Genetic contribution of major histocompatibility complex class II region to type 1 autoimmune hepatitis susceptibility in Venezuela.

AIMS: Autoimmune hepatitis (AIH) is a progressive liver disease characterized by the presence of circulating autoantibodies, hypergammaglobulinaemia and a favourable response to immunosuppressive treatment. Although the pathogenesis of type 1 AIH is unknown, disease susceptibility is partially determined by genes linked to the class II region of the major histocompatibility complex. Type 1 AIH has been associated with DRB1*03, DRB1*04 and DRB3 alleles in European and North American Caucasians, with DRB1*0405 in Japanese, with DRB1*0404 in Mexican, and with DRB1*1301 in Argentinean populations. METHODS: To analyse the molecular basis of these associations in Venezuela (mestizo population), we examined the frequency of human leucocyte antigens (HLA)-A -B -C, HLA-DQ and HLA-DR genes by low- and high-resolution oligonucleotide typing in a population of 41 type 1 AIH patients and 111 ethnic- and aged-matched healthy subjects. RESULTS: The frequencies of both DRB1(*)1301 (P<0.0001) and DRB1*0301 (P<0.005) were significantly higher in patients than in controls. In addition, patients showed a strong association with the DRB3 allele (P<0.01). In contrast, the DQB1*04 allele was significantly decreased in the patient group (P<0.01). The frequencies of haplotypes A*01-B*08-DQB1*02-DRB1*03-DRB3, DQB1*05-DRB1*1301, DQB1*06-DRB1*1301 and A*02-DRB1*1301, B*45-DRB3 were significantly increased in type 1 AIH patients compared with the controls (P<0.01). CONCLUSIONS: In conclusion, our data indicate that type 1 AIH predisposition in a Venezuelan mestizo population of different ethnic backgrounds is associated with DRB1*1301 and DRB1*0301 alleles. In addition, our findings suggest that protection against disease might be conferred by the DQB1*04 allele, with distinct ethnic differences from other populations.     

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.     

Human leukocyte antigen allele associations in type-1 autoimmune hepatitis patients from western India

BACKGROUND AND AIMS: The immunogenetic basis of autoimmune diseases has become more and more evident. We have analyzed the human leukocyte antigen (HLA) associations with type-1 autoimmune hepatitis (AIH) among patients from western India. METHODS: In 20 patients and 120 healthy controls, polymerase chain reaction amplified with sequence specific primers and hybridized with oligoprobes was carried out to elucidate the HLA A, B, C and DRB1 allele associations. RESULTS: The study revealed that A*0222 (20% vs 1.66%; P = 0.0001), A*3201 (15% vs 0.83%; P = 0.0004), A*680102 (30% vs 6.66%; P = 0.001), B*35 (40% vs 11.66%; P = 0.001), B*5501 (10% vs 0.83%; P = 0.008), Cw*0102 (15% vs 1.66%; P = 0.002) and Cw*070101 (50% vs 11.66%; P = 2.5E-05) were significantly increased among the A, B and C alleles of AIH patients. Among the HLA DRB1 alleles, DRB1*0301 (20% vs 6.19%; P = 0.03), DRB1*1301 (15% vs 2.65%; P = 0.01), DRB1*14 (30% vs 11.5%; P = 0.02) and DRB1*1501 (40% vs 22.12%; P = 0.08) were increased in AIH patients when compared with the controls. CONCLUSIONS: The present study indicates that the HLA susceptibility to type 1 AIH in the different populations studied is complex.     

上海地区Ⅰ型自身免疫性肝炎与HLA-DRB1等位基因的相关性研究

目的 分析HLA－DRB1等位基因与上海地区I型自身免疫性肝炎（AIH）的相关性，探讨AIH的遗传易感背景。方法 采用序列特异性多聚酶链反应（PCR－SSP），对32例I型AIH患者和48例健康对照者进行HLA－DRB1等位基因及有关基因亚型的分析。结果 HLA－DR4基因频率在I型AIH患者中较健康对照组显著增高[46.9%与20.8%；相对危险度（RR）＝3．35，χ^2=5.99,P=0.014]。其他等位基因在两组间差异无显著性。进一步对HLA－DR4等位基因亚型的分析表明，I型AIH患者组DRB1^*0405的基因频率较健康对照组有增加趋势（21．9％与6．3％，χ^2=4.23,P=0.04，但Pc=0.08)。HLA－DRβ分子的第3等位基因高变区第71位精氨酸残基的频率在I型AHI患者中显著增高（46.9%与18.8%,χ^2=7.14,P=0.008)。结论 上海地区I型AIH的发病与HLA－DR4以及HLA－DRB1第3高变区DR7位精氨酸残基相关。     

Relationship of human leukocyte antigen class Ⅱ genes with the susceptibility to hepatitis B virus infection and the response to interferon in HBV-infected patients

AIM: To study the relationship of human leukocyte antigen (HLA)-DRB1 and -DQB1 alleles with the genetic susceptibility to HBV infection and the response to interferon (IFN) in HBV-infected patients.METHODS: Low-resolution DNA typing kit was used to determine HLA-DR-1 and -DQB1 genes in 72 patients with chronic hepatitis B (CHB) and HLA-DRB1 in 200 healthy people ready to donate their bone marrow in Shanghai.Among CHB patients, 35 were treated with IFNα-1b for 24 wk.RESULTS: The frequencies of HLA-DRB1*06, DRB1*08and DRB1*16 alleles in 72 patients were higher than in 200 healthy people (2.08% vs0%, OR = 3.837, P= 0.018;11.11% vs5.50%, OR = 2.148, P= 0.034; and 6.94% vs 3.00%, OR = 0.625, P = 0.049, respectively); whereas that of DRB1*07 allele was lower (2.78% vs 7.75%,OR = 0.340, P = 0.046). The frequency of HLA-DRB1* 14allele was higher in 11 responders to IFN compared with 24 non-responders (18.18% vs2.08%, OR = 10.444,P = 0.031), whereas that of DQB1*07 allele was inverse (9.09% vs 37.50%, OR = 0.167, P= 0.021).CONCLUSION: The polymorphism of HLA class Ⅱ may influence the susceptibility to HBV infection and the response to IFN in studied CHB patients. Compared with other HLA-DRB1 alleles, HLA-DRB1*06, DRB1*08, and DRB1*16 may be associated with chronicity of HBV infection, HLA-DRB1*07 with protection against HBV infection, and HLA-DRB1*14 allele may be associated with a high rate of the response of CHB patients to IFN treatment.Compared with other HLA-DQB1 alleles, HLA-DQB1*07 may be associated with low response rate to IFN.     

Molecular typing of HLA-class II alleles reveals an association with autoantibodies and disease subsets of systemic sclerosis in a North Indian (Kashmir) population

Aim of the workTo identify specific human leukocyte antigen (HLA)-Class II (DRB/DQB1/DPB1) alleles associated with systemic sclerosis (SSc) and to explore their relation with SSc autoantibodies, clinical manifestations, and disease subsets.Patients and methodsHLA-class II alleles (DRB1/DRB3/DRB4/DRB5/DQB1) were determined by DNA typing in 80 SSc cases and 60 matched controls and HLA-DPB1 in 40 SSc patients and 30 controls by allele-specific-polymerase chain reaction with sequence-specific primers (PCR-SSP).ResultsThe mean age of SSc patients was 36.9 ± 9.4 years; 76 females and 4 males (F:M 19:1) and a disease duration of 5.3 ± 3.3 years, they were 43(53.7%) limited and 37(46.2%) diffuse subtypes. SSc was significantly associated with DRB1*11, DRB1*01, DQB1*04, and DQB1*03*03 in a >4-fold manner, whereas DPB1*04 had a >7-fold increased risk compared to controls. There was a strong association between DRB1*11 (p = 0.04), DQB1*03*03 (p = 0.005), and DPB1*13 (p = 0.009) with anti-topoisomerase I (anti-topoI) whereas the frequency of DRB1*01 (p < 0.0001) was increased in patients with anti-centromere (ACA) positive SSc compared those negative (56% vs 25%; p < 0.0001). DRB1*03, DRB1*15, and DQB1*03*01 were SSc protective alleles in patients with positive ACA. Anti-topo I was associated with interstitial lung disease (ILD) (p < 0.01), whereas ACA with pulmonary arterial hypertension (PAH) (p = 0.01) and protection against ILD (p < 0.001). In addition, HLA-DRB1*03, DQB1*03*01and DPB1*03 were more frequent in patients with ILD than in patients without.ConclusionAssociations between specific HLA-class II alleles with certain SSc-specific autoantibodies (anti-topo I and ACA) were identified. Specific HLA associations with clinical and serological subtypes could serve as biomarkers of disease severity and progression in SSc.     

The role of hemochromatosis susceptibility gene mutations in protecting against iron deficiency in celiac disease

BACKGROUND & AIMS: Celiac disease and hereditary hemochromatosis are common HLA-defined conditions in northwestern Europe. We sought to determine whether there is a genetic relationship between the 2 diseases and if hemochromatosis susceptibility gene (HFE) mutations are protective against iron deficiency in celiac disease. METHODS: Polymerase chain reaction amplification using sequence-specific primers capable of identifying the 2 HFE gene mutations (H63D and C282Y) and the HLA class I and II alleles was used to type 145 white patients with celiac disease and 187 matched controls. Hemoglobin and fasting serum iron levels in celiac patients were measured at diagnosis. RESULTS: HFE gene mutations, H63D or C282Y, were identified in 70 celiac patients (48.3%) and 61 controls (32.6%) (P = 0.004). The C282Y mutation was associated with HLA-A*03 and B*07 alleles in controls and with A*01, A*03, B*08, and DRB1*0301 alleles in celiac patients; the H63D mutation was associated with HLA-A*25 and DRB1*03 alleles in controls and A*29 and DRB1*03 alleles in celiac patients. At diagnosis, celiac patients with the C282Y mutation had higher mean hemoglobin and fasting serum iron levels compared with the HFE wild type (P = 0.0002 and 0.006, respectively). This was not observed with the H63D mutation. CONCLUSIONS: In celiac disease, HFE gene mutations are common and are in linkage disequilibrium with different HLA alleles compared with controls. A disease-specific haplotype that carries C282Y and DQB1*02 is suggested. We propose that HFE gene mutations provide a survival advantage by ameliorating the iron deficiency seen in celiac patients.     

Association of HLA class II genes with susceptibility to Crohn's disease.

BACKGROUND: Published studies on the association between HLA class II genes and inflammatory bowel disease are contradictory perhaps because of the limited size and ethnic heterogeneity of the populations studied. AIM: To compare the frequencies of HLA class II genes in a large number of French patients with Crohn''s disease and in an ethnically matched control group. METHODS: 344 patients (196 F, 148 M, mean age 23.6 years) with Crohn''s disease were molecularly genotyped for the HLA-DQB1 and DRB1 alleles. The results were compared with those for an ethnically matched control population of 488 white adults. RESULTS: There were two significant variations of alleles at the DQB1 locus: an increase in DQB1*0501 allele frequency (chi 2 = 10.6, corrected p value (pc) = 0.01, odds ratio (OR) = 1.61) and a decrease in DQB1*0602/0603 allele frequencies (chi 2 = 8.43, pc = 0.037, OR = 0.66). DRB1 analysis showed associations with three allelic variations: an increase in the frequencies of DRB1*01 (chi 2 = 12.86, pc = 0.003, OR = 1.75) and DRB1*07 alleles (chi 2 = 11.18, pc = 0.008, OR = 1.58) and a very significant decrease in that of the DRB1*03 allele (chi 2 = 19.7, pc = 9.10(-5), OR = 0.46). CONCLUSION: The alleles DRB1*01 and DRB1*07 are associated with susceptibility to Crohn''s disease. The strong negative association between the DRB1*03 allele and Crohn''s disease suggests that the HLA-DRB1*03 allele mediates ''resistance'' to Crohn''s disease.     

Relationship of human leukocyte antigen class Ⅱ genes with the susceptibility to hepatitis B virus infection and the response to interferon in HBV-infected patients

AIM: To study the relationship of human leukocyte antigen (HLA)-DRB1 and -DQB1 alleles with the genetic susceptibility to HBV infection and the response to interferon (IFN) in HBV-infected patients. METHODS: Low-resolution DNA typing kit was used to determine HLA-DR-1 and -DQB1 genes in 72 patients with chronic hepatitis B (CHB) and HLA-DRB1 in 200 healthy people ready to donate their bone marrow in Shanghai. Among CHB patients, 35 were treated with IFNa-lb for 24 wk. RESULTS: The frequencies of HLA-DRB1~*06, DRB1~*08 and DRB1~*16 alleles in 72 patients were higher than in 200 healthy people (2.08% vs0%, OR=3.837, P=0.018; 11.11% vs 5.50%, OR=2.148, P=0.034; and 6.94% vs 3.00%, OR=0.625, P=0.049, respectively); whereas that of DRB1~*07 allele was lower (2.78% vs 7.75%, OR=0.340, P=0.046). The frequency of HLA-DRB1~*14 allele was higher in 11 responders to IFN compared with 24 non-responders (18.18% vs 2.08%, OR=10.444, P=0.031), whereas that of DQB1*07 allele was inverse (9.09% vs 37.50%, OR=0.167, P=0.021). CONCLUSION: The polymorphism of HLA class II may influence the susceptibility to HBV infection and the response to IFN in studied CHB patients. Compared with other HLA-DRB1 alleles, HLA-DRB1~*06, DRB1~*08, and DRB1~*16 may be associated with chronicity of HBV infection, HLA-DRB1~*07 with protection against HBV infection, and HLA-DRB1~*14 allele may be associated with a high rate of the response of CHB patients to IFN treatment. Compared with other HLA-DQB1 alleles, HLA-DQB1~*07 may be associated with low response rate to IFN.     

Relationship between human leukocyte antigen-DRB1 and autoimmune hepatitis type I in Chinese patients

AIM: To analyze the association of human leukocyte antigen (HLA)-DRB1 with autoimmune hepatitis type I (AIH) among Chinese patients in the Shanghai area. METHODS: In 32 patients and 48 healthy controls, polymerase chain reaction amplified with sequence-specific primers (PCR-SSP) was performed to elucidate the relevance of certain alleles or polymorphic sequences of HLA-DRB1 with autoimmune hepatitis. RESULTS: The HLA-DRB1 typing by PCR-SSP showed that DR4 had a significantly increased frequency among patients with AIH versus that of healthy controls (46.9 vs 20.8%; relative risk = 3.35, P = 0.014). In the subtypes of DR4, there was a trend of an increase in the gene frequency of DRB1*0405 in patients with AIH versus that of healthy controls (21.9 vs 6.3%, P = 0.04, but corrected P (Pc) = 0.08). In addition, our analysis indicated a significant increase in the alleles frequency encoding Leu-Leu-Glu-Gln-Lys-Arg (LLEQRR) from the third hyperpolymorphic region (HVR3) of DR4 in the patients with AIH (86.7% of DR4 positive patients vs 40.0% in DR4 positive controls, P = 0.016, Pc = 0.028, relative risk (RR) = 9.75). CONCLUSION: Type I AIH among Chinese patients is associated with HLA-DR4. There is a relevance of type I AIH and LLEQRR sequence within the third hyperpolymorphic region of the DRB1 allele.     

Novel association of HLA-haplotypes with primary sclerosing cholangitis (PSC) in a southern European population

AIMS: In patients with with primary sclerosing cholangitis we investigated the major histocompatibility complex (MHC) genes and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. METHODS: In 64 PSC patients and 183 normal controls of the same population (Northern Italy), allelic polymorphisms at the DNA level were investigated in MHC region genes: HLA-DRB1, HLA-DQB1 and HLA-B, tumour necrosis factor A (TNFA), and in CFTR gene, with polymerase chain reaction-based methodologies. RESULTS: Frequencies of DRB1*01, DQA1*0101, DQB1*0102 (14 vs. 8%, p<0.05), DRB1*16, DQA1*0102, DQB1*0502 (8 vs. 3%, p<0.025) and DRB1*04, DQA1*03, DQB1*0301 (10 vs. 4%, p<0.005) haplotypes were more elevated in PSC patients. The frequency of patients positive for HLA DRB1*01, *1601 or *04 related haplotypes was significantly increased (32 vs. 14%, p<0.00025). DRB1*07, DQA1*0201, DQB1*02 haplotype frequency was significantly decreased (4 vs. 15%, p<0.001). After removing HLA-DRB1*01, *1601, *04 related haplotype sharing patients, HLA-DRB1*03, DQA1*0501, DQB1*02 haplotype frequency was significantly increased (32 vs. 14%, p<0.01). TNFA2 allele frequency was significantly increased in PSC patients (23 vs. 14%, p<0.025), as well as the TNFA2 homozygous genotype (9 vs. 0.5%, p=0.0013). No mutations were found on the CFTR gene and the allelic frequency of the 5T polymorphism in intron 8 was not increased. CONCLUSION: These data suggest that the role of genes in the HLA region is relevant, but not necessarily disease-specific and it might be different in populations with divergent ancestries.     

Clinical significance of HLA DRB103-DRB104 in type 1 autoimmune hepatitis.

BACKGROUND: HLA DRB1*03-DRB1*04 combines both susceptibility factors for type-1 autoimmune hepatitis. AIMS: Determine whether this phenotype is a risk factor for autoimmune hepatitis in white North American patients, assess its associations with clinical features and treatment outcome, and determine whether alleles within this phenotype affect prognosis. METHODS: One hundred and ninety-eight patients with type 1 autoimmune hepatitis and 102 normal adults were evaluated. HLA typing was performed by DNA-based techniques. RESULTS: Twenty-eight patients had HLA DRB1*03-DRB1*04, and the frequency was higher than in normal subjects (14% vs 4%, OR 4.0%, 95% CI 1.4-11.8, P = 0.01). Patients with DRB1*03-DRB1*04 relapsed less frequently than patients with DRB1*03 (1.3 +/- 0.3 vs 2.1 +/- 0.2, P = 0.04), but they otherwise had outcomes similar to patients with other phenotypes. Patients with DRB1*03-DRB1*04 who had 3-4 alleles encoding lysine at position DRbeta71 within the class II molecule of the major histocompatibility complex developed cirrhosis more commonly (75% vs 9%, P = 0.05) and had a higher frequency of hepatic-related death or liver transplantation (40% vs 0%, P = 0.04) than patients with fewer alleles. CONCLUSIONS: HLA DRB1*03-DRB1*04 is a risk factor for type-1 autoimmune hepatitis, and its impact on outcome relates to the diversity of DRB1*04 alleles that encode a critical motif.     

DRB1, DQA1, DQB1 genes in Turkish children with rheumatic fever

OBJECTIVES: Several studies have suggested that genetic susceptibility to rheumatic fever (RF) may be linked to HLA Class II alleles. The purpose of this study was to examine the association between HLA Class II genes and RF in Turkish children. METHODS: DNA typing HLA Class II genes (DRB1, DQA1, DQB1) were performed in 55 children with RF and 50 healthy unrelated controls using sequence specific primers (SSP). RESULTS: The frequency of the HLA DQA1*03 (OR: 0.462, p < 0.05) allele was significantly decreased in the patient group. Also, the frequency of the combination of DRB1*04 and DQA1*03 allele (OR: 0.42, p < 0.01) was more significantly decreased in the patient group. Differences in frequencies of the DRB1 and DQB1 alleles between groups were not significant. CONCLUSIONS: Our data indicate that the HLA DQA1*03 allele may be a protecting factor in Turkish children with RF. Our results also suggest that the combination of the DRB1*04 and DQA1*03 alleles may be a stronger protective factor than the DQA1*03 allele alone.     

Relationship between autoimmune hepatitis and HLA-DR4 and DRβ allelic sequences in the third hypervariable region in Chinese

AIM To analyze the association of HLA-DRB1 withautoimmune hepatitis(AIH)in patients from China.METHODS In 32 patients and 48 healthy controls,polymerase chain reaction amplification with sequence-specific primers(PCR-SSP)was performed to examine theassociation of certain alleles or polymorphic sequences ofHLA-DRB1 with AIH.RESULTS HLA-DRB1 typing by PCR-SSP showed that DR4had a significantly increased frequency among patientswith AIH versus healthy control(46.9% versus 20.8%;relative risk=3.35,P=0.014).In subtypes of DR4,therewas a trend of increase in the gene frequency of DRB1~*0405 in patients with AIH versus healthy controls(21.9%vs 6.3%,P=0.04,but P_c=0.08).In addition,asignificant increase was found in the alleles frequencyencoding QRRAA from the third hyperpolymorphic regionof DR4 in the patients with AIH(86.7% of DR4 positivepatients vs 40.0% in DR4 positive controls,P=0.016,P_c=0.028,RR=9.75).CONCLUSION AIH in Chinese is associated with HLA-DR4.There is a relationship between QRRAA sequencewithin the third hyperpolymorphic region of the DRB alleleand AIH in Chinese.     

Frequency of DRB1-DQB1 two-locus haplotypes in tuberculosis: preliminary report

Analysis of correlation between tuberculosis (TB) and human leukocyte antigen (HLA) in populations from Asia and Latin America has shown conflicting results. The aim of this study was to evaluate the frequency of HLA-DRB1-DQB1 two-locus haplotypes of 61 TB patients and 125 healthy volunteers in the same ethnic group in Poland. DRB1 and DQB1 alleles were determined by PCR-SSP "low-resolution" and "high-resolution" methods. Our study showed that DRB1*1601 and DQB1*0502 alleles were more frequent, whereas DQB1*0201 was rarer in TB than in controls. DRB1*16-DQB1*05, DRB1*04-DQB1*03 and DRB1*1601-DQB1*0502 haplotype were more common, and DRB1*11-DQB1*03 less frequent in TB in comparison to controls. Positive linkage disequilibrium (LD) for DRB1*01-DQB1*05, DRB1*03-DQB1*02, DRB1*11-DQB1*03, DRB1*13-DQB1*06 and DRB1*15-DQB1*06 was found in controls. A trend towards the positive LD for DRB1*01-DQB1*05, DRB1*03-DQB1*02, DRB1*11-DQB1*03, DRB1*15-DQB1*06 and DRB1*16-DQB1*05 was shown in TB. The trend towards the positive LD for DRB1*16-DQB1*05 haplotype in TB patients was not observed in the control group. It seems likely that the presence of DRB1*1601, DQB1*0502 alleles and DRB1*1601-DQB1*0502, DRB1*04-DQB1*03, DRB1*14-DQB1*05 haplotypes may be related to a higher risk of developing TB, whereas low frequency of DQB1*0201 and DRB1*11-DQB1*03 haplotype may be linked to the resistance to TB.     

Genetic Distinctions between Types 1 and 2 Autoimmune Hepatitis

Objectives: Our aim was to determine whether alleles affecting susceptibility to type 1 autoimmune hepatitis in the United States occur as commonly in German patients with type 2 disease. Methods : DNA specimens from 12 German patients with type 2 autoimmune hepatitis were tested for class II alleles of the major histocompatibility complex by polymerase chain reaction using sequence specific primers. Eighty-six American patients with type 1 disease and 102 Caucasoid normal subjects from the United States were tested in a similar manner. Results : American patients with type 1 autoimmune hepatitis had DRB1×03 alleles more commonly than the German patients with type 2 disease (51% vs 17%, p = 0.03) and DRB1×0301 occurred more frequently in the type 1 patients (51% vs 17%, p = 0.03). The frequency of DRB1×O4 alleles was also higher in the type 1 patients after exclusion of the DR1×O3 alleles (64 % vs 20%, p = 0.01). In contrast, patients with type 2 disease more commonly had DRB1×O7 ( p = 0.003), DRB1×15 ( p = 0.004), and DQB1×O6 ( p = 0.0004). DRB1×O7 ( p = 0.005), DRB4×01 ( p = 0.03), and DQB1×O6 ( p = 0.03) also occurred more frequently in the type 2 patients from Germany than in the normal subjects from the United States, although none of these frequencies were statistically significant by an adjusted p value. Conclusions : German patients with type 2 autoimmune hepatitis do not have the same susceptibility alleles as American patients with type 1 disease. Regional differences in prevalence may reflect the genetic profiles of the populations at risk.     

Association of human leukocyte antigen DQB1 and DRB1 alleles with chronic hepatitis B

AIM: To investigate the effect of human leukocyte antigen (HLA) DRB1 and DQB1 alleles on the inactive and advanced stages of chronic hepatitis B.METHODS: Patient records at a single institution’s hepatology clinic were reviewed. Demographic data, laboratory results, endoscopy results, virological parameters, biopsy scores and treatment statuses were recorded. In total, 355 patients were eligible for the study, of whom 226 (63.7%) were male. Overall, 82 (23.1%) were hepatitis B early antigen (HBeAg) positive, 87 (24.5%) had cirrhosis, and 66 (18.6%) had inactive disease. The presence of DQB1 and DRB1 alleles was determined by polymerase chain reaction with sequence-specific primers. The distribution of the genotyped alleles among patients with cirrhosis and patients with chronic active hepatitis was analyzed.RESULTS: The most frequent HLA DQB1 allele was DQB1*03:01 (48.2%), and the most frequent HLA DRB1 allele was DRB1*13/14 (51.8%). DQB1*05:01 was more frequent in patients with active disease than in inactive patients (27% vs 9.1%; P = 0.002, P_c = 0.026). DRB1*07 was rare in patients with cirrhosis compared with non-cirrhotics (3.4% vs 16%; P = 0.002, P_c = 0.022). Older age (P < 0.001) and male gender (P = 0.008) were the other factors that affected the presence of cirrhosis. In a multivariate logistic regression analysis, DRB1*07 remained a significant negative predictor of cirrhosis (P = 0.015). A bioinformatics analysis revealed that a polymorphic amino acid sequence in DRB1*07 may alter interaction with the T-cell recognition site.CONCLUSION: This study demonstrates that HLA alleles may influence cirrhosis development and disease activity in Turkish chronic hepatitis B patients.     

Linkage disequilibrium between HLA class II region and autoimmune hepatitis in pediatric patients

BACKGROUND/AIMS: Susceptibility HLA class II alleles associated with autoimmune hepatitis (AIH) were only described in case-control studies. METHODS: The transmission/disequilibrium test was used in 50 simplex families with AIH, to determine if affected offspring received the disease-associated allele more frequently than its alternate. HLA-DRB1 and DQB1 allele genotyping and autoimmune regulator (AIRE) polymorphisms located in exons 6, 8 and 10 were investigated by PCR-based methods. RESULTS: HLA-DRB1*03 allele was significantly transmitted from heterozygous parent to affected offspring (81.5%) with type 1 AIH compared to random expected frequency (50.0%; P=0.004) or to unaffected offspring (42.8%; P=0.03). HLA-DRB1*1301 allele showed an excess transmission to affected children (100%) than expected frequency (P<0.0001) or unaffected offspring (P=0.001). The transmission of DQB1*201 or DQB1*0603 alleles showed significant deviation in patients compared to random frequencies: (84.8%; P<0.0001 for DQB1*0201 or 100%; P<0.0001 for DQB1*0603). HLA-DQB1*0201 showed a strong association with type 2 AIH in children (100.0%, P=0.0005). CONCLUSIONS: HLA-DRB1 gene is the major genetic determinant in HLA class II region for children with type 1 AIH. Type 2 AIH is associated with the HLA-DQB1gene. Finally, AIRE gene abnormality does not contribute to the development of isolated AIH.     

Association of HLA class II genes with systemic sclerosis in Koreans

OBJECTIVE: To investigate HLA class II associations with systemic sclerosis (SSc) in Koreans according to anti-topoisomerase I (anti-topo I), anti-centromere antibody (ACA), and anti-U1 ribonucleoprotein (RNP) status. METHODS: HLA class II alleles (DRB1, DRB5, DQB1) were determined by DNA typing in 200 healthy control subjects and 74 patients with SSc: 35 anti-topo I positive, 3 ACA positive, and 19 anti-U1 RNP positive; among them were 34 diffuse and 40 limited subtypes, and 16 overlap syndrome. RESULTS: Anti-topo I positive SSc was strongly associated with DRB1*1502 compared with both controls (23% vs 5%; Pcorr = 0.003) and anti-topo I negative patients (23% vs 3%; p = 0.009); our study confirms observations in Japanese. HLA-DR 67FLEDR71, especially 38V-67FLEDR71 sequence (carried on DRB5*0102 in linkage disequilibrium with DRB1*1502, DRB1*0802, DRBI*1101), showed the strongest association with anti-topo I response (46% vs 16% in controls; Pcorr = 0.001), and 38L-67FLEDR71 group alleles were not associated with anti-topo I response. Anti-topo I response was not significantly associated with HLA-DQB1 alleles in Koreans. There were only 3 ACA positive patients, and all patients had DRB1*1501 and DQB1*0602 as heterozygotes. Anti-U1 RNP occurred at a high frequency (63%) among patients with overlap syndrome, and was not associated with HLA-DR or DQ genes. Among anti-topo I negative patients, diffuse and limited subtypes of SSc were significantly associated with DRB1*0803 (47% vs 15% in controls; Pcorr < 0.05) and DRB1*1501 (50% vs 17% in controls; Pcorr < 0.01), respectively. These HLA associations have not been reported in other ethnic groups and possible associations with certain autoantibody subsets remain to be confirmed. CONCLUSION: HLA-DR gene has a primary association with anti-topo I response, and HLA-DR 38V-67FLEDR71 group alleles including DRB5*0102 (in linkage disequilibrium with DRB1*1502) show the strongest association with anti-topo I response in Korean patients with SSc.     

Association of HLA Class II Genes with Idiopathic Pulmonary Arterial Hypertension in Koreans

The aim of this study was to compare the frequency of the HLA-DRB1 and HLA-DQB1 alleles in Korean patients with idiopathic pulmonary arterial hypertension (IPAH) and in normal controls and to determine any association that may exist between clinical characteristics of IPAH and specific HLA alleles. IPAH patients seen between October 1998 and September 2001 were retrospectively assessed, and 19 patients and 193 controls were HLA typed at the HLA-DRB1 and DQB1 loci. Clinical characteristics and hemodynamic parameters were reviewed. The patients with IPAH had a significantly higher frequency of the HLA-DRB1*0406 allele (18% vs. 6%, p = 0.004) and the HLA-DQB1*0302 allele (24% vs. 12%, p = 0.034), as well as a significantly higher frequency of haplotype DRB1*0406-DQB1*0302 (p = 0.0006). All 6 patients with haplotype DRB1*0406-DQB1*0302 (H+ group) were women, compared with 8 of the 13 patients lacking the DRB1*0406-DQB1*0302 haplotype (H- group), but without statistical significance. Three of 19 patients showed a positive short-term hemodynamic response to NO inhalation, all 3 of whom had the DRB1*0406-DQB1*0302 haplotype. There were no other significant differences in clinical characteristics and hemodynamic parameters between the H+ and H- groups. We conclude from this study that the HLA-DRB1*0406-DQB1*0302 haplotype is associated with IPAH in Korean patients. These results suggest that certain clinical characteristics of IPAH may be controlled in part by patients' HLA alleles.