Gene Summary

Gene:HLA-DQA1; major histocompatibility complex, class II, DQ alpha 1
Aliases: DQ-A1, CELIAC1, HLA-DQA
Summary:HLA-DQA1 belongs to the HLA class II alpha chain paralogues. The 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 alpha chain is approximately 33-35 kDa. It is encoded by 5 exons; exon 1 encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, and exon 4 encodes the transmembrane domain and 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. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:HLA class II histocompatibility antigen, DQ alpha 1 chain
Source:NCBIAccessed: 16 March, 2017


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

Research Indicators

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

Literature Analysis

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

Specific Cancers (6)

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-DQA1 (cancer-related)

Zamani-Ahmadmahmudi M, Aghasharif S, Ilbeigi K
Prognostic efficacy of the human B-cell lymphoma prognostic genes in predicting disease-free survival (DFS) in the canine counterpart.
BMC Vet Res. 2017; 13(1):17 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Canine B-cell lymphoma is deemed an ideal model of human non-Hodgkin's lymphoma where the lymphomas of both species share similar clinical features and biological behaviors. However there are some differences between tumor features in both species. In the current study, we sought to evaluate the prognostic efficacy of human B-cell lymphoma prognostic gene signatures in canine B-cell lymphoma.
METHODS: The corresponding probe sets of 36 human B-cell lymphoma prognostic genes were retrieved from 2 canine B-cell lymphoma microarray datasets (GSE43664 and GSE39365) (76 samples), and prognostic probe sets were thereafter detected using the univariate and multivariate Cox proportional-hazard model and the Kaplan-Meier analysis. The two datasets were employed both as training sets and as external validation sets for each other. Results were confirmed using quantitative real-time PCR (qRT-PCR) analysis.
RESULTS: In the univariate analysis, CCND1, CCND2, PAX5, CR2, LMO2, HLA-DQA1, P53, CD38, MYC-N, MYBL1, and BIRCS5 were associated with longer disease-free survival (DFS), while CD44, PLAU, and FN1 were allied to shorter DFS. However, the multivariate Cox proportional-hazard analysis confirmed CCND1 and BIRCS5 as prognostic genes for canine B-cell lymphoma. qRT-PCR used for verification of results indicated that expression level of CCND1 was significantly higher in B-cell lymphoma patients with the long DFS than ones with the short DFS, while expression level of BIRCS5 wasn't significantly different between two groups.
CONCLUSION: Our results confirmed CCND1 as important gene that can be used as a potential predictor in this tumor type.

Singh SK, Lupo PJ, Scheurer ME, et al.
A childhood acute lymphoblastic leukemia genome-wide association study identifies novel sex-specific risk variants.
Medicine (Baltimore). 2016; 95(46):e5300 [PubMed] Free Access to Full Article Related Publications
Childhood acute lymphoblastic leukemia (ALL) occurs more frequently in males. Reasons behind sex differences in childhood ALL risk are unknown. In the present genome-wide association study (GWAS), we explored the genetic basis of sex differences by comparing genotype frequencies between male and female cases in a case-only study to assess effect-modification by sex.The case-only design included 236 incident cases of childhood ALL consecutively recruited at the Texas Children's Cancer Center in Houston, Texas from 2007 to 2012. All cases were non-Hispanic whites, aged 1 to 10 years, and diagnosed with confirmed B-cell precursor ALL. Genotyping was performed using the Illumina HumanCoreExome BeadChip on the Illumina Infinium platform. Besides the top 100 statistically most significant results, results were also analyzed by the top 100 highest effect size with a nominal statistical significance (P <0.05).The statistically most significant sex-specific association (P = 4 × 10) was with the single nucleotide polymorphism (SNP) rs4813720 (RASSF2), an expression quantitative trait locus (eQTL) for RASSF2 in peripheral blood. rs4813720 is also a strong methylation QTL (meQTL) for a CpG site (cg22485289) within RASSF2 in pregnancy, at birth, childhood, and adolescence. cg22485289 is one of the hypomethylated CpG sites in ALL compared with pre-B cells. Two missense SNPs, rs12722042 and 12722039, in the HLA-DQA1 gene yielded the highest effect sizes (odds ratio [OR] ∼ 14; P <0.01) for sex-specific results. The HLA-DQA1 SNPs belong to DQA1*01 and confirmed the previously reported male-specific association with DQA1*01. This finding supports the proposed infection-related etiology in childhood ALL risk for males. Further analyses revealed that most SNPs (either direct effect or through linkage disequilibrium) were within active enhancers or active promoter regions and had regulatory effects on gene expression levels.Cumulative data suggested that RASSF2 rs4813720, which correlates with increased RASSF2 expression, may counteract the suppressor effect of estrogen-regulated miR-17-92 on RASSF2 resulting in protection in males. Given the amount of sex hormone-related mechanisms suggested by our findings, future studies should examine prenatal or early postnatal programming by sex hormones when hormone levels show a large variation.

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

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

Schaid DJ, Spraggs CF, McDonnell SK, et al.
Prospective validation of HLA-DRB1*07:01 allele carriage as a predictive risk factor for lapatinib-induced liver injury.
J Clin Oncol. 2014; 32(22):2296-303 [PubMed] Related Publications
PURPOSE: Liver injury is a serious adverse event leading to permanent discontinuation of lapatinib in affected patients. This study aimed to validate previously associated major histocompatibility complex (MHC) variants as predictors of risk of liver injury by using a large, randomized, placebo-controlled trial of lapatinib in human epidermal growth factor receptor 2-positive, early-stage breast cancer (Tykerb Evaluation After Chemotherapy [TEACH]: Lapatinib Versus Placebo In Women With Early-Stage Breast Cancer).
PATIENTS AND METHODS: The frequency of ALT elevation cases was compared among four MHC variants in 1,194 patients randomly assigned to lapatinib. Cumulative ALT elevation time courses during treatment were also compared between carriers and noncarriers of specified MHC variants.
RESULTS: In lapatinib-treated patients, there was a significant difference in ALT case incidence between HLA carriers and noncarriers. The highly correlated alleles HLA-DRB1*07:01 and HLA-DQA1*02:01 (study frequency, 22.4%) were associated with ALT elevation (odds ratio, 14) between cases (n = 37) and controls (n = 1,071). These associations strengthened at higher ALT elevation thresholds and in Hy's Law cases. In lapatinib-treated patients, the overall risk for National Cancer Institute-Common Terminology Criteria for Adverse Events grade 3 ALT elevation (> 5× upper limit of normal) was 2.1%; HLA allele carriers had an increased risk of 7.7%; in noncarriers, risk was reduced to 0.5%, comparable to ALT elevation for all patients receiving placebo. The increase in ALT case incidence in the lapatinib arm showed no evidence of plateau during 1 year of lapatinib treatment.
CONCLUSION: These results validate HLA-DRB1*07:01 allele carriage as a predictor of increased risk of lapatinib-induced liver injury and implicate an immune pathology. The HLA association could support clinical management of patients experiencing hepatotoxicity during lapatinib treatment.

Shen FF, Yue WB, Zhou FY, et al.
Variations in the MHC region confer risk to esophageal squamous cell carcinoma on the subjects from high-incidence area in northern China.
PLoS One. 2014; 9(3):e90438 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The human major histocompatibility complex (MHC) is the most important region in vertebrate genome, and is crucial in innate immunity. Recent studies have demonstrated the possible role of polymorphisms in the MHC region to high risk for esophageal squamous cell carcinoma (ESCC). Our previous genome-wide association study (GWAS) has indicated that the MHC region may confer important risk loci for ESCC, but without further fine mapping. The aim of this study is to further identify the risk loci in the MHC region for ESCC in Chinese population.
METHODS: Conditional logistic regression analysis (CLRA) was performed on 24 single nucleotide polymorphisms (SNPs) within the MHC region, which were obtained from the genetically matched 937 cases and 692 controls of Chinese Han population. The identified promising SNPs were further correlated with clinical and clinicopathology characteristics. Immunohistochemistry was performed to explore the protein expression pattern of the related genes in ESCC and neighboring normal tissues.
RESULTS: Of the 24 promising SNPs analyzed, we identified three independent SNPs in the MHC region associated with ESCC: rs35399661 (P = 6.07E-06, OR = 1.71, 95%CI = 1.36-2.17), rs3763338 (P = 1.62E-05, OR = 0.63, 95%CI = 0.50-0.78) and rs2844695 (P = 7.60E-05, OR = 0.74, 95%CI = 0.64-0.86). These three SNPs were located at the genes of HLA-DQA1, TRIM27, and DPCR1, respectively. Further analyses showed that rs2844695 was preferentially associated with younger ESCC cases (P = 0.009). The positive immunostaining rates both for HLA-DQA1 and TRIM27 were much higher in ESCC tissues than in neighboring normal tissues (69.4% vs. 26.8% for HLA-DQA1 and 77.6% vs. 47.8% for TRIM27, P<0.001). Furthermore, the overexpression of HLA-DQA1 is correlated significantly with age (P = 0.001) and family history (P<0.001).
CONCLUSION: This study for the first time provides evidence that multiple genetic factors within the MHC region confer risk to ESCC on the subjects from high-risk area in northern China.

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.

Chen D, Juko-Pecirep I, Hammer J, et al.
Genome-wide association study of susceptibility loci for cervical cancer.
J Natl Cancer Inst. 2013; 105(9):624-33 [PubMed] Related Publications
BACKGROUND: Cervical carcinoma has a heritable genetic component, but the genetic basis of cervical cancer is still not well understood.
METHODS: We performed a genome-wide association study of 731 422 single nucleotide polymorphisms (SNPs) in 1075 cervical cancer case subjects and 4014 control subjects and replicated it in 1140 case subjects and 1058 control subjects. The association between top SNPs and cervical cancer was estimated by odds ratios (ORs) and 95% confidence intervals (CIs) with unconditional logistic regression. All statistical tests were two-sided.
RESULTS: Three independent loci in the major histocompatibility complex (MHC) region at 6p21.3 were associated with cervical cancer: the first is adjacent to the MHC class I polypeptide-related sequence A gene (MICA) (rs2516448; OR = 1.42, 95% CI = 1.31 to 1.54; P = 1.6×10(-18)); the second is between HLA-DRB1 and HLA-DQA1 (rs9272143; OR = 0.67, 95% CI = 0.62 to 0.72; P = 9.3×10(-24)); and the third is at HLA-DPB2 (rs3117027; OR=1.25, 95% CI = 1.15 to 1.35; P = 4.9×10(-8)). We also confirmed previously reported associations of B*0702 and DRB1*1501-DQB1*0602 with susceptibility to and DRB1*1301-DQA1*0103-DQB1*0603 with protection against cervical cancer. The three new loci are statistically independent of these specific human leukocyte antigen alleles/haplotypes. MICA encodes a membrane-bound protein that acts as a ligand for NKG2D to activate antitumor effects. The risk allele of rs2516448 is in perfect linkage disequilibrium with a frameshift mutation (A5.1) of MICA, which results in a truncated protein. Functional analysis shows that women carrying this mutation have lower levels of membrane-bound MICA.
CONCLUSIONS: Three novel loci in the MHC may affect susceptibility to cervical cancer in situ, including the MICA-A5.1 allele that may cause impaired immune activation and increased risk of tumor development.

Li S, Qian J, Yang Y, et al.
GWAS identifies novel susceptibility loci on 6p21.32 and 21q21.3 for hepatocellular carcinoma in chronic hepatitis B virus carriers.
PLoS Genet. 2012; 8(7):e1002791 [PubMed] Free Access to Full Article Related Publications
Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV-related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV-positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV-positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR = 1.30, P = 1.13×10⁻¹⁹) and rs455804 (GRIK1) on 21q21.3 (OR = 0.84, P = 1.86×10⁻⁸), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×10⁻⁴; rs455804: OR = 0.84, P = 6.92×10⁻³). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV-related HCC, suggesting the involvement of glutamate signaling in the development of HBV-related HCC.

Tsai SC, Sheen MC, Chen BH
Association between HLA-DQA1, HLA-DQB1 and oral cancer.
Kaohsiung J Med Sci. 2011; 27(10):441-5 [PubMed] Related Publications
Cancer is one of the most common causes of morbidity and mortality. Genes whose products play a critical role in regulation of the immune response include the HLA antigen and cytokine families of genes. Oral cancer is common in men in developing countries, and its frequency is increased by using betel-quid, tobacco, and alcohol. The association between certain HLA Class I and Class II haplotypes and cancer has been documented in a variety of tumors. There was no previous data concerning the association of specific HLA Class II DQA1, DQB1 alleles, or haplotypes with oral cancer patients. In this study, we enrolled 134 Taiwanese patients with histologically confirmed oral cancer and 268 age- and gender-matched healthy Taiwanese adults as control group to investigate the association between HLA-DQA1, HLA-DQB1 allele frequencies and oral cancer patients by using polymerase chain reaction with sequence-specific primers. We found that both HLA-DQA1* and HLA-DQB1* allele frequencies in oral cancer patients revealed no significant difference from those of control groups. Haplotype frequencies of HLA*DQA1-0103-DQB1*0601 in oral cancer patients were significantly lower than those of the control group (odds ratio: 0.18, 95% confidence interval: 0.054-0.583, p(c)=0.02). Our data suggest that HLA DQA1*0103-DQB1*0601 haplotype may be protective with regard to the development of oral cancer.

Yang H, Hao J, Peng X, et al.
The association of HLA-DQA1*0401 and DQB1*0604 with thymomatous myasthenia gravis in northern Chinese patients.
J Neurol Sci. 2012; 312(1-2):57-61 [PubMed] Related Publications
Genetic analyses indicate that HLA complex genes can be involved in susceptibility to autoimmune myasthenia gravis (MG). Various HLA alleles serve as genetic elements that either predispose to or protect against MG. This study investigates the probable relationship between HLA-DQ allele polymorphisms and MG cases in northern China. The HLA-DQA1 and DQB1 alleles were determined by polymerase chain reaction/sequence-specific primers (PCR-SSP) in 84 MG patients, and the results were compared to 293 healthy controls. Our findings indicate that DQ A1*0401(P=0.008, OR: 2.5, 95%CI: 1.24-3.07) and B1*0301(P=0.000, OR: 2.29, 95%CI: 1.48-3.54) were the most frequent allele; the frequencies of DQA1*0103(P=0.000, OR:0.24, 95%CI 0.13-0.49) and DQB1*0601(P=0.001, OR:0.40, 95%CI 0.22-0.50) were significantly decreased in MG patients compared with healthy controls. Patients with thymomatous MG were positively associated with DQA1 *0401(P=0.011, OR:4.57, 95% CI 1.40-14.90) and DQB1 *0604 (P=0.001, OR:4.01, 95% CI 1.65-9.73) as compared to MG patients without thymoma. Different genetic mechanisms may exist between MG patients with thymoma and those without thymoma. The HLA-DQ associations in MG subgroups suggest that disease heterogeneity may be influenced by different genes or alleles.

Mahmoodi M, Nahvi H, Mahmoudi M, et al.
HLA-DRB1,-DQA1 and -DQB1 allele and haplotype frequencies in female patients with early onset breast cancer.
Pathol Oncol Res. 2012; 18(1):49-55 [PubMed] Related Publications
Based on the reports, few HLA class II alleles are associated with susceptibility or protection in breast cancer. Here we investigate the association between HLA class II alleles and breast cancer in Iranian women. 100 patients with pathologically proven breast cancer who referred to Cancer Institute were randomly selected and compared with a group of 80 healthy blood donor subjects. The patients were studied in two groups, group 1 includes patients aging 40 years or younger and group 2 include patients aging over 40 years. HLA class II alleles were determined by amplification of DNA followed by HLA-typing using sequence-specific primer (SSP) for each allele. In group 1, the most frequent alleles were HLA-DQA1*0301 (P = 0.002, OR = 3.3) and HLA-DQB1*0302 (P = 0.04, OR = 2.8). In group 2, the following alleles increased significantly than those in controls including HLA-DQA1*0301 (P = 0.001, OR = 3.4) and HLA-DRB1*0301 (P = 0.04, OR = 2.3). In complete group of patients, the frequency of HLA-DQA1*0301 (P = 0.001, OR = 3.4) and HLA-DRB1*1303 (P = 0.02, OR = 2.3) increased significantly than those in control group. HLA-DQA1*0505, HLA-DQA1*0101, HLA-DRB1*1301and HLA-DRB1*0101 alleles showed negative association with breast cancer. Our findings suggest that HLA-DQA1*0301 allele is mainly associated with increased risk of breast cancer including early-onset of the disease. HLA-DQA1*0505 and HLA-DRB1*1301 are involved in protection. We conclude that specific alleles of HLA class II influence breast cancer risk.

Kohno T, Kunitoh H, Mimaki S, et al.
Contribution of the TP53, OGG1, CHRNA3, and HLA-DQA1 genes to the risk for lung squamous cell carcinoma.
J Thorac Oncol. 2011; 6(4):813-7 [PubMed] Related Publications
INTRODUCTION: Recent genome-wide association studies (GWASs) have identified polymorphisms in several genes associated with lung cancer risk. Nevertheless, functional polymorphisms in DNA repair and metabolic genes that had been reported as being associated with risk for lung cancer, particularly for lung squamous cell carcinoma (SQC), were not examined in those studies. Therefore, significance of these functional polymorphisms was evaluated in a population, in which polymorphisms in the GWAS genes showed associations with lung SQC risk.
METHODS: Polymorphisms in three DNA repair genes, TP53, MDM2, and OGG1, and two metabolic genes, CYP1A1 and GSTM1, were examined for associations with lung SQC risk in a hospital-based case-control study consisting of 377 cases and 325 controls, which had been previously subjected to association studies on GWAS genes, CHRNA3, TERT, and HLA-DQA1.
RESULTS: Genotypes for two DNA repair genes, TP53 and OGG1, showed significant associations with SQC risk (p < 0.05), and those for two GWAS genes, CHRNA3 and HLA-DQA1, showed significant associations with SQC risk (P < 0.05) with odds ratios between 1.65 (95% confidence interval = 1.06-2.57 for OGG1) and 2.57 (95% confidence interval = 1.03-6.87 for CHRNA3). Marginally significant associations were also observed for MDM2 and CYP1A1 genes. Interactions among these polymorphisms on SQC risk were not observed.
CONCLUSIONS: Association of functional polymorphisms in DNA repair and metabolic genes with lung SQC risk was appreciated. This result indicates the necessity of reevaluation for the significance of functional polymorphisms in DNA repair and metabolic genes on lung cancer risk in other populations subjected to GWASs.

Spraggs CF, Budde LR, Briley LP, et al.
HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer.
J Clin Oncol. 2011; 29(6):667-73 [PubMed] Related Publications
PURPOSE: Hepatobiliary adverse events (AEs) have been observed in a small proportion of patients with metastatic breast cancer (MBC) treated with lapatinib. This study sought to identify gene variants associated with lapatinib-induced ALT elevation and hepatobiliary AEs.
PATIENTS AND METHODS: A two-stage pharmacogenetic investigation of ALT elevation was conducted in lapatinib-treated patients with MBC. Exploratory marker identification evaluated classical HLA alleles, candidate genes, and genome-wide screening in 37 cases with ALT greater than 3 times the upper limit of normal (ULN) and 286 controls with ALT ≤ 1× ULN, selected from 901 lapatinib-treated patients in 12 trials. Markers achieving prespecified association thresholds were progressed to an independent confirmatory data set of 24 ALT cases and 155 controls selected from a subsequent trial of 374 lapatinib-treated patients.
RESULTS: Of 58 variants associated with ALT elevation in the exploratory data set, four exceeded the prespecified significance threshold in the confirmatory analysis. These variants reside in the same MHC genomic locus and include HLA-DQA1*02:01. In the confirmatory study, DQA1*02:01 allele carriage was present in 71% of ALT cases and in 21% of controls (P < .001; odds ratio, 9.0; 95% CI, 3.2 to 27.4). As a predictor of liver safety risk in ALT cases versus noncases, DQA1*02:01 had negative and positive predictive values of 0.97 (95% CI, 0.95 to 0.99) and 0.17 (95% CI 0.10 to 0.26), respectively.
CONCLUSION: These results support a role for immune mechanisms in lapatinib-induced hepatotoxicity. Further work is required to determine whether testing for DQA1*02:01 allele carriage is clinically useful in managing liver safety risk during lapatinib treatment.

Slager SL, Rabe KG, Achenbach SJ, et al.
Genome-wide association study identifies a novel susceptibility locus at 6p21.3 among familial CLL.
Blood. 2011; 117(6):1911-6 [PubMed] Free Access to Full Article Related Publications
Prior genome-wide association (GWA) studies have identified 10 susceptibility loci for risk of chronic lymphocytic leukemia (CLL). To identify additional loci, we performed a GWA study in 407 CLL cases (of which 102 had a family history of CLL) and 296 controls. Moreover, given the strong familial risk of CLL, we further subset our GWA analysis to the CLL cases with a family history of CLL to identify loci specific to these familial CLL cases. Our top hits from these analyses were evaluated in an additional sample of 252 familial CLL cases and 965 controls. Using all available data, we identified and confirmed an independent association of 4 single-nucleotide polymorphisms (SNPs) that met genome-wide statistical significance within the IRF8 (interferon regulatory factor 8) gene (combined P values ≤ 3.37 × 10(-8)), located in the previously identified 16q24.1 locus. Subsetting to familial CLL cases, we identified and confirmed a new locus on chromosome 6p21.3 (combined P value = 6.92 × 10(-9)). This novel region harbors the HLA-DQA1 and HLA-DRB5 genes. Finally, we evaluated the 10 previously reported SNPs in the overall sample and replicated 8 of them. Our findings support the hypothesis that familial CLL cases have additional genetic variants not seen in sporadic CLL. Additional loci among familial CLL cases may be identified through larger studies.

Hosking FJ, Leslie S, Dilthey A, et al.
MHC variation and risk of childhood B-cell precursor acute lymphoblastic leukemia.
Blood. 2011; 117(5):1633-40 [PubMed] Related Publications
A role for specific human leukocyte antigen (HLA) variants in the etiology of childhood acute lymphoblastic leukemia (ALL) has been extensively studied over the last 30 years, but no unambiguous association has been identified. To comprehensively study the relationship between genetic variation within the 4.5 Mb major histocompatibility complex genomic region and precursor B-cell (BCP) ALL risk, we analyzed 1075 observed and 8176 imputed single nucleotide polymorphisms and their related haplotypes in 824 BCP-ALL cases and 4737 controls. Using these genotypes we also imputed both common and rare alleles at class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DRB1, HLA-DQA1, and HLA-DQB1) HLA loci. Overall, we found no statistically significant association between variants and BCP-ALL risk. We conclude that major histocompatibility complex-defined variation in immune-mediated response is unlikely to be a major risk factor for BCP-ALL.

Kohno T, Kunitoh H, Shimada Y, et al.
Individuals susceptible to lung adenocarcinoma defined by combined HLA-DQA1 and TERT genotypes.
Carcinogenesis. 2010; 31(5):834-41 [PubMed] Related Publications
Adenocarcinoma (ADC) is the commonest histological type of lung cancer, and its weak association with smoking indicates the necessity to identify high-risk individuals for targeted screening and/or prevention. By a genome-wide association study (GWAS), we identified an association of polymorphisms in the 6p21.31 locus containing four human leukocyte antigen (HLA) class II genes with lung ADC risk. DQA1*03 of the HLA-DQA1 gene was defined as a risk allele with odds ratio (OR) of 1.36 [95% confidence interval (CI) = 1.21-1.54, P = 5.3 x 10(-7)] by analysis of 1656 ADC cases and 1173 controls. DQA1*03 and the minor allele for a polymorphism, rs2736100, in TERT, another lung cancer susceptibility locus identified in recent GWASs on Europeans and Americans, were indicated to independently contribute to ADC risk with per allele OR of 1.43 (95% CI = 1.31-1.56, P = 7.8 x 10(-16)). Individuals homozygous both for the DQA1*03 and minor TERT alleles were defined as high-risk individuals with an OR of 4.76 (95% CI = 2.53-9.47, P = 4.2 x 10(-7)). The present results indicated that individuals susceptible to lung ADC can be defined by combined genotypes of HLA-DQA1 and TERT.

Spaapen RM, Lokhorst HM, van den Oudenalder K, et al.
Toward targeting B cell cancers with CD4+ CTLs: identification of a CD19-encoded minor histocompatibility antigen using a novel genome-wide analysis.
J Exp Med. 2008; 205(12):2863-72 [PubMed] Free Access to Full Article Related Publications
Some minor histocompatibility antigens (mHags) are expressed exclusively on patient hematopoietic and malignant cells, and this unique set of antigens enables specific targeting of hematological malignancies after human histocompatability leucocyte antigen (HLA)-matched allogeneic stem cell transplantation (allo-SCT). We report the first hematopoietic mHag presented by HLA class II (HLA-DQA1*05/B1*02) molecules to CD4(+) T cells. This antigen is encoded by a single-nucleotide polymorphism (SNP) in the B cell lineage-specific CD19 gene, which is an important target antigen for immunotherapy of most B cell malignancies. The CD19(L)-encoded antigen was identified using a novel and powerful genetic strategy in which zygosity-genotype correlation scanning was used as the key step for fine mapping the genetic locus defined by pairwise linkage analysis. This strategy was also applicable for genome-wide identification of a wide range of mHags. CD19(L)-specific CD4(+) T cells provided antigen-specific help for maturation of dendritic cells and for expansion of CD8(+) mHag-specific T cells. They also lysed CD19(L)-positive malignant cells, illustrating the potential therapeutic advantages of targeting this novel CD19(L)-derived HLA class II-restricted mHag. The currently available immunotherapy strategies enable the exploitation of these therapeutic effects within and beyond allo-SCT settings.

de Araujo Souza PS, Maciag PC, Ribeiro KB, et al.
Interaction between polymorphisms of the human leukocyte antigen and HPV-16 variants on the risk of invasive cervical cancer.
BMC Cancer. 2008; 8:246 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Persistent infection with oncogenic types of human papillomavirus (HPV) is the major risk factor for invasive cervical cancer (ICC), and non-European variants of HPV-16 are associated with an increased risk of persistence and ICC. HLA class II polymorphisms are also associated with genetic susceptibility to ICC. Our aim is to verify if these associations are influenced by HPV-16 variability.
METHODS: We characterized HPV-16 variants by PCR in 107 ICC cases, which were typed for HLA-DQA1, DRB1 and DQB1 genes and compared to 257 controls. We measured the magnitude of associations by logistic regression analysis.
RESULTS: European (E), Asian-American (AA) and African (Af) variants were identified. Here we show that inverse association between DQB1*05 (adjusted odds ratio [OR] = 0.66; 95% confidence interval [CI]: 0.39-1.12]) and HPV-16 positive ICC in our previous report was mostly attributable to AA variant carriers (OR = 0.27; 95%CI: 0.10-0.75). We observed similar proportions of HLA DRB1*1302 carriers in E-P positive cases and controls, but interestingly, this allele was not found in AA cases (p = 0.03, Fisher exact test). A positive association with DRB1*15 was observed in both groups of women harboring either E (OR = 2.99; 95% CI: 1.13-7.86) or AA variants (OR = 2.34; 95% CI: 1.00-5.46). There was an inverse association between DRB1*04 and ICC among women with HPV-16 carrying the 350T [83L] single nucleotide polymorphism in the E6 gene (OR = 0.27; 95% CI: 0.08-0.96). An inverse association between DQB1*05 and cases carrying 350G (83V) variants was also found (OR = 0.37; 95% CI: 0.15-0.89).
CONCLUSION: Our results suggest that the association between HLA polymorphism and risk of ICC might be influenced by the distribution of HPV-16 variants.

Karanikiotis C, Daniilidis M, Karyotis N, et al.
HLA Class II alleles and the presence of circulating Epstein-Barr virus DNA in Greek patients with nasopharyngeal carcinoma.
Strahlenther Onkol. 2008; 184(6):325-31 [PubMed] Related Publications
BACKGROUND AND PURPOSE: Nasopharyngeal carcinoma (NPC) represents a seldom malignancy in most developed countries. Nevertheless, NPC receives an endemic form in concrete racial entities. The aims of this study were to detect the presence of Epstein-Barr virus DNA (EBV-DNA) in peripheral blood of NPC patients, to molecularly define human leukocyte antigens (HLA) DRB1*, DQA1* and DQB1* allele frequencies, and, finally, to determine whether the genetic predisposition of an individual to NPC depends on the liability to EBV infection.
PATIENTS AND METHODS: A total of 101 patients of Hellenic origin and nationality, with histologically proven NPC, participated in this study. EBV-DNA detection was also applied in 66 patients with EBV-related malignancies (Hodgkin's [HL] and non-Hodgkin's lymphoma [NHL]) and infectious mononucleosis (IM), as well as in 80 healthy EBV-seropositive controls.
RESULTS: 81% of the NPC patients, 77.8% with HL, 72.2% with NHL, and 66.7% with IM were EBV-DNA positive, whereas the EBV genome was detected only in 15% of the healthy controls. These differences were statistically significant in all cases. Analysis of HLA class II antigens showed decreased frequency of the DRB1*07 (p = 0.003), DQA1*0103 (p = 0.002), and DQA1*0201 (p = 0.003) alleles among NPC patients. A significant association between the HLA-DR/DQ alleles and the presence of EBV-DNA in peripheral whole blood was not established.
CONCLUSION: Circulating EBV-DNA and specific HLA class II alleles may predispose to or protect from NPC. However, the results of this study suggest that the genetic predisposition of an individual to NPC is independent of the liability to EBV infection.

Liu C, Cheng B
Association of polymorphisms of human leucocyte antigen-DQA1 and DQB1 alleles with chronic hepatitis B virus infection, liver cirrhosis and hepatocellular carcinoma in Chinese.
Int J Immunogenet. 2007; 34(5):373-8 [PubMed] Related Publications
To investigate whether human leucocyte antigen (HLA) class II DQA1 and DQB1 gene polymorphisms are associated with chronic hepatitis B virus (HBV) infection and development of HBV-related liver cirrhosis (LC) and hepatocellular carcinoma (HCC), we detected the DQA1 and DQB1 allele polymorphisms in 168 HBV carriers (including 48 chronic hepatitis B, 42 LC and 78 HCC patients) and 100 controls who had recovered from HBV infection by using polymerase chain reaction amplification with sequence-specific primers (PCR-SSP). Our data suggest that DQA1*0102 and DQA1*0104 were associated with protection from chronic HBV infection (P(c) = 0.003) and development of LC (P(c) = 0.001), respectively, whereas DQB1*0201 conferred susceptible effect on chronic HBV infection (P(c) = 0.008). We also found that DQA1*0601, DQB1*0601 and DQA1*0201 showed some susceptible effect on chronic HBV infection and LC, respectively, however, these associations were no longer significant after Bonferroni correction (P(c) = 0.390, P(c) = 0.475 and P(c) = 0.140, respectively). No significant association has been found between DQA1 and DQB1 alleles and development of HCC. These results indicate that different subtypes of HLA-DQA1 and DQB1 are associated with development of chronic HBV infection and LC, respectively, in Han Chinese population.

Chen PC, Tsai EM, Er TK, et al.
HLA-DQA1 and -DQB1 allele typing in southern Taiwanese women with breast cancer.
Clin Chem Lab Med. 2007; 45(5):611-4 [PubMed] Related Publications
BACKGROUND: The pathogenesis of breast cancer is multifactorial. Genetic predisposition, environmental factors, hormones and even infection agents are thought to interact in the manifestation of breast cancer. In particular, human leukocyte antigen (HLA) alleles play a pivotal role in cellular immunity and may be an important genetically determined host trait. Regardless of the importance and functions of HLA genes in the evolution of cancer, the allele-specific association of HLA molecules in cancer patients has not been well established. Recently, a few studies have concentrated on the association between HLA and breast cancer, but the results of these studies are controversial.
METHODS: We designed a study to evaluate the association between the genotype of HLA class II genes and breast cancer. HLA-DQA1 and -DQB1 polymorphisms were determined by PCR with sequence-specific primers (PCR-SSP) in 101 Taiwanese women patients with breast cancer and 115 matched control subjects.
RESULTS: Using PCR-SSP typing, HLA-DQA1 and -DQB1 locus comparison of allele frequencies between breast cancer patients and healthy controls showed no significant difference.
CONCLUSIONS: We have established a significant lack of HLA-DQA1 and -DQB1 association with breast cancer in southern Taiwanese women. The results of this study may provide information for further clarification of the etiology of breast cancer in this region.

Amirzargar AA, Khosravi F, Dianat SS, et al.
Association of HLA class II allele and haplotype frequencies with chronic myelogenous leukemia and age-at-onset of the disease.
Pathol Oncol Res. 2007; 13(1):47-51 [PubMed] Related Publications
Chronic myelogenous leukemia (CML) is characterized by the presence of Philadelphia chromosome resulting from bcr/abl translocation. To clarify the association between HLA class II allele and haplotype frequencies in CML, 50 patients referred to Hematology Oncology and Bone Marrow Transplantation (BMT) center, Shariaty Hospital, Tehran, Iran, were randomly selected and compared with a group of 80 unrelated healthy blood donor subjects. HLA class II alleles were determined by PCR-SSP method. The results showed that the frequencies of DQB1*03011 (P=0.01) and DQA1*0505 (P=0.05) were higher, while that of DQB1*03032 (P=0.04) was lower in patients than in the controls. Regarding age-at-onset, the frequency of HLA-DRB1*07 (P=0.03) and -DQA1*0201 (P=0.03) alleles were higher in patients younger than 35 years. The most frequent haplotypes in our CML patients were HLA-DRB1*11/-DQB1*03011/-DQA1*0505 (P=0.01) and HLA-DRB1*04/-DQB1*0302/-DQA1*03011 (P=0.02). In conclusion, it is suggested that positive and negative association in certain HLA alleles and haplotypes exist in Iranian patients with CML.

Sarafnejad A, Khosravi F, Alimoghadam K, et al.
HLA class II allele and haplotype frequencies in iranian patients with acute myelogenous leukemia and control group.
Iran J Allergy Asthma Immunol. 2006; 5(3):115-9 [PubMed] Related Publications
Previous studies have demonstrated some significant differences in HLA allele frequencies in leukemic patients and normal subjects. We have analyzed HLA class II alleles and haplotypes in 60 Iranian patients with acute myelogenous leukemia (AML) and 180 unrelated normal subjects. Blood samples were collected after obtaining informed consents. From the patients and control DNA extraction and HLA typing were performed using PCR-SSP method. Significant positive association with the disease was found for HLA-DRB1*11 allele (35% vs. 24.7%, p=0.033). Two alleles including HLA-DRB4 and -DQB1*0303 were found to be significantly decreased in patients compared to controls. Regarding haplotype analysis, no significant association was found between case and control groups. It is suggested that HLA-DRB1*11 allele plays as a presumptive predisposing factor while the HLA-DRB4 and -DQB1*0303 alleles are suggested as protective genetic factors against acute myelogenous leukemia. Larger studies are needed to confirm and establish the role of these associations with acute myelogenous leukemia.

Kübler K, Arndt PF, Wardelmann E, et al.
HLA-class II haplotype associations with ovarian cancer.
Int J Cancer. 2006; 119(12):2980-5 [PubMed] Related Publications
The development of cancer is a multistep process that is characterized by the accumulation of genetic alterations in cells and changed cellular interactions with the surrounding healthy tissues. The human immune system is believed to be intrinsically involved in this process. The correlation of certain human leukocyte antigen (HLA)-class I and II haplotypes with tumorigenesis is documented in a variety of tumors. However, few data exist on the possible association of specific HLA-class II alleles or haplotypes with ovarian cancer. In our sample of 52 Caucasian patients with primary ovarian carcinoma and 239 female healthy local controls, we observed a significantly increased incidence of the HLA-class II haplotypes DRB1*0301 - DQA1*0501 - DQB1*0201 (p < 0.001) and DRB1*1001 - DQA1*0101 - DQB1*0501 (p < 0.001) in the patients. Our data suggest that HLA-class II loci or individual HLA-class II haplotypes may be involved in the pathogenesis of ovarian cancer.

Planelles D, Nagore E, Moret A, et al.
HLA class II polymorphisms in Spanish melanoma patients: homozygosity for HLA-DQA1 locus can be a potential melanoma risk factor.
Br J Dermatol. 2006; 154(2):261-6 [PubMed] Related Publications
BACKGROUND: The association of melanoma with HLA class II loci is under extensive debate. Different investigators have found discrepant results due to, at least in part, sample size, patient series heterogeneity, choice of control population and differences in the techniques employed for the detection of HLA antigens and alleles.
OBJECTIVES: This study was designed to analyse the possible association of melanoma with HLA class II loci with regard to different clinic pathological factors and to investigate other risk factors for melanoma susceptibility, such as HLA homozygosity.
PATIENTS AND METHODS: HLA-DRB1, -DQA1 and -DQB1 genotyping was performed for 117 eastern Spanish patients presenting with primary melanoma.
RESULTS: Although there were no significant alterations in the phenotypic frequencies of HLA-DQA1, -DQB1 or -DRB1 alleles in any subgroup of patients when compared with controls, patients exhibited a statistically significant increase in HLA-DQA1 homozygosity rate. This DQA1 homozygosity-specific association was particularly dependent on some features in melanoma patients such as light hair colour, skin type I or II, early age at diagnosis, absence of atypical naevi, or abscence of atypical naevus syndrome phenotype (aetiological fractions about 10-20%). Analysis of homozygosity for single DQA1 alleles showed an increased homozygosity rate for DQA1*0505 and DQA1*0301 in comparison with controls. These DQA1 alleles are in strong linkage disequilibrium with DQB1*0301 in white populations, and DQB1*0301 homozygous individuals were significantly increased in red in or fair-haired patients (relative risk 5.65).
CONCLUSIONS: Our results indicate that the contribution of HLA class II alleles to primary melanoma incidence is not significant in the Spanish population. However, homozygosity for the HLA-DQA1 locus (and, perhaps, for the HLA-DQB1*0301 allele) might be considered a potential risk factor for developing melanoma depending on the person's genetic background and, perhaps, on certain environmental conditions.

Schiff MA, Apple RJ, Lin P, et al.
HLA alleles and risk of cervical intraepithelial neoplasia among southwestern American Indian women.
Hum Immunol. 2005; 66(10):1050-6 [PubMed] Related Publications
An increase in cervical intraepithelial neoplasia (CIN) has been described in American Indian women in New Mexico. Differences in human leukocyte antigen (HLA) alleles have been reported in cervical intraepithelial neoplasia (CIN) compared with controls in other populations. We investigated HLA alleles and CIN in Southwest American Indian women. The case control study included 89 women with biopsy-proven CIN II/III (diagnosed November 1994 through October 1997) and 271 similar women with normal cervical epithelium from the same clinics. DRB1, DQB1, and DPB1 alleles were determined using DNA typing techniques. DQA1 and HLA-A allele typing was included for some subjects (randomly chosen n = 37 and n = 163 cases and controls, respectively). We found a decreased risk of CIN with DRB1*1402 (OR 0.5, 95% CI 0.3-0.9) and an increased risk with DRB1*1501 (OR 2.7, 95% CI 0.9-7.3). Additionally, DQA1*0102 was associated with increased risk (OR 4.5, 95% CI 1.3-5.3) and HLA-A*02 with decreased risk (OR 0.4, CI 0.2-0.9). Our findings are discussed along with studies in other populations.

Kawahara Y, Mizuno M, Yoshino T, et al.
HLA-DQA1*0103-DQB1*0601 haplotype and Helicobacter pylori-positive gastric mucosa-associated lymphoid tissue lymphoma.
Clin Gastroenterol Hepatol. 2005; 3(9):865-8 [PubMed] Related Publications
BACKGROUND & AIMS: Immune responses to Helicobacter pylori are important in the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. In this retrospective case study, we investigated whether certain alleles and haplotypes of major histocompatibility complex genes are associated with gastric MALT lymphoma and the efficacy of H pylori eradication therapy on the lymphoma.
METHODS: Blood samples were obtained from 18 patients with H pylori-positive gastric MALT lymphoma (5 men and 13 women; age range, 51-80 years), 30 patients with H pylori-positive non-ulcer dyspepsia (17 men and 13 women; age range, 37-77 years), and 30 patients with H pylori-negative non-ulcer dyspepsia (12 men and 18 women; age range, 37-77 years). HLA-DQA1 and DQB1 allele typing was performed by use of a polymerase chain reaction sequence-specific oligonucleotide procedure. All patients with MALT lymphoma were treated with H pylori eradication therapy and followed up by repeated endoscopy and biopsy.
RESULTS: We found a significant increase in alleles HLA-DQA1*0103 and HLA-DQB1*0601, and a haplotype DQA1*0103-DQB1*0601, in MALT lymphoma patients when compared with non-ulcer dyspepsia patients who were either H pylori-positive or not and with a healthy control population. After H pylori eradication, the lymphomas regressed completely in all 10 patients who possessed the DQA1*0103-DQB1*0601 haplotype but in only 4 of the 8 without this haplotype (P = .023).
CONCLUSIONS: DQA1*0103-DQB1*0601 haplotype-positive gastric MALT lymphoma is likely to respond to therapy by eradication of H pylori.

Masala MV, Carcassi C, Cottoni F, et al.
Classic Kaposi's sarcoma in Sardinia: HLA positive and negative associations.
Int J Dermatol. 2005; 44(9):743-5 [PubMed] Related Publications
BACKGROUND: The incidence of classic Kaposi's sarcoma (CKS) in northern Sardinia is one of the highest in the world.
METHODS: Sixty-two patients with CKS were typed for class I and class II antigens. All patients had been born and were living in northern Sardinia.
RESULTS: In the Sardinian patients, we observed a positive CKS association with Cw7, DRB1*1104, DRB1*1302, DQA1*0302, and DQB1*0604, and a negative CKS association with A30, B58, Cw5, DRB1*1601, and DQB1*0502.
CONCLUSIONS: The strong positive CKS association with DRB1*1104 and DQB1*0604 and negative association with B58 are particularly significant and further support the notion of a genetic predisposition to CKS.

Monos DS, Pappas J, Magira EE, et al.
Identification of HLA-DQalpha and -DRbeta residues associated with susceptibility and protection to epithelial ovarian cancer.
Hum Immunol. 2005; 66(5):554-62 [PubMed] Related Publications
Substantial evidence has been accumulated suggesting that T cells in patients with epithelial ovarian carcinoma (EOC) exhibit an antigen-driven immune response directed against the tumor cells. In the context of human leukocyte antigen (HLA), this suggests its possible involvement in the disease. Therefore, we examined the distribution of the HLA-DRB1*, -DQA1*, and -DQB1* alleles in 47 patients with EOC and 67 healthy Caucasian women. The frequency of D(70) and E(71) polymorphic residues of the DRB1 alleles was significantly reduced in EOC patients versus controls (pD(70)E(71) = 0.009), suggesting a protective role against the disease. The DQalpha residues R(52) and Y(11)R(55) were increased in the patients (p = 0.008 and 0.012, respectively). Because residues 11 and 55 participate in the formation of pocket 1, they may be functionally important amino acid positions that influence disease susceptibility. The frequency of the DQalpha susceptibility epitope (R(52)Y(11)R(55)) among the DRbetaD(70)E(71)-positive EOC patients was increased when compared with DRbetaD(70)E(71)-positive controls (EOC, 100%; control, 52%; p = 0.028). Among individuals without the DQalpha susceptibility epitope, the distribution of DRbetaD(70)E(71)-positive cases was significantly different between EOC patients and controls (EOC, 0%; control, 60%; p = 0.039). Therefore, it appears that the presence of DQalpha susceptibility elements overrides the protective effect of the DRbetaD(70)E(71) epitope and suggests an interactive relationship between DRbeta and DQalpha epitopes that may be of importance for disease susceptibility. Because positions DRbeta 70,71 and DQalpha 52 have been implicated in immunologic diseases, it is likely that besides being critical for T-cell recognition, they may also play a role in T-cell development and acquisition of the T-cell repertoire.

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