPV-infected individuals, but the significance and etiology of these infections remain unclear. Though current evidence suggests that women with coinfections have increased HPV exposure (i.e., more sexual partners), it is also hypothesized that these women may represent a subgroup with increased biologic susceptibility. This study sought to examine determinants of coinfections in a cohort of young women, examining both behavioral and biologic factors related to HPV acquisition over time.
METHODS: Female university students (n = 537) in Montreal, Canada, were followed for 2 years at 6-month intervals. At each visit, cervical specimens were collected for cytology and HPV testing, and women completed a questionnaire about lifestyle and behavior. HLA alleles were typed from purified DNA collected from cervical specimens. Two definitions of coinfections were used: cumulative coinfection over follow-up and concurrent coinfection at each visit. Multiple logistic regression was used to determine predictors of both cumulative and concurrent coinfections using baseline and time-dependent covariates.
RESULTS: The most consistent determinant of coinfection occurrence was number of sexual partners, though several genes of the immune response (HLA-DQB1*06:02, HLA-G*01:01:03, and HLA-G*01:01:05) were also identified as significant predictors of cumulative coinfections.
CONCLUSIONS: HPV coinfections mainly occur due to increased sexual activity, but biologic susceptibility may also be involved in a subset of women. Immunologic factors may put women at greater risk of coinfections over the long term, but short-term risk is almost exclusively driven by modifiable sexual behaviors.
IMPACT: Additional research should continue to further identify immunologic biomarkers of HPV susceptibility.

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] Article available free on PMC after 01/09/2015 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] Article available free on PMC after 01/09/2015 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.

Testi M, Troiano M, Guagnano A, et al.
A new allele, HLA-DQB1*04:09.
Tissue Antigens. 2013; 82(3):215-6 [PubMed] Related Publications
The novel allele HLA-DQB1*04:09 differs from DQB1*04:02:01 by three nonsynonymous nucleotide substitutions in exon 2.

Alcoceba M, Sebastián E, Marín L, et al.
HLA specificities are related to development and prognosis of diffuse large B-cell lymphoma.
Blood. 2013; 122(8):1448-54 [PubMed] Related Publications
Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease influenced by genetic and environmental factors. The role of the HLA system in tumor antigen presentation could be involved in susceptibility and disease control. We analyzed the phenotypic frequencies of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 in 250 DLBCLs, comparing them with 1940 healthy individuals. We also evaluated the influence of HLA polymorphisms on survival in those patients treated with curative intention using cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-like regimen without (n = 64, 26%) or with (n = 153, 61%) rituximab. DLBCL patients have a higher phenotypic frequency of HLA-DRB1*01 (29% vs 19.5%, P = .0008, Pc = .0104) and a lower frequency of HLA-C*03 (6.4% vs 17.9%, P < .0005, Pc = .007) compared with healthy individuals. Irrespective of the age-adjusted International Prognostic Index, those patients receiving a CHOP-like plus rituximab regimen and carrying the HLA-B44 supertype had worse 5-year progression-free (54% vs 71%, P = .019) and 5-year overall (71% vs 92%, P = .001) survival compared with patients without this supertype. Our data suggest that some HLA polymorphisms influence the development and outcome of DLBCL, allowing the identification of an extremely good-risk prognostic subgroup. However, these results are preliminary and need to be validated in order to exclude a possible population effect.

Tanaka S, Aida K, Nishida Y, Kobayashi T
Pathophysiological mechanisms involving aggressive islet cell destruction in fulminant type 1 diabetes.
Endocr J. 2013; 60(7):837-45 [PubMed] Related Publications
Fulminant type 1 diabetes is characterized by a rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetic complications. This review summarizes new findings related to the pathophysiology of accelerated β-cell failure in fulminant type 1 diabetes. Immunohistological examination revealed the presence of enterovirus in pancreatic islet cells and exocrine tissues and hyperexpression of pattern recognition receptors (PRRs) including melanoma differentiation-associated antigen 5 (MDA5), retinoic acid-inducible gene-I (RIG-I), Toll-like receptor (TLR)3 and TLR4, essential sensors of innate immunity, in islet cells and mononuclear cells (MNCs) infiltrating islets. Interferon (IFN)-α and IFN-β, products of PRR cascades, were expressed in both islet cells and infiltrating MNCs. Phenotypes of infiltrating cells around and/or into islets were mainly dendritic cells, macrophages and CD8+ T cells. Islet β-cells simultaneously expressed CXC chemokine ligand 10 (CXCL10), IFN-γ and interleukin-18, indicating that these chemokines/ cytotoxic cytokines mutually amplify their cytoplasmic expression in the islet cells. These positive feedback systems might enhance adaptive immunity, leading to rapid and complete loss of β-cells in fulminant type 1 diabetes. In innate and adaptive/autoimmune immune processes, the mechanisms behind bystander activation/killing might further amplify β-cell destruction. In addition to intrinsic pathway of cell apoptosis, the Fas and Fas ligand pathway are also involved as an extrinsic pathway of cell apoptosis. A high prevalence of anti-amylase autoantibodies was recognized in patients with fulminant type 1 diabetes, which suggests that Th2 T-cell reactive immunity against amylase might contribute to β-cell destruction in fulminant type 1 diabetes.

Morishima Y, Kawase T, Malkki M, et al.
Significance of ethnicity in the risk of acute graft-versus-host disease and leukemia relapse after unrelated donor hematopoietic stem cell transplantation.
Biol Blood Marrow Transplant. 2013; 19(8):1197-203 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
The significance of patient and donor ethnicity on risk of acute graft-versus-host disease (GVHD) and disease relapse after unrelated donor hematopoietic cell transplantation (HCT) is not known. A total of 4335 patient-donor pairs from the International Histocompatibility Working Group in HCT met the following 3 criteria: (1) HLA-A, -B, -C, -DRB1, and -DQB1 allele matched donor, (2) diagnosis of leukemia, and (3) non-T cell depleted GVHD prophylaxis. Posttransplantation risks of acute GVHD and leukemia relapse were defined in Asian/Pacific Islander, white, African American, Hispanic, and Native American patients that underwent transplantation from donors with the same self-described background. Asian patients had a significantly lower incidence of acute GVHD (Japanese patients: 40.0% grades II to IV and 15.3% grades III to IV; non-Japanese Asian patients: 42.1% grades II to IV and 15.7% grades III to IV) compared with white patients (56.5% grades II to IV and 22.6% grades III to IV) (P < .001). The hazard ratio of acute GVHD for white patients was significantly higher than for Japanese patients. Unexpectedly, the hazard ratio of leukemia relapse in white patients with early disease status was also significantly higher than that in Japanese patients. These results provide a platform for future investigation into the genetic factors for unrelated donor HCT and clinical implications of diverse ethnic background.

Chalub SR, da Silva RM, da Silva AP, et al.
Evaluation of a histocompatibility antigen related to hepatitis B virus in patients with hepatocellular carcinoma in the western Brazilian Amazon.
Genet Mol Res. 2013; 12(2):1336-46 [PubMed] Related Publications
Hepatocellular carcinoma is an infection of variable incidence that can be caused by hepatitis B virus (HBV), which is endemic in the Amazon region. The diagnosis of HBV can be performed through the use of serum markers such as the hepatitis B surface antigen. The chronic HBV can cause mutagenesis and carcinogenesis, being the susceptibility of infection due to allele human leukocyte antigen (HLA). Thus, we evaluated the clinical, molecular and laboratory profile (histocompatibility complex) of HBV in 22 patients with hepatocellular carcinoma in Amazonia, including 18 males and 4 females, using a blood sample for generic HLA class II. The results showed increased frequency of disease evolution in adults between 25 and 64 years old, who comprised 19 of the 22 patients studied. Most patients (16/22) presented high levels of alpha-fetoprotein and transaminases (14/22). The most common HLA alleles were DRB1 04 (8/44), DRB1 08 (9/44), DRB 03 (16/44), and DQB1 04 (9/44). When we compared specific phenotype frequencies of HLA-DRB1 between patients and controls, we found that patients had a significantly higher frequency of allele DRB1 08 and a significantly lower frequency of DRB1 07 and DRB1 12 compared to previous studies on Asian and Amazonian populations suggesting ethnic differences. We suggest that alleles HLA-DRB 08, HLA-DRB 03 and HLA-DQB1 04 may be risk factors for hepatocellular carcinoma in Amazon.

Rubicz R, Yolken R, Drigalenko E, et al.
A genome-wide integrative genomic study localizes genetic factors influencing antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA-1).
PLoS Genet. 2013; 9(1):e1003147 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Infection with Epstein-Barr virus (EBV) is highly prevalent worldwide, and it has been associated with infectious mononucleosis and severe diseases including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal lymphoma, and lymphoproliferative disorders. Although EBV has been the focus of extensive research, much still remains unknown concerning what makes some individuals more sensitive to infection and to adverse outcomes as a result of infection. Here we use an integrative genomics approach in order to localize genetic factors influencing levels of Epstein Barr virus (EBV) nuclear antigen-1 (EBNA-1) IgG antibodies, as a measure of history of infection with this pathogen, in large Mexican American families. Genome-wide evidence of both significant linkage and association was obtained on chromosome 6 in the human leukocyte antigen (HLA) region and replicated in an independent Mexican American sample of large families (minimum p-value in combined analysis of both datasets is 1.4×10(-15) for SNPs rs477515 and rs2516049). Conditional association analyses indicate the presence of at least two separate loci within MHC class II, and along with lymphocyte expression data suggest genes HLA-DRB1 and HLA-DQB1 as the best candidates. The association signals are specific to EBV and are not found with IgG antibodies to 12 other pathogens examined, and therefore do not simply reveal a general HLA effect. We investigated whether SNPs significantly associated with diseases in which EBV is known or suspected to play a role (namely nasopharyngeal lymphoma, Hodgkin lymphoma, systemic lupus erythematosus, and multiple sclerosis) also show evidence of associated with EBNA-1 antibody levels, finding an overlap only for the HLA locus, but none elsewhere in the genome. The significance of this work is that a major locus related to EBV infection has been identified, which may ultimately reveal the underlying mechanisms by which the immune system regulates infection with this pathogen.

Conde L, Bracci PM, Richardson R, et al.
Integrating GWAS and expression data for functional characterization of disease-associated SNPs: an application to follicular lymphoma.
Am J Hum Genet. 2013; 92(1):126-30 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Development of post-GWAS (genome-wide association study) methods are greatly needed for characterizing the function of trait-associated SNPs. Strategies integrating various biological data sets with GWAS results will provide insights into the mechanistic role of associated SNPs. Here, we present a method that integrates RNA sequencing (RNA-seq) and allele-specific expression data with GWAS data to further characterize SNPs associated with follicular lymphoma (FL). We investigated the influence on gene expression of three established FL-associated loci-rs10484561, rs2647012, and rs6457327-by measuring their correlation with human-leukocyte-antigen (HLA) expression levels obtained from publicly available RNA-seq expression data sets from lymphoblastoid cell lines. Our results suggest that SNPs linked to the protective variant rs2647012 exert their effect by a cis-regulatory mechanism involving modulation of HLA-DQB1 expression. In contrast, no effect on HLA expression was observed for the colocalized risk variant rs10484561. The application of integrative methods, such as those presented here, to other post-GWAS investigations will help identify causal disease variants and enhance our understanding of biological disease mechanisms.

Stockmann P, Nkenke E, Englbrecht M, et al.
Major histocompatibility complex class II polymorphisms are associated with the development of anti-resorptive agent-induced osteonecrosis of the jaw.
J Craniomaxillofac Surg. 2013; 41(1):71-5 [PubMed] Related Publications
The aetiology of anti-resorptive agent-induced osteonecrosis of the jaw (ARONJ) is still under debate. Clinical and genetic risk factors are currently being investigated to help understand its pathogenesis. This case-control study analysed a large number of cancer patients (n = 230) under therapy with intravenous bisphosphonates, half of which were diagnosed with ARONJ. Multiple myeloma, greater patient age and the use of more than one bisphosphonate were identified as clinical risk factors on logistic regression analysis. In addition, 204 patients were genotyped for HLA-DRB1 and DQB1 and the allele frequencies were compared between ARONJ (n = 94) and unaffected cancer patients (n = 110). For the HLA class II alleles, a strong increase in the frequency of DRB1*15, DQB1*06:02, DRB1*01 and DQB1*05:01 was observed in the ARONJ group. These results were reinforced on analysis of the respective haplotypes, with DRB1*15-DQB1*06:02 being significantly associated with the development of ARONJ (odds ratio [OR] 2.5; 95% confidence interval [CI] 1.3-5.0). The presence of at least one of the haplotypes DRB1*15-DQB1*06:02 and DRB1*01-DQB1*05:01 was highly associated with the development of ARONJ (OR 3.0; 95% CI 1.7-5.5). The data in this study of a large number of cancer patients receiving intravenous bisphosphonates suggest that MHC class II polymorphisms represent genetic risk factors for the development of ARONJ. This result supports recent findings that inflammation and infection might play an important role in the pathogenesis of ARONJ.

Ben Othmane Y, Ghazouani E, Mezlini A, et al.
HLA class II susceptibility to cervical cancer among Tunisian women.
Bull Cancer. 2012; 99(9):81-6 [PubMed] Related Publications
The variability in host immunogenetic background, especially in human major histocompatibilty genes, has been shown to influence the susceptibility to human papillomavirus (HPV) infection and cervical neoplasia. Here, we conducted a case-control study in Tunisian women to examine the effect of genetic variation in HLA class II DRB1 and DQB1 genes on invasive cervical cancer (ICC) and squamous cell carcinoma (SCC). HLA genotyping was performed by PCR sequence-specific primers technique. The data revealed significant positive and negative associations, suggesting either predisposing or protective effects of these genes in the disease outcome. DRB1*15, alone or linked to DQB1*06, was associated with a 2.7- and 3.5-fold increase in risk for ICC, respectively. DRB1*13-DQB1*03 showed a similar 3.5 risk effect. Concerning SCC, we observed a relatively higher, about 1.2 times more, risk effect for these genetic markers. In contrast, only one haplotype - DRB1*13-DQB1*06 - provides evidence for a weak protection (about 0.3-fold reduction) of ICC and SCC. In conclusion, we suggest that HLA class II polymorphisms are involved in the genetic susceptibility to cervical cancer in Tunisian women.

Kim S, Kon M, DeLisi C
Pathway-based classification of cancer subtypes.
Biol Direct. 2012; 7:21 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Molecular markers based on gene expression profiles have been used in experimental and clinical settings to distinguish cancerous tumors in stage, grade, survival time, metastasis, and drug sensitivity. However, most significant gene markers are unstable (not reproducible) among data sets. We introduce a standardized method for representing cancer markers as 2-level hierarchical feature vectors, with a basic gene level as well as a second level of (more stable) pathway markers, for the purpose of discriminating cancer subtypes. This extends standard gene expression arrays with new pathway-level activation features obtained directly from off-the-shelf gene set enrichment algorithms such as GSEA. Such so-called pathway-based expression arrays are significantly more reproducible across datasets. Such reproducibility will be important for clinical usefulness of genomic markers, and augment currently accepted cancer classification protocols.
RESULTS: The present method produced more stable (reproducible) pathway-based markers for discriminating breast cancer metastasis and ovarian cancer survival time. Between two datasets for breast cancer metastasis, the intersection of standard significant gene biomarkers totaled 7.47% of selected genes, compared to 17.65% using pathway-based markers; the corresponding percentages for ovarian cancer datasets were 20.65% and 33.33% respectively. Three pathways, consisting of Type_1_diabetes mellitus, Cytokine-cytokine_receptor_interaction and Hedgehog_signaling (all previously implicated in cancer), are enriched in both the ovarian long survival and breast non-metastasis groups. In addition, integrating pathway and gene information, we identified five (ID4, ANXA4, CXCL9, MYLK, FBXL7) and six (SQLE, E2F1, PTTG1, TSTA3, BUB1B, MAD2L1) known cancer genes significant for ovarian and breast cancer respectively.
CONCLUSIONS: Standardizing the analysis of genomic data in the process of cancer staging, classification and analysis is important as it has implications for both pre-clinical as well as clinical studies. The paradigm of diagnosis and prediction using pathway-based biomarkers as features can be an important part of the process of biomarker-based cancer analysis, and the resulting canonical (clinically reproducible) biomarkers can be important in standardizing genomic data. We expect that identification of such canonical biomarkers will improve clinical utility of high-throughput datasets for diagnostic and prognostic applications.

Prestes-Carneiro LE, Nai GA, Silva MG, et al.
Clinical presentation of tuberculoid leprosy in an epidermodysplasia verruciformis patient.
J Infect Dev Ctries. 2012; 6(6):526-30 [PubMed] Related Publications
Epidermodysplasia verruciformis (EV) is triggered by a variety of mechanisms that at least partly include genetic background. We present a Brazilian man with a 30-year history of flat, wart-like lesions with clinical, histopathological, and evolutive aspects consistent with papillomavirus (HPV)-associated EV. Histological analysis of the wart lesions showed epidermis with hyperkeratosis, regular acanthosis, hypergranulosis, and cells with abundant basophilic cytoplasm. Moreover, a perivascular lymphocytic infiltrate was found in the superficial dermis, consistent with a viral wart. Type-2-HPV DNA was detected in various fragments of skin-wart lesions using the polymerase chain reaction (PCR). Two years after the EV diagnosis, the patient presented with an anesthetic well-demarcated, erythematous and mildly scaly plaque on his right forearm. A histopathological analysis of this lesion demonstrated the presence of a compact tuberculoid granuloma. Ziehl-Neelsen staining demonstrated the presence of rare acid-fast bacilli and confirmed the tuberculoid leprosy diagnosis. The patient's Mitsuda Intradermal Reaction was positive. To elucidate the possible mechanism involved in this case of EV, we genotyped the HLA genes of this patient. DQB genotyping showed the polymorphic HLA alleles DQB1*0301 and 0501. The patient was treated with a paucibacillary multi-drug therapy scheme, and the disease was cured in six months. This report describes an EV patient with an M. leprae infection, confirming that tuberculoid leprosy patients possess a relatively specific and efficient cell-mediated immunity against the bacillus and, therefore, localized forms of the disease. Moreover, we show the possible involvement of the polymorphic HLA alleles DQB1*0301 and 0501 in EV induction mechanisms.

Hu J, Li L, Pang L, et al.
HLA-DRB1*1501 and HLA-DQB1*0301 alleles are positively associated with HPV16 infection-related Kazakh esophageal squamous cell carcinoma in Xinjiang China.
Cancer Immunol Immunother. 2012; 61(11):2135-41 [PubMed] Related Publications
Multiple determinant factors are involved in the occurrence and progression of esophageal squamous cell carcinoma (ESCC). Human papillomavirus (HPV) and human leukocyte antigen (HLA) polymorphism were identified as important factors. This study examined the associations between the development of Kazakh ESCC and the determinant factors including HLA-DRB1*0901, 1501; DQB1*0301, 0602; high-risk HPV infection in the area of Xinjiang, China. 200 Kazakh patients with ESCC and 150 controls were recruited, and polymerase chain reaction (PCR) was performed to detect HLA-DRB1*0901, 1501 and DQB1*0301,0602 using sequence-specific primers (SSPs). HPV16 was detected in esophageal specimens using PCR. HPV16 infection rate in Kazakh ESCC case group was 41 %, significantly higher than that of control group 14 % (OR = 3.62; 95 % CI, 2.15-6.09; P < 0.001). A positive association between ESCC and HLA-DRB1*1501 (OR = 2.46, P < 0.0125) or HLA-DQB1*0301 (OR = 3.34, P < 0.0125) alleles was observed. Similar tendencies were observed for HLA-DRB1*1501 (OR = 3.095, P < 0.0125) and HLA-DQB1*0301 (OR = 2.410, P < 0.0125) alleles with HPV16-positive ESCC. HLA-DRB1*1501, HLA-DQB1*0301 and DQB1*0602 were significantly associated with ESCC when the age was ≥55 years (P < 0.0125 for all), whereas only HLA-DQB1*0301 was significantly associated with ESCC when the age was <55 years (P < 0.0125). HLA-DRB1*1501 and HLA-DQB1*0301 were significantly associated with an increase in ESCC occurrence in females (P < 0.0125), whereas only HLA-DQB1*0301 was significantly associated with ESCC in males. Moreover, the occurrence of HLA-DQB1*0602 gene in poorly differentiated ESCC group (68.8 %) was slightly higher than that of well-differentiated squamous cell carcinoma group (31.2 %). The difference was not statistically significant (P > 0.0125). The study suggests that HLA-DRB1*1501 and HLA-DQB1*0301 may influence the immune response to specific tumor and HPV-encoded epitopes and affect the risk of Kazakh ESCC in XinJiang, China.

Orouji E, Tavakkol Afshari J, Badiee Z, et al.
Association between HLA-DQB1 gene and patients with acute lymphoblastic leukemia (ALL).
Int J Hematol. 2012; 95(5):551-5 [PubMed] Related Publications
Acute lymphoblastic leukemia (ALL) affects both children and adults. Survival in ALL has improved in recent decades due to recognition of its biological heterogeneity. Although children have higher remission and cure rates than adults, both populations have benefited from these improvements. Our aim in this study is to determine the association between HLA-DQB1 genes with childhood and adult ALL patients. To define this association, we compared HLA-DQB1 allele frequencies and allele carrier frequencies in a cohort of 135 adults and children with ALL with 150 controls, using polymerase chain reaction with sequence-specific primers. Allele carrier frequencies in childhood ALL show a deficiency in DQ2 (*0201) (P 0.049 and RR 0.75), but an increase in DQ5 (*0501-*0504) and DQ7 (*0301, *0304) compared to the control group (P 0.001 RR 1.89, P 0.003 RR 1.48, respectively). Allele carrier frequencies in adult ALL indicated an increase in DQ5 (*0501-*0504) (P0.045 RR 2.28). Allelic frequencies in childhood ALL revealed the same increase in DQ5 and DQ7, and a decrease in DQ2. In adult ALL it shows a decrease in DQ7. Therefore, our results in adult ALL were similar to childhood ALL addressing DQ5 allele carriers, which showed an increase in both age groups. We suggest that DQ5 could be more strongly considered as an ALL susceptibility allele, and that this allele may underlie a pathogenic phenotype with a major role in the immunologic process involved in both adults and children with ALL.

Milovanovic M, Volarevic V, Radosavljevic G, et al.
IL-33/ST2 axis in inflammation and immunopathology.
Immunol Res. 2012; 52(1-2):89-99 [PubMed] Related Publications
Interleukin-33 (IL-33), a member of the IL-1 family of cytokines, binds to its plasma membrane receptor, heterodimeric complex consisted of membrane-bound ST2L and IL-1R accessory protein, inducing NFkB and MAPK activation. IL-33 exists as a nuclear precursor and may act as an alarmin, when it is released after cell damage or as negative regulator of NFκB gene transcription, when acts in an intracrine manner. ST2L is expressed on several immune cells: Th2 lymphocytes, NK, NKT and mast cells and on cells of myeloid lineage: monocytes, dendritic cells and granulocytes. IL-33/ST2 axis can promote both Th1 and Th2 immune responses depending on the type of activated cell and microenvironment and cytokine network in damaged tissue. We previously described and discuss here the important role of IL-33/ST2 axis in experimental models of type 1 diabetes, experimental autoimmune encephalomyelitis, fulminant hepatitis and breast cancer. We found that ST2 deletion enhance the development of T cell-mediated autoimmune disorders, EAE and diabetes mellitus type I. Disease development was accompanied by dominantly Th1/Th17 immune response but also higher IL-33 production, which suggest that IL-33 in receptor independent manner could promote the development of inflammatory autoreactive T cells. IL-33/ST2 axis has protective role in Con A hepatitis. ST2-deficient mice had more severe hepatitis with higher influx of inflammatory cells in liver and dominant Th1/Th17 systemic response. Pretreatment of mice with IL-33 prevented Con A-induced liver damage through prevention of apoptosis of hepatocytes and Th2 amplification. Deletion of IL-33/ST2 axis enhances cytotoxicity of NK cells, production of IFN-γ in these cells and systemic production of IFN-γ, IL-17 and TNF-α, which leads to attenuated tumor growth. IL-33 treatment of tumor-bearing mice suppresses activity of NK cells, dendritic cell maturation and enhances alternative activation of macrophages. In conclusion, we observed that IL-33 has attenuated anti-inflammatory effects in T cell-mediated responses and that both IL-33 and ST2 could be further explored as potential therapeutic targets in treatment of immune-mediated diseases.

He YM, Zhang W, Zhu FM, et al.
Identification of a novel HLA-DQB1*03:03:04 allele by polymerase chain reaction sequence-based typing in a Chinese leukemia patient.
Tissue Antigens. 2012; 79(3):214-5 [PubMed] Related Publications
Nucleotide sequence of HLA-DQB1*03:03:04 allele was different from that of HLA-DQB1*03:03:02 by a single nucleotide substitution at position 603 C>T.

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Cite this page: Cotterill SJ. HLA-DQB1, Cancer Genetics Web: http://www.cancer-genetics.org/HLA-DQB1.htm Accessed:

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