An increased risk of Crohn's disease in individuals who inherit the HLA class II DRB3*0301 allele.

The role of inflammatory T cells in Crohn's disease suggests that inherited variations in major histocompatibility complex (MHC) class II genes may be of pathogenetic importance in inflammatory bowel disease. The absence of consistent and strong associations with MHC class II genes in Caucasian patients with inflammatory bowel disease probably reflects the use of less precise typing approaches and the failure to type certain loci by any means. A PCR-sequence-specific oligonucleotide-based approach was used to type individual alleles of the HLA class II DRB1, DRB3, DRB4, and DRB5 loci in 40 patients with ulcerative colitis, 42 Crohn's disease patients, and 93 ethnically matched healthy controls. Detailed molecular typing of the above alleles has previously not been reported in patients with inflammatory bowel disease. A highly significant positive association with the HLA-DRB3*0301 allele was observed in patients with Crohn's disease (P = 0.0004) but not in patients with ulcerative colitis. The relative risk for this association was 7.04. Other less significant HLA class II associations were also noted in patients with Crohn's disease. One of these associations involved the HLA-DRB1*1302 allele, which is known to be in linkage disequilibrium with HLA-DRB3*0301. These data suggest that a single allele of an infrequently typed HLA class II locus is strongly associated with Crohn's disease and that MHC class II molecules may be important in its pathogenesis.     

HLA DPB1*0201 gene confers disease susceptibility in japanese with childhood onset type I diabetes, independent of HLA-DR and DQ genotypes

HLA is an important etiologic genetic factor in Type I diabetes and specific HLA-class II genes are closely related to the onset of the disease. Many differences in the patterns of susceptible and resistant DRB1, DQA1, and DQB1 genes have been observed among various ethnic groups. We have previously shown that DRB1*0405, DRB1*0901 and DQA1*0301-DQB1*0302 were the major susceptible alleles or haplotype to Type I diabetes while DR-DQ haplotype studies suggested the important role of DR and DQ alleles in susceptibility and resistance in Japanese patients. Based on the analysis of 90 Japanese patients with childhood onset Type I diabetes and 136 unrelated healthy Japanese controls by polymerase chain reaction-restriction fragment polymorphism method (PCR-RFLP), we report here the association of Type I diabetes with DPB1*0201 (relative risk = 2.29; Pc = 0.027) in this population. Comparison of linkage disequilibrium patterns between patients and controls showed that the significantly high prevalence of DPB1*0201 among patients cannot be attributed simply to linkage disequilibrium with susceptible DRB1 alleles and DQA1-DQB1 haplotypes. Our results suggest that in addition to alleles at the DRB1, DQA1, DQB1 loci, polymorphism at DPB1 locus also influences the risk of Type I diabetes.     

HLA Class II Polymorphism in Egyptian Children with Lymphomas

The major histocompatibility complex (MHC) is a set of closely-linked genes encoded on the short arm of chromosome 6. It is important for understanding human immunological diseases, transplantation and in host defense against infection. The membrane proteins are two types; class I MHC proteins and class II MHC proteins. Strong arguments supporting genetic linkage between susceptibility to lymphomas and human leukocyte antigens (HLA)-class II are reported and give a clue about susceptibility or protection from the disease.

Aim: To evaluate the possible changes of HLA class II (DR, DQ) alleles in children with lymphoma.

Methods: Thirty cases were included in this limited study. Nineteen cases of non Hodgkin's lymphoma (NHL) and eleven patients with Hodgkin's lymphoma (HD). Their ages ranged from 1.5 to 15 years. The control group consisted of 121 unrelated healthy subjects for DRB1 alleles and 59 unrelated healthy subjects for DQB1 alleles (only 59 subjects were typed for both DRB1 and DQB1). All cases in the study were assessed by thorough history taking, physical examination and laboratory investigations that included complete blood count, renal function tests, liver function tests, serum uric acid and HLA typing. Patients and controls were typed for HLA class II DRB1 and DQB1 alleles using INNO-LIPA reverse hybridization line probe assay (Innogenetic, Belgium).

Results: HLA-DRB1 *0403 and *1301 and HLA-DQB1 *0501,* 0201 and *0301 were significantly increased in patients with NHL when compared with control; whereas HLA-DRB1 *1302 and HLA-DQB1 *0502 and *0602 were significantly decreased when compared with control. In patients with HD, HLA-DRB1 *0403 and *1202 and HLA-DQB1 *0604, *0201 and *0203 were significantly increased when compared with control.

Conclusions: (1) The susceptibility to NHL is related to HLA-DRB1 *0403 and *1301 and HLA-DQB1 *0501,* 0201 and *0301. (2) The susceptibility to HD is related to HLA-DRB1 *0403 and *1202 and HLA-DQB1 *0604, *0201 and *0203. (3) HLA-DRB1 *1302 and HLA-DQB1 *0502 and *0602 may confer protection to NHL. (4) Different HLA alleles may have a role in patients with both groups of lymphoma and further study is needed to better define the possible prognostic value of different HLA associations in patients with lymphomas regarding increased risk in the presence of certain HLA alleles and the possibility for treatment modifications in the future based on the presence or absence of certain HLA alleles.     

Association of human leukocyte antigen class II genes with autoantibody profiles, but not with disease susceptibility in Japanese patients with systemic sclerosis.

OBJECT: To examine the role of human leukocyte antigen (HLA) class II genes in the development of systemic sclerosis (SSc) as well as in the clinical and serologic expression of SSc in patients. METHODS: HLA-DRB1, DRB3, DRB4, DQB1, and DPB1 alleles were determined by genotyping; and serum antinuclear antibodies were identified using indirect immunofluorescence, double immunodiffusion and immunoprecipitation. PATIENTS: One hundred and five Japanese patients with SSc and 104 race-matched healthy controls. RESULTS: Frequencies of DRB1 and DQB1 alleles were not different between SSc patients and healthy controls, while DPB1*0901 was marginally increased in SSc patients. In contrast, SSc-related autoantibodies were closely associated with the clinical features. HLA class II genes were detected as follows: anti-DNA topoisomerase I antibody with diffuse cutaneous involvement, pulmonary fibrosis, and DRB1*1502-DQB1*0601-DPB1*0901; anti-U1RNP antibody with overlapping features of lupus and/or myositis and DRB1*0401/*0802-DQB1*0302; and anticentromere antibody with limited cutaneous involvement and DRB1*0101-DQB1*0501-DPB1*0402. In the analysis of the association of HLA class II and the clinical features in SSc patients significant differences were obtained only for the increased frequencies of arthritis and rheumatoid factor in patients with DRB1*0405 compared to those without. CONCLUSION: HLA class II genes strongly influence the production of SSc-related autoantibodies rather than the development of SSc. In addition, SSc is a composite disease of distinctive subsets defined by serum autoantibodies, which have specific clinical and HLA class II associations.     

Association of antiphosphatidylserine/prothrombin autoantibodies with HLA class II genes

OBJECTIVE: To investigate the associations between HLA class II genes and antiphosphatidylserine/prothrombin antibodies (aPS/PT) in a group of British caucasoid patients with antiphospholipid antibodies (aPL). METHODS: This study included 82 patients with aPL. IgG aPS/PT were detected in sera using enzyme-linked immunosorbent assays. HLA-DQB1, DQA1, and DRB1 genotypes were determined by polymerase chain reaction using sequence-specific primers. All results were compared with 177 matched healthy control subjects. RESULTS: IgG aPS/PT were present in 41 of 82 patients (50%). The frequencies of DQB1*0301/4, DQB1*0604/5/6/7/9, and DRB1*1302 alleles were increased in patients with aPS/PT compared with controls. To minimize the interference of the association between anti-beta2-glycoprotein I (anti-beta2GPI) and HLA, patients with anti-beta2GPI were excluded from further analyses, and only HLA-DQB1*0301/4 remained significant compared with controls (odds ratio [OR] 2.75, 95% confidence interval [95% CI] 1.2-6.5, P < 0.03). In the haplotype analysis, HLA-DQB1*0301/4;DQA1* 0301/2;DRB1*04 was significantly increased in patients with IgG aPS/PT compared with controls (OR 4.75, 95% CI 1.72-13.10, P = 0.0063). CONCLUSION: The HLA-DQB1*0301/4;DQA1*0301/ 2;DRB1*04 haplotype and its components may influence the production of aPS/PT in the antiphospholipid syndrome, which partly explains the correlation between the lupus anticoagulant and DQB1*03.     

HLA class II genotypes associated with chronic hepatitis C virus infection and response to alpha-interferon treatment in Poland

AIMS/BACKGROUND: Recent evidence suggests that spontaneous clearance of hepatitis C virus (HCV) may be associated with the HLA DQB1*0301 allele but there is still some debate over the role of other alleles and HLA haplotypes in HCV infection. As this may best be resolved by studying genetically different populations, we have investigated HLA class II-encoded susceptibility and resistance to HCV infection in a relatively sedentary population of patients from northwestern Poland. METHODS: The distributions of HLA class II DRB1, DQA1, DQB1 and DPB1 alleles were determined by standard PCR-protocol in 129 unrelated patients with chronic hepatitis C (anti-HCV and HCV-RNA positive) and 103 healthy unrelated racially-matched control subjects. Fifty-five patients were treated with alpha-interferon (5 MIU thrice weekly for 6 months) out of whom 29 showed a complete response and 26 were non-responders. RESULTS: A significantly reduced frequency of the DQB1*0301 allele in the patients was observed (24.0% vs. 38.8%; p=0.015). Additionally, two different DR-DQ haplotypes were found to be associated with chronic HCV infection: DRB1*1501-DQA1*01-DQB1*0602 (24.0% vs. 12.6%; p= 0.027) and DRB1*0701-DQA1*0201-DQB1*02 (31.8 vs. 12.6%; p=0.0006), the latter difference being most pronounced in those patients who responded to alpha-interferon treatment (41.4% vs. 12.6%; p=0.00048). CONCLUSIONS: The results confirm the negative association between chronic HCV and DQB1*0301 and identify two novel genetic associations. In particular, the DRB1*0701-DQA1*0201-DQB1*02 haplotype is associated with both chronic infection and response to alpha-interferon. Interestingly, the same haplotype is reportedly associated with non-response to hepatitis B vaccination.     

HLA class II polymorphism in Egyptian children with lymphomas

The major histocompatibility complex (MHC) is a set of closely-linked genes encoded on the short arm of chromosome 6. It is important for understanding human immunological diseases, transplantation and in host defense against infection. The membrane proteins are two types; class I MHC proteins and class II MHC proteins. Strong arguments supporting genetic linkage between susceptibility to lymphomas and human leukocyte antigens (HLA)-class II are reported and give a clue about susceptibility or protection from the disease. AIM: To evaluate the possible changes of HLA class II (DR, DQ) alleles in children with lymphoma. METHODS: Thirty cases were included in this limited study. Nineteen cases of non Hodgkin's lymphoma (NHL) and eleven patients with Hodgkin's lymphoma (HD). Their ages ranged from 1.5 to 15 years. The control group consisted of 121 unrelated healthy subjects for DRB1 alleles and 59 unrelated healthy subjects for DQB1 alleles (only 59 subjects were typed for both DRB1 and DQB1). All cases in the study were assessed by thorough history taking, physical examination and laboratory investigations that included complete blood count, renal function tests, liver function tests, serum uric acid and HLA typing. Patients and controls were typed for HLA class II DRB1 and DQB1 alleles using INNO-LIPA reverse hybridization line probe assay (Innogenetic, Belgium). RESULTS: HLA-DRB1 *0403 and *1301 and HLA-DQB1 *0501,* 0201 and *0301 were significantly increased in patients with NHL when compared with control; whereas HLA-DRB1 *1302 and HLA-DQB1 *0502 and *0602 were significantly decreased when compared with control. In patients with HD, HLA-DRB1 *0403 and *1202 and HLA-DQB1 *0604, *0201 and *0203 were significantly increased when compared with control. CONCLUSIONS: (1) The susceptibility to NHL is related to HLA-DRB1 *0403 and *1301 and HLA-DQB1 *0501,* 0201 and *0301. (2) The susceptibility to HD is related to HLA-DRB1 *0403 and *1202 and HLA-DQB1 *0604, *0201 and *0203. (3) HLA-DRB1 *1302 and HLA-DQB1 *0502 and *0602 may confer protection to NHL. (4) Different HLA alleles may have a role in patients with both groups of lymphoma and further study is needed to better define the possible prognostic value of different HLA associations in patients with lymphomas regarding increased risk in the presence of certain HLA alleles and the possibility for treatment modifications in the future based on the presence or absence of certain HLA alleles.     

HLA-DQB1 DPB1 alleles in Japanese patients with adult-onset Still’s disease

Abstract

Objective: HLA class II alleles are major determinants of genetic predisposition to rheumatic diseases. Predisposing effects of HLA had been suggested in AOSD, however, ethnic differences may account for variations in AOSD association with HLA. We determined the contribution of HLA-DQB1, DPB1 alleles to susceptibility to Adult-onset Still’s disease (AOSD) in the Japanese population.

Methods: HLA-DQB1 and DPB1 alleles were analyzed in 87 Japanese patients with AOSD and 413 Japanese healthy subjects.

Results: We found significant association between HLA-DQB1*06:02 (Pc?=?0.010, odds ratio: 2.54) and AOSD, whereas there was no association between the DQB1*06:02 allele and disease phenotypes of AOSD. Moreover, we did not find a predisposing effect of the HLA-DPB1 allele to AOSD. Haplotype analysis showed that presence of DRB1*15:01–DQB1*06:02 was associated with Japanese patients with AOSD. However, conditional logistic regression tests were unable to demonstrate independent association between DRB1*1501 or DQB1*0602 and AOSD.

Conclusions: Our results show significant association between AOSD and the HLA DQB1*06:02 allele, and between the DRB1*1501–DQB1*06:02 haplotype and AOSD susceptibility. These findings suggest that genetic susceptibility to AOSD depends on the genotype combinations of HLA DRB1 and DQB1 alleles.     

Human leukocyte antigen class II alleles and rubella-specific humoral and cell-mediated immunity following measles-mumps-rubella-II vaccination

We examined associations between human leukocyte antigen (HLA) class II genes and both rubella-specific immunoglobulin G antibodies and lymphoproliferative responses after measles-mumps-rubella-II (MMR-II) vaccination, in a population-based sample of 346 schoolchildren. The DPB1*0301, DPB1*0401, DPB1*1301, and DPB1*1501 alleles were significantly associated with rubella vaccine-induced antibodies. Alleles suggestive of being positively associated with rubella-specific lymphoproliferative stimulation indices were DPB1*0301, DQB1*0501, DRB1*0101, and DRB1*1104. Conversely, the DPB1*0401, DPB1*1001, DPB1*1101, DQB1*0202, and DRB1*0701 alleles were negatively associated with rubella-specific lymphoproliferation. This study of HLA class II-restricted humoral and cellular immune responses to rubella provides significant insight into mechanisms of vaccine response and new vaccine development.     

HLA DRB1/DQA1/DQB1 haplotype determines thyroid autoimmunity in patients with insulin-dependent diabetes mellitus

OBJECTIVE  Thyroid autoimmunity is frequently associated with insulin-dependent diabetes mellitus (IDDM). The genetic factors which contribute to thyroid autoimmunity and IDDM have been described but vary between different races. We have therefore investigated the effect of class II HLA genes at both loci and the HLA haplotypes on the presence of autoimmunity in patients with IDDM in Taiwan.
SUBJECTS AND MEASUREMENTS  Eighty-three patients with IDDM and 105 unrelated normal controls were recruited for the measurement of thyroid autoantibodies and for genotyping of HLA DRB1, DQA1 and DQB1 by polymerase chain reaction-based DNA typing techniques.
RESULTS  Among 83 patients with IDDM, 23 (27.7%) were positive for antithyroid autoantibodies. Compared to those without thyroid autoimmunity, there was a female preponderance for IDDM with thyroid autoimmunity (female: male, 3:20 vs 29:31). Among the DR specificities, DR6 was associated with a weak protective effect against thyroid autoimmunity in IDDM patients. Upon detailed analysis of class II HLA haplotypes, the DRB1*0301/DQA1*0501/DQB1*0201 haplotype was found to be associated with an increased risk of IDDM regardless of thyroid autoimmunity, while DRB1*0405/DQA1*0301/DQB1*0401 was significantly increased only in the IDDM patients with thyroid autoimmunity. IDDM individuals with the HLA DRB1*0405/DQA1*0301/DQB1*0302 haplotype were not at risk of thyroid autoimmunity.
CONCLUSIONS  Our data indicated that there was a generalized genetic factor within or associated with the DRB1*0301/DQA1*0501/DQB1*0201 haplotype, and a more restricted effect with the DRB1*0405/DQA1*0301/DQB1*0401 haplotype which led to thyroid autoimmunity in patients with insulin-dependent diabetes mellitus.     

Contribution of major histocompatibility complex genes to susceptibility and resistance in Helicobacter pylori related diseases.

BACKGROUND/AIM: Although there have been numerous reports concerning the virulence factors of isolates for investigating the pathogenesis of Helicobacter pylori infection, few studies have been carried out regarding the association of HLA class II genes of the host with H. pylori related diseases. Two published studies have only analysed the HLA DQ locus alone. The aim of this study was thus to determine the association of HLA class II genes (DR, DQ and DP) with H. pylori related diseases using the DNA typing method. METHODS: Fifty-eight patients with H. pylori positive gastric ulcers, 44 patients with H. pylori positive duodenal ulcers, 45 patients with H. pylori positive gastritis and 34 healthy subjects without H. pylori infection were typed for HLA class II genes by means of DNA typing with the polymerase chain reaction-sequence specific oligonucleotide probes method. RESULTS: A negative association with DRB1*1501, DQA1*01021 and DQB1*0602 alleles was noted in all three of the patient groups studied. Compared with the healthy controls, a positive association with DPA1*0201 (P= 0.032) and DPB1*0901 (P=0.005) in gastric ulcers, a positive association with DRB1*0405 (P=0.022) and DQB1*0401 (P=0.044) in duodenal ulcers, and a positive association with DPB1*0901 (P=0.016) in gastritis were observed. A haplotype analysis showed that the association of alleles with H. pylori related disease was with the haplotype rather than with either of the alleles individually. After correction for multiple comparisons, all the significant associations obtained between H. pylori related diseases and HLA class II genes disappeared. CONCLUSIONS: The interplay between host immunogenetic factors, bacterial virulence factors and environmental conditions may thus play a more important role in the outcome of H. pylori infection than immunogenetic factors alone.     

Histocompatibility leucocyte antigens and closely linked immunomodulatory genes in autoimmune thyroid disease

OBJECTIVES: Associations between autoimmune thyroid disease and antigens of the major histocompatibility complex (MHC) have long been recognized. Graves' disease (GD) is associated with the histocompatibility leucocyte antigen (HLA) haplotype A*01-B*0801-DRB1*0301-DQA1*0501-DQB1*0201 (or B8/DR3) whereas autoimmune hypothyroidism (AIH) has been weakly associated with HLA DRB1*03, *04 and *11/*12 alleles (or DR3, DR4 and DR5). However, the presence of important immunoregulatory genes within the HLA Class II and III regions raises the possibility that these genes harbour the primary susceptibility locus. This study examines genetic variation across the MHC in UK Caucasoid subjects with autoimmune thyroid disease. PATIENTS AND METHODS: DNA extracted from venous blood samples from 215 patients with autoimmune thyroid disease (GD 135, AIH 77) and 267 control subjects was analysed. Genotyping was performed using polymerase chain reaction and sequence specific primers for HLA Class I and II alleles and polymorphisms within the TAP1, TAP2, tumour necrosis factor (TNF), lymphotoxin alpha (LTalpha), heat shock protein (HSP)70-1, HSP70-2 and HSP70-Hom genes. RESULTS: For GD, the strongest association was with DRB1*03 [56% patients positive vs. 24% controls, P = 2 x 10(-10), odds ratio (OR) 4.0]. Positive associations were also seen for DRB1*03 linked alleles, B*0801, DRB3*01/02, DQA1*05, DQB1*02 and DPB1*0101 (OR 2.3-3.4). Specific TNF and LTalpha alleles were strongly associated with GD (Pc = 3 x 10(-5) and 0.001) and weak associations were seen for HSP70-1 + 190C and HSP70-2 + 1267G polymorphisms (Pc = 0.05 and 0.01). These associations were not significant when DRB1*03 status was considered. Patients with AIH showed only a weak association with DQB1*03 (P = 0.02). CONCLUSIONS: These results show that, of the polymorphisms tested within the MHC, GD is most strongly associated with DRB1*03, and associations with other immunoregulatory genes previously described in Caucasian subjects most likely reflect linkage disequilibrium. AIH differs from GD, being less influenced by the MHC region.     

Influence of human leukocyte antigen class II alleles on susceptibility to Entamoeba histolytica infection in Bangladeshi children

BACKGROUND: The association of antibody responses with both innate and acquired immunity to amebiasis indicate that CD4+ T cells play a role in protection against Entamoeba histolytica infection. To test this hypothesis, we compared the genotype frequencies of human leukocyte antigen (HLA) class II alleles in a cohort of Bangladeshi children intensively monitored for E. histolytica infection for a 3-year period. METHODS: Using logistic regression, we calculated the odds of disease by genotype and by haplotype. RESULTS: The DQB1*0601 heterozygous and homozygous genotypes were found in 55% of E. histolytica-negative children but in only 34% of E. histolytica-positive children (overall odds ratio, 2.39; 95% confidence interval [CI], 1.26-4.54). Children who were heterozygous for the DQB1*0601/DRB1*1501 haplotype were 10.1 times (95% CI, 2.02-50.6) more likely to be both E. histolytica negative and serum anti-lectin immunoglobulin G negative at baseline. Other DQB1 and DRB1 alleles (DQB1*0202, DQB1*0301, and DRB1*0701) were not associated with any of the clinical outcomes related to amebiasis. CONCLUSION: A potential protective association was observed with the HLA class II allele DQB1*0601 and the heterozygous haplotype DQB1*0601/DRB1*1501. This association may explain why amebiasis does not occur in some children who are exposed to the parasite and implicates HLA class II-restricted immune responses in protection against E. histolytica infection.     

Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis

BACKGROUND & AIMS: In a recent study, we suggested that susceptibility to type 1 autoimmune hepatitis is associated with a six-amino acid motif, LLEQKR, within the DR beta polypeptide, but these data are in conflict with contemporary reports from Japan and Argentina. The purpose of the present study was to reexamine this question in a large independent cohort of patients. METHODS: Eighty-six North American white patients and 102 control subjects were studied. HLA class I antigens were determined serologically, and the DRB1, DQA1, DQB1, and DPB1 genes and the DRB3/4/5 subtypes were determined by high-resolution genotyping. RESULTS: The greatest risk was associated with DRB1*0301 (corrected probability [Pc] = 0.00003; relative risk [RR] = 4.58), and a secondary association with DRB1*0401 was identified (Pc = 0.000132; RR = 5.97). Protection from disease was associated with the DRB5*0101- DRB1*1501 haplotype (Pc = 0.021; RR = 0.3). However, further analysis indicated that a lysine residue at position 71 of the DR beta polypeptide may be the most important determinant of disease susceptibility (P = 0.0000003; RR = 8.6, increasing to RR = 16.38 with four lysine residues). CONCLUSIONS: DRB1*0301 and DRB1*0401 are confirmed as the principal susceptibility alleles for type 1 autoimmune hepatitis, and these data support the hypothesis that a lysine residue at position 71 of the DR beta-polypeptide chain may be the major risk factor. (Gastroenterology 1997 Jun;112(6):2028-35)     

Autoantibodies to fibrillarin in systemic sclerosis (scleroderma). An immunogenetic,serologic, and clinical analysis

Objective. To determine the frequency, clinical associations, and any major histocompatibility complex correlations of antifibrillarin antibodies in patients with systemic sclerosis (SSc). Methods. Antifibrillarin antibodies were determined by indirect immunofluorescence, immunoblotting, and immunoprecipitation, and HLA class II alleles by DNA oligotyping, in a large cohort of SSc patients. Results. Antifibrillarin was found in 8% of 335 SSc sera and was significantly more common in blacks (16%) than whites (5%), in males (33%) than females (14%), and in patients with cardiac, renal, or gut involvement. The HLA class II haplotype DRB1*1302, DQB1*0604 was found significantly more frequently in SSc patients with antifibrillarin compared with racematched normal controls and 260 SSc patients without antifibrillarin. In addition, 1 or more of the HLA–DQB1 alleles *0604, *0301, *0602, and/or *0302 was found in all antifibrillarin-positive patients, and 62% of the antifibrillarin-positive patients had 2 of these HLA–DQB1 alleles, a highly significant difference from both race-matched normal controls and antifibrillarin-negative SSc patients. Conclusion. Antifibrillarin, although an infrequent nucleolar autoantibody, is a marker for severe SSc, especially in blacks and males, and is strongly associated with a unique HLA haplotype, as well as with combinations of certain HLA–DQB1 alleles.     

Racial differences in HLA class II associations with hepatitis C virus outcomes

A broad, vigorous CD4 T cell response, mediated by class II human leukocyte antigens (HLAs), favors hepatitis C virus (HCV) clearance. HLA-DQB1*0301 has been associated with viral clearance in an ethnically homogeneous cohort. To validate this association and to identify other class II associations in an ethnically varied cohort, molecular class II HLA typing was performed on 200 HCV clearance and 374 matched persistently infected subjects. HLA-DQB1*0301 was weakly associated with viral clearance in combined ethnic groups (odds ratio [OR], 0.72; 95% confidence interval [CI], 0.53-0.97) but was stronger in black subjects. In white subjects, viral clearance was associated with DRB1*0101 (OR, 0.32; 95% CI, 0.17-0.60) and its DQB1*0501 haplotype, whereas viral persistence was associated with DRB1*0301 (OR, 2.36; 95% CI, 1.23-4.52) and its DQB1*0201 haplotype. These results support a role for class II alleles in the immune response to HCV and underscore the importance of studying genetic associations in an ethnically diverse cohort.     

Genetic susceptibility to breast cancer: HLA DQB*03032 and HLA DRB1*11 may represent protective alleles

Tumors are believed to emerge only when immune surveillance fails. We wished to ascertain whether the failure to inherit putative protective alleles of HLA class II genes is linked to the development of breast cancer. We molecularly typed HLA DPB1, DQB1, DRB1, and DRB3 alleles in 176 Caucasian women diagnosed with early-onset breast cancer and in 215 ethnically matched controls. HLA DQB*03032 was identified in 7% of controls but in no patients with early-onset breast cancer (P = 0.0001). HLA DRB1*11 alleles were also significantly overrepresented (P < 0.0001) in controls (16. 3%) as compared with patients with early-onset breast cancer (3.5%). HLA DQB*03032 and HLA DRB1*11 alleles may have a protective role in human breast cancer.     

The association between the genetic polymorphism of HLA-DQA1, DQB1, and DRB1 and serum alanine aminotransferase levels in chronic hepatitis C in the Chinese population

Background and Aim:  To investigate a possible association between HLA genes with serum alanine aminotransferase (ALT) levels and evaluate whether the HLA-DQA1, DQB1, and DRB1 genes could influence the development of liver damage in chronic hepatitis C.
Methods:  A total of 145 patients with chronic hepatitis C virus (HCV) infection (36 patients with persistently normal ALT values; 109 patients with elevated ALT levels) and 160 uninfected healthy controls were examined for HLA-DQA1, DQB1, and DRB1 molecules by using polymerase chain reaction–sequencing based typing (PCR-SBT).
Results:  Among the patients chronically infected with HCV, the frequencies of DQA1*0501, DQB1*0301, and DRB1*0401 alleles were significantly increased in the normal ALT group compared with those with abnormal ALT levels, whereas that of DQB1*0201 was significantly lower. As compared to uninfected healthy controls, DQA1*0501, DQB1*0301, and DRB1*0401 allele frequencies were also statistically higher in the normal ALT group, whereas that of DQB1*0201 was the inverse. The haplotype frequencies of DQA1*0301-DQB1*0301, DQA1*0501-DQB1*0301, and DRB1*1101-DQB1*0301 were found to be significantly higher in the normal ALT group. Multivariate logistic regression indicated that female sex, and the DQB1*0301 allele and DRB1*0401 allele were independently associated with normal ALT values, whereas DQB1*0201 allele was the inverse.
Conclusions:  These results suggest that particular HLA alleles may have an influence on the serum ALT level of chronic HCV infection as a host genetic factor in the Chinese population. The DQA1*0501, DQB1*0301, and DRB1*0401 alleles, and the DQA1*0301-DQB1*0301, DQA1*0501-DQB1*0301, and DRB1*1101-DQB1*0301 haplotypes seem to be associated with low hepatitis activity; whereas DQB1*0201 allele is closely correlated with the progression of liver injury in chronic HCV infection.     

HLA-DR and -DQ phenotypes in inflammatory bowel disease: a meta-analysis.

BACKGROUND: Susceptibility to inflammatory bowel disease (IBD) is partially genetically determined and the HLA class II genes are candidates for a role in genetic susceptibility to IBD, because their products play a central role in the immune response. Multiple studies have reported associations between HLA-DR or -DQ phenotypes and either ulcerative colitis or Crohn's disease, but much of the data are still controversial. AIMS: To estimate overall associations between HLA class II phenotypes and IBD, and to establish the relative risk conferred by HLA-DR and -DQ phenotypes by meta-analysis. METHODS: Medline was searched for publications reporting on the relation between IBD and HLA class II phenotypes. Raw data were extracted by recalculating the number of phenotypes or the number of alleles of the main antigens. Odds ratios and confidence intervals were calculated according to the Mantel-Haenszel method. RESULTS: DR2, DR9, and DRB1*0103 were positively associated with ulcerative colitis, and a negative association was found for DR4 and ulcerative colitis. For Crohn's disease a positive association was found with DR7, DRB3*0301, and DQ4 and a negative association with DR2 and DR3. CONCLUSIONS: Both ulcerative colitis and Crohn's disease are associated with specific HLA class II phenotypes. Further analysis of these phenotypes and subgroup analysis may elucidate how these alleles contribute to susceptibility to IBD.     

HLA class II genotypes associated with chronic hepatitis C virus infection and response to α‐interferon treatment in Poland

Abstract: Aims/Background: Recent evidence suggests that spontaneous clearance of hepatitis C virus (HCV) may be associated with the HLA DQB1*0301 allele but there is still some debate over the role of other alleles and HLA haplotypes in HCV infection. As this may best be resolved by studying genetically different populations, we have investigated HLA class II‐encoded susceptibility and resistance to HCV infection in a relatively sedentary population of patients from northwestern Poland. Methods: The distributions of HLA class II DRB1, DQA1, DQB1 and DPB1 alleles were determined by standard PCR‐protocol in 129 unrelated patients with chronic hepatitis C (anti‐HCV and HCV‐RNA positive) and 103 healthy unrelated racially‐matched control subjects. Fifty‐five patients were treated with α‐interferon (5 MIU thrice weekly for 6 months) out of whom 29 showed a complete response and 26 were non‐responders. Results: A significantly reduced frequency of the DQB1*0301 allele in the patients was observed (24.0% vs. 38.8%; p=0.015). Additionally, two different DR‐DQ haplotypes were found to be associated with chronic HCV infection: DRB1*1501‐DQA1*01‐DQB1*0602 (24.0% vs. 12.6%; p=0.027) and DRB1*0701‐DQA1*0201‐DQB1*02 (31.8 vs. 12.6%; p=0.0006), the latter difference being most pronounced in those patients who responded to α‐interferon treatment (41.4% vs. 12.6%; p=0.00048). Conclusions: The results confirm the negative association between chronic HCV and DQB1*0301 and identify two novel genetic associations. In particular, the DRB1*0701‐DQA1*0201‐DQB1*02 haplotype is associated with both chronic infection and response to α‐interferon. Interestingly, the same haplotype is reportedly associated with non‐response to hepatitis B vaccination.