Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 604305

MAJOR HISTOCOMPATIBILITY COMPLEX, CLASS II, DQ BETA-1; HLA-DQB1

HGNC Approved Gene Symbol: HLA-DQB1

Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38) : 6:32,659,467-32,666,657 (from NCBI)

Gene-Phenotype Relationships

TEXT

The genes for the heteromeric major histocompatibility complex class II proteins, the alpha and beta subunits, are clustered in the 6p21.3 region. Todd et al. (1987) presented a map of the class II loci. They suggested that the structure of the DQ molecule, in particular residue 57 of the beta-chain, specifies the autoimmune response against insulin-producing islet cells that leads to insulin-dependent diabetes mellitus (IDDM; 222100). Of the approximately 14 class II HLA genes within the HLA-D region, the DQ3.2-beta gene accounts for the well-documented association of HLA-DR4 with insulin-dependent diabetes mellitus and is the single allele most highly correlated with this disease. Kwok et al. (1989) found that amino acid 45 was critical for generating serologic epitopes characterizing the DQ3.2-beta gene and its nondiabetic allele, DQ3.1-beta. Todd et al. (1990) found that in Japanese IDDM was more strongly associated with HLA-DQ than with HLA-DR (142857); that the A3 allele at the DQA1 (146880) locus was most strongly associated with disease; that the DQw8 allele of the DQB1 locus, which is associated with susceptibility to type I diabetes in Caucasians and blacks, was not increased in frequency in Japanese patients; and that asp57-encoding DQB1 alleles, which are associated with reduced susceptibility to type I diabetes in Caucasians, was present in all except 1 of 49 Japanese patients and in all of 31 controls, in at least heterozygous state. Forty percent of patients were homozygous for asp57-encoding DQB1 alleles versus 35% of controls. The high frequency of asp57-encoding DQB1 alleles in Japanese may account for the rarity of type I diabetes in Japan.

The extremely high polymorphism of HLA class II transmembrane heterodimers is due to a few hypervariable segments present in the most external domain of their alpha and beta chains. Some changes in amino acid sequence are critical in disease susceptibility associations as well as the ability to present processed antigens to T cells. By screening a B-cell cDNA library with a DQ-beta probe, Giorda et al. (1991) obtained the cDNAs corresponding to the beta chains of the HLA-DQw7, -DQw8, and -DQw9 alleles. Sequence analysis revealed differences between DQw8 and DQw9 in 6 nucleotide positions that resulted in only 1 amino acid change. DQw9 encodes an aspartic acid instead of alanine at position 57. DQw7 is the same as DQw9 at this position but differs in 9 other amino acids.

In addition to insulin-dependent diabetes mellitus, an increased frequency of specific alleles at the DQB1 locus has been claimed for narcolepsy (161400), pemphigus vulgaris (169610), and ocular cicatricial pemphigoid (OCP; 164185).

Mignot et al. (1997) found that narcolepsy is tightly associated with the HLA-DQB1*0602 allele, especially when the manifestations include typical cataplexy.

The molecule encoded by DQA1*0102/DQB1*0602, termed DQ0602, confers strong susceptibility to narcolepsy but dominant protection against type I diabetes. To elucidate the molecular features underlying these contrasting genetic properties, Siebold et al. (2004) determined the crystal structure of the DQ0602 molecule at 1.8-angstrom resolution. Structural comparisons to homologous DQ molecules with differential disease associations highlighted a previously unrecognized interplay between the volume of the P6 pocket and the specificity of the P9 pocket, which implies that presentation of the expanded peptide repertoire is critical for dominant protection against type I diabetes. In narcolepsy, the volume of the P4 pocket appears central to the susceptibility, suggesting that the presentation of a specific peptide population plays a major role.

Cicatricial pemphigoid (CP) is a chronic autoimmune blistering disease affecting multiple mucous membranes derived from stratified squamous epithelium and occasionally the skin. CP has a wide spectrum of disease manifestations. Patients with oral pemphigoid (OP) have a benign self-limited disease in which pathologic changes are restricted to the oral mucosa. On the other hand, patients with ocular cicatricial pemphigoid, a chronic condition marked by relapses and remissions, have ocular involvement and also perhaps involvement of other mucous membranes. All clinical types are characterized by the presence of similar anti-basement zone autoantibody. The factors that determine the development of one form of CP or the other are not known. Yunis et al. (1994) studied class II alleles by DNA testing in 22 Caucasian patients with OP and their families (19 families). The results were compared to those obtained from 17 OCP patients and their family controls and those of 42 control Caucasian families studied for bone marrow transplantation. The results indicated that HLA-DQB1*0301 is a marker of susceptibility for both oral and ocular forms of CP. The analysis of the amino acid sequence of the DQB1 alleles present in both OP and OCP suggested that amino acid residues at position 57 and positions 71-77 may also be markers.

Delgado et al. (1996) compared the high-resolution typing of MHC class II loci, HLA-DRB1 (142857) and HLA-DQB1, in 21 patients with bullous pemphigoid (see 113810), 17 patients with ocular cicatricial pemphigoid, and 22 patients with oral pemphigoid to a panel of 218 haplotypes of normal individuals. They found that the 3 diseases had significant association with DQB1*0301 (P = 0.005, P less than 0.0001, and P = 0.001 respectively). The frequencies of alleles DQB1*0302, *0303, and *06, which shared a specific amino acid sequence from position 71 to 77, were also increased (P = 0.01). The findings suggested that the autoimmune response in the 3 clinically different variants of pemphigoid involves recognition by T cells of a class II region of DQB1, bound to a peptide from the basement membrane of skin, conjunctiva, or oral mucosa.

HLA-DRB1 allele mismatching between the donor and recipient is associated with an increased risk of acute graft-versus-host disease (GVHD; see 614395) after unrelated marrow transplantation (Petersdorf et al., 1995). Petersdorf et al. (1996) examined also the clinical importance of the HLA-DQ locus in unrelated transplantation. The HLA-DQ locus maps 110 kb centromeric to the HLA-DR locus and is composed of a polymorphic HLA-DQB1 gene encoding at least 22 alleles and an HLA-DQA1 gene encoding at least 12 alleles. Linkage disequilibrium of DQA1, DQB1, and DRB1 alleles in defined populations produced predictable extended haplotypes. For Caucasian populations, most HLA-A (142800), -B (142830), and -DRB1 matched donor-recipient transplant pairs are also HLA-DQB1 and HLA-DQA1 allele matched, and thus the analysis of transplant cases with isolated HLA-DQB1 allele disparity was not possible until a large clinical experience had accumulated. With broadened racial diversity among volunteer donor registers worldwide, unusual HLA-DR/DQ associations were likely to become frequent among HLA-A, -B, and -DRB1 matched pairs. By retrospective analysis of 449 serologically matched transplants, Petersdorf et al. (1996) demonstrated that the relative risk of acute GVHD associated with a single locus HLA-DQB1 mismatch was 1.8, and the risk associated with any HLA-DQB1 and/or HLA-DRB1 mismatch was 1.6. These results provided evidence that HLA-DQ is a transplant antigen and suggested that evaluation of both HLA-DQB1 and HLA-DRB1 is necessary in selecting potential donors.

Premature ovarian failure (POF; 311360) has an autoimmune pathogenesis in a significant proportion of cases. Arif et al. (1999) found that HLA-DQB1 genotypes encoding aspartate-57 are associated with 3-beta-hydroxysteroid dehydrogenase (see 109715) autoimmunity in POF. Two HLA-DQB1 alleles showed positive association with 3-beta-HSD autoantibodies: *0301 and *0603, which share an asp codon at position 57. Eighteen of 21 (86%) POF patients with 3-beta-HSD autoantibodies had DQ-beta-asp57-encoding genotypes compared with 92 of 134 control subjects, and 9 of 21 (43%) cases were homozygous for codon 57 genotypes compared with 17 of 134 (13%) control subjects. These probability values were not significant after correction for multiple testing. The authors concluded that their demonstration of an association between POF, 3-beta-HSD autoimmunity, and a distinctive HLA-DQ molecule supported the hypothesis that autoantibodies to 3-beta-HSD may be markers of autoimmune ovarian failure and suggested that presentation of autoantigenic or external peptides to T lymphocytes by HLA-DQ molecules with asp57-beta chains is important in the pathogenesis of this disease.

Thursz et al. (1999) studied the distribution of MHC class II alleles in 85 patients with self-limiting hepatitis C infection versus 170 matched patients with persistent infection. They found that self-limiting and hepatitis C virus infection was associated with HLA-DRB1*1101, with an odds ratio of 2.14, and HLA-DQB1*0301, with an odds ratio of 2.22. Persistent hepatitis C virus infection was associated with HLA-DRB1*0701 (odds ratio 2.04) and HLA-DRB4*0101 (odds ratio 2.38). They confirmed their results with a second-stage study of 52 patients with self-limiting infection versus 152 with persistent infection.

Susceptibility to murine and human insulin-dependent diabetes mellitus correlates strongly with major histocompatibility complex II 1-A or HLA-DQ alleles that lack an aspartic acid at position beta-57. I-Ag7 lacks this aspartate and is the only class II allele expressed by the nonobese diabetic mouse. Corper et al. (2000) determined the crystal structure of the I-Ag7 molecule at 2.6-angstrom resolution as a complex with a high-affinity peptide from the autoantigen glutamic acid decarboxylase (GAD) 65. I-Ag7 has a substantially wider peptide-binding groove around beta-57, which accounts for distinct peptide preferences compared with other MHC class II alleles. Loss of asp-beta-57 leads to an oxyanion hole in I-Ag7 that can be filled by peptide carboxyl residues or, perhaps, through interaction with the T-cell receptor (see 186830).

Jackson et al. (2001) reported a significantly reduced frequency of HLA class II type DQ7 allele in patients with variant CJD (vCJD; see 123400), but not in those with classical CJD. In a sample of 50 British Caucasians with variant CJD compared with 26 patients with sporadic CJD and 197 cadaveric controls, the frequency of the DQ7 allele was far reduced, being present in 12% of variant CJD patients versus 46% of sporadic CJD patients and 35.5% of the cadaveric controls (P = 0.001). Individuals not carrying the DQ7 allele have a 3.3-fold relative risk of contracting variant CJD versus others who do carry the DQ7 allele. The DQ7 allele is also known as DQB1*0301/4/9.

Kotb et al. (2002) reported that the immunogenetics of the host influence the outcome of invasive streptococcal infection (see 607395). They found that specific HLA class II haplotypes conferred strong protection from severe systemic disease, whereas others increased the risk of severe disease. Patients with the DRB1*1501/DQB1*0602 haplotype mounted significantly reduced responses and were less likely to develop severe systemic disease (p less than 0.0001). Kotb et al. (2002) proposed that class II HLA allelic variation contributes to differences in the severity of invasive streptococcal infections through the ability of distinct HLA alleles/haplotypes to regulate cytokine responses triggered by streptococcal superantigens.

In 30 unrelated patients with Kleine-Levin syndrome (148840), a disorder characterized by recurrent episodes of hypersomnia, cognitive and mood disturbances during symptomatic episodes, and variable hyperphagia and hypersexuality, Dauvilliers et al. (2002) found an increased frequency of the HLA-DQB1*0201 allele (28.3% vs 12.5% in controls). One subject and his affected mother were DQB1*0201 homozygous. Viral infections were the most frequent precipitating factor (70%). Dauvilliers et al. (2002) suggested that their findings may be consistent with an autoimmune etiology for the disorder.

In a study of 149 patients fulfilling the American-European Consensus Group criteria for Sjogren syndrome (270150) and 222 controls, Gottenberg et al. (2003) confirmed the association of Sjogren syndrome with HLA alleles DRB1*03 and DQB1*02. They found, however, that the association was restricted to patients with anti-SSA (see 109092 and 600063) and/or anti-SSB (see 109090) antibodies. The absence of a difference in disease severity between patients with anti-SSA and those with anti-SSA and anti-SSB antibodies, together with a high frequency of HLA-DRB1*03 in the latter group, suggested to the authors that HLA alleles predispose to autoantibody secretion but are not associated with clinical outcome.

An underlying complex genetic susceptibility exists in multiple sclerosis (MS; 126200), and an association with the HLA-DRB1*1501-DQB1*0602 haplotype has been repeatedly demonstrated in high-risk (northern European) populations. African populations are characterized by greater haplotypic diversity and distinct patterns of linkage disequilibrium compared with northern Europeans. To better localize the HLA gene responsible for MS susceptibility, Oksenberg et al. (2004) performed case-control and family-based association studies for these 2 loci in a large and well-characterized African American data set. A selective association with HLA-DRB1*15 was revealed, indicating a primary role for the DRB1 locus in MS independent of DQB1*0602. A substantial proportion of the susceptibility chromosomes from African American patients with MS displayed haplotypes consistent with an African origin.

Vyakarnam et al. (2004) examined the effect of HLA class II polymorphisms on human immunodeficiency virus (HIV)-1 disease progression. Kaplan-Meier survival analysis showed a slower rate of CD4 (186940) T-cell decline in patients with the DRB1*15-DQB1*06 haplotype compared with those without the haplotype. In addition, DQB1*06 alleles were overrepresented in patients surviving more than 14 years. The rate of CD4 decline was not associated with expression of the DQB1 asp57 polymorphism.

Goldfeld et al. (1998) demonstrated a significant association between the HLA-DQB1*0503 allele and susceptibility to tuberculosis (607948) in Cambodian patients. This appeared to be the first identified gene associated with the development of clinical tuberculosis.

In a study of 436 Cambodian patients with tuberculosis, Delgado et al. (2006) found that susceptibility to tuberculosis was significantly associated with homozygosity for the asp57 allele of HLA-DQB1. Two immunogenic proteins of Mycobacterium tuberculosis, Esat6 and Cfp10, bound less well to asp57 than to ala57. Presentation of these tuberculosis proteins to T cells resulted in significantly decreased production of IFNG (147570) when the antigen-presenting cells expressed asp57 rather than ala57. Delgado et al. (2006) concluded that HLA-DQB1 has a role in the host immune response to tuberculosis.

Nejentsev et al. (2007) used several large type I diabetes data sets to analyze a combined total of 1,729 polymorphisms, and applied statistical methods--recursive partitioning and regression--to pinpoint disease susceptibility to the MHC class I genes HLA-B (142830) and HLA-A (142800) (risk ratios greater than 1.5; P(combined) = 2.01 x 10(-19) and 2.35 x 10(-13), respectively) in addition to the established associations of the MHC class II genes HLA-DQB1 and HLA-DRB1 (142857). Nejentsev et al. (2007) suggested that other loci with smaller and/or rarer effects might also be involved, but to find these future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, Nejentsev et al. (2007) concluded that MHC class I-mediated events, principally involving HLA-B*39, contribute to the etiology of type I diabetes.

Secondary recurrent miscarriage (SRM) is defined as a minimum of 3 consecutive miscarriages subsequent to the birth of a child. Among SRM patients, a boy prior to a series of miscarriages is significantly more common than a girl and also reduces the chance of a subsequent live birth. Healthy females, pregnant with a boy, generate immune responses against male-specific minor histocompatibility (HY) antigens. Nielsen et al. (2009) genotyped HLA-A, -B, -DRB1, DRB3, -DRB4, -DRB5, and DQB1 in 358 SRM patients and in 203 of their children born prior to the miscarriages. The subsequent chance of live birth in women with boys prior to the miscarriages compared to women with girls was lower in women with with either the HLA-DRB1*15 or HLA-DQB1*0501/0502 allele (OR = 0.17, p = 0.0001). One HY-restricting HLA class II allele in women with first-born boys significantly reduced the chance of a live birth (OR = 0.46, p = 0.02). Two HY-restricting HLA class II alleles further reduced this chance (OR = 0.21, p = 0.02). HY-restricting HLA class II did not reduce the chance of a live birth in SRM women with first-born girls. Nielsen et al. (2009) proposed an aberrant maternal immune reaction against fetal HY-antigens in SRM.

Chikungunya virus (CHIKV) is a mosquito-borne pathogen that causes a disease syndrome characterized by fever, headache, rash, nausea, vomiting, myalgia, arthralgia, and, in its most severe form, induction of fatal hemorrhagic disease. CHIKV is geographically distributed from Africa to South America and Southeast Asia. In 101 patients from the Andaman Islands with clinical features suggestive of CHIKV infection and 104 healthy controls, Chaaithanya et al. (2013) performed HLA class II typing focusing on the peptide-binding pockets of HLA-DRB1 and HLA-DQB1. The authors found significantly lower frequencies of the HLA-DQB1*03:03 allele and of glu86 in peptide-binding pocket-1 of HLA-DQB1 in CHIKV patients compared with controls. The frequencies of HLA-DRB1 alleles were not significantly different between CHIKV patients and controls. Computational binding analyses suggested HLA-DQB1 molecules bind more CHIKV peptides than do HLA-DRB1 molecules. Chaaithanya et al. (2013) proposed that HLA-DQB1 alleles may have a role in influencing infection and pathogenesis of CHIKV.

For discussion of a possible association between variation in the HLA-DQB1 gene and primary biliary cirrhosis, see PBC2 (613007).

For a discussion of a possible association between the HLA-DQB1*0202 allele and susceptibility to podoconiosis, see 614590.

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9. Gottenberg, J.-E., Busson, M., Loiseau, P., Cohen-Solal, J., Lepage, V., Charron, D., Sibilia, J., Mariette, X.In primary Sjogren's syndrome, HLA class II is associated exclusively with autoantibody production and spreading of the autoimmune response. Arthritis Rheum. 48: 2240-2245, 2003. [PubMed: 12905478] [Full Text: https://doi.org/10.1002/art.11103\]
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Contributors:

Paul J. Converse - updated : 3/19/2015
Paul J. Converse - updated : 4/12/2012
George E. Tiller - updated : 10/15/2009
Marla J. F. O'Neill - updated : 9/9/2009
Marla J. F. O'Neill - updated : 7/10/2009
Ada Hamosh - updated : 4/24/2008
Paul J. Converse - updated : 8/2/2006
Paul J. Converse - updated : 1/28/2005
Victor A. McKusick - updated : 5/17/2004
Marla J. F. O'Neill - updated : 4/27/2004
Victor A. McKusick - updated : 1/8/2004
Cassandra L. Kniffin - updated : 1/22/2003
Victor A. McKusick - updated : 11/26/2002
Ada Hamosh - updated : 11/15/2001
Ada Hamosh - updated : 4/20/2000
Paul J. Converse - updated : 4/3/2000
Ada Hamosh - updated : 2/15/2000
John A. Phillips, III - updated : 12/8/1999

Creation Date:

Ada Hamosh : 11/18/1999

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