Polymorphism of immunoglobulin enhancer element HS1,2A: allele *2 associates with systemic sclerosis. Comparison with HLA-DR and DQ allele frequency

OBJECTIVE: To investigate the relationship of the polymorphic enhancer HS1,2 central to the 3' enhancer complex regulatory region (IgH3'EC) of the immunoglobulin heavy chain genes with systemic sclerosis (SSc) disease and compare it with HLA-DR and DQ associations. METHODS: A total of 116 patients with SSc were classified as diffuse (dSSc) or limited (lSSc), and as carriers of antitopoisomerase I (anti-Scl70) or anticentromere (ACA) antibodies. Allele and genotype frequencies were assessed in the population as a whole and in the two major subsets, dSSc and lSSc. The concentration of peripheral blood immunoglobulin levels was also determined and analysed according to the genotypes. RESULTS: The analysis of genotypes for the four alleles of the HS1,2A enhancer showed an increased frequency of allele *2 in the SSc cohort highly significant versus controls (57% vs. 40%, p<0.0001). Considering the autoantibody pattern, we found that the frequency of the 2/2 genotype was increased in ACA+ patients (42%) and anti-Scl70+ patients (31%) compared with the control group (15%). The differences of allelic frequencies among dSSc versus lSSc or ACA+ versus anti-Scl70+ patients were not significant, although highly significant when comparing each subgroup with the control group. HLA-DRB1*11 and DQB1*03 associated with SSc. No association was seen between HS1,2A enhancer polymorphism and HLA alleles. CONCLUSIONS: These data confirm there was an increased risk of having SSc in carriers of allele *2, suggesting an intriguing function of this polymorphism for B-cell regulation.     

HLA class II alleles in systemic sclerosis patients with anti-RNA polymerase I/III antibody: associations with subunit reactivities

OBJECTIVE: To examine HLA class II gene associations with anti-RNA polymerase (RNAP) I/III antibody responses in patients with systemic sclerosis (SSc). METHODS: HLA-DRB1, DRB3, DRB4, and DQB1 alleles were determined using polymerase chain reaction-based methods in 257 SSc patients (129 Japanese and 128 Caucasians) and 271 race-matched regional controls (138 Japanese and 133 Caucasians). Anti-RNAP I/III antibodies were identified by immunoprecipitation assay, and reactivities to individual RNAP subunits were determined by immunoblots using affinity-purified RNAP I, II, and III. RESULTS: Serum anti-RNAP I/III antibody was detected in 10 (8%) Japanese and 24 (19%) Caucasian patients with SSc. The presence of anti-RNAP I/III antibodies was associated with DRB1*0405, DRB4*01, and DQB1*0401 in Japanese, and with DRB3*02 in Caucasians, but these associations were weak and inconsistent between these 2 ethnic groups. When anti-RNAP I/III-positive SSc patients were divided into 2 groups based on the presence or absence of reactivities to individual RNAP subunit proteins, significant associations of anti-IIa/IIo reactivity with DRB3*02, anti-Ia reactivity with DRB1*04, anti-43-kDa subunit reactivity with DRB4*01, and anti-34-kDa subunit reactivity with DRB1*15 were detected. These HLA associations with subunit reactivities were generally shared by Japanese and Caucasian patients with SSc. CONCLUSION: Our results suggest that in patients with SSc, anti-RNAP I/III antibodies are composed of subsets defined by combinations of reactivities to individual RNAP subunits having specific HLA class II correlations.     

The conundrum of HLA-DRB1*14:01/*14:54 and HLA-DRB3*02:01/*02:02 mismatches in unrelated hematopoietic SCT

Uncertainty still exists on the role of polymorphisms outside the HLA-DRB1 binding site or inside the HLA-DRB3 binding groove in unrelated hematopoietic SCT (HSCT). The ideal model to solve the conundrum consists of the transplants mismatched for HLA-DRB1*14:01/*14:54 and/or for HLA-DRB3*02:01/*02:02. A task force was set up in Italy to recruit transplanted pairs defined as HLA-DRB1*14:01 before 2006, the year crucial for the proper definition of the HLA-DRB1*14:54 allele in molecular biology. Out of 2723 unrelated pairs, 189 transplanted in Italy from 1995 to 2006 were HLA-DRB1*14:01 positive; 103/189 pairs with good historical DNA were retyped for HLA-DRB1*14 and HLA-DRB3 at-high resolution level; 31/103 pairs had HLA-DRB1*14 and/or HLA-DRB3 mismatched; 99/103, having complete clinical data, underwent statistical analysis for OS, TRM, disease-free survival and acute and chronic GvHD. No significant involvement of HLA-DRB1*14:01/*14:54 or HLA-DRB3*02:01/*02:02 mismatches was found, either alone or combined. Our findings suggest that disparities at exon 3 of the HLA-DRB1 gene seem unlikely to influence the outcome after HSCT. The same may be envisaged for HLA-DRB3(*)02:01 and (*)02:02 alleles which, although differing in the Ag binding site, seem unable to modulate an appreciable immune response in an HSCT setting.     

Association between the HLA-DRB1 gene and clinical features of systemic sclerosis in Korea

OBJECTIVE: To determine whether HLA-DR alleles are associated with the development and clinical features of systemic sclerosis (SSc) in Koreans. METHODS: Seventy-nine patients (74 women and five men; 45 diffuse types and 34 limited types; mean age at diagnosis 43.9 years) fulfilling the American College of Rheumatology (ACR) classification criteria for SSc were enrolled. The controls were 144 healthy, disease-free Koreans. HLA-DRB1 genotypes were assessed by the polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. RESULTS: The HLA-DRB1*15 allele was increased in anti-topoisomerase I autoantibody (anti-topo I)-positive SSc patients [p = 0.003, p corrected (p(corr)) = 0.039, odds ratio (OR) = 3.43, 95% confidence interval (CI) 1.45-8.13] compared with controls. The DRB1*11 allele was also observed more frequently in anti-topo I-positive SSc than in controls (13.3% vs. 4.2%) but not statistically significant (p = 0.053, p(corr) = 0.689). In patients with SSc, the DRB1*04 allele was associated with subcutaneous calcinosis (p = 0.048, OR = 4.56, 95% CI 1.07-19.37). Patients with overlap syndrome showed a negative association with the DRB1*04 allele (p = 0.036, OR = 0.26, 95% CI 0.08-0.91). CONCLUSION: The HLA-DRB1*15 allele was associated with the development of anti-topo I-positive SSc in Koreans. In addition, the DRB1*04 allele was associated with certain clinical features in SSc patients.     

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.     

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.     

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.     

HLA-DRB1*04 subtypes are associated with increased inflammatory activity in early rheumatoid arthritis

The sequence polymorphism of HLA-DRB1 molecules in 84 rheumatoid arthritis (RA) patients with early RA has been analysed to evaluate whether particular HLA-DR alleles influence disease progression in the early stage of the disease. Clinical data were analysed by grouping the patients according to disease-associated haplotype combinations (DRB1*04,04/DRB1*04,01/DRB1*04,X/DRB1*01,X) in comparison to patients who did not carry these haplotypes (DRB1*X,X). Our results indicate that patients with early RA who are homozygous for DRB1*04 exhibit an elevated inflammatory activity and an increase of joint affections. In addition, the amino acid polymorphism (QR/KRAA) at position 70-74 seems to affect the production of rheumatoid factors. These results support the role of HLA-DRB1 alleles in the pathogenesis of RA and indicate that patients with particular HLA-DRB1*04 haplotype combinations may require intensified therapeutic interventions in the early stage of the disease to prevent disease progression.      

HLA-DRB3*0101 is associated with Graves' disease in Jamaicans

OBJECTIVES: Graves' disease is associated with different human leucocyte antigen (HLA) genes in different populations. This studywasdesigned to examinethe HLA class II associations with Graves' disease in Jamaicans. PATIENTS: One hundred and six Jamaicans with Graves' disease and 104 controls. DESIGN: Oligotyping for HLA-DRB1, DRB3, DQA1 and DQB1 alleles was performed using the polymerase chain reaction sequence specific oligonucleotide probe (PCR-SSOP) technique. RESULTS The frequency of HLA-DRB3 *0101 was increased significantly in the patients compared to controls (38.7% vs. 19.2%; RR = 2.72; Pc < 0.015). The protective alleles for Graves' disease were DRB1 *0901 (0.9% vs. 20.2%; RR = 0.04; Pc < 0.001), DRB1*1001 (0.0% vs. 11%; RR = 0.0%; Pc < 0.01) and DRB4 *0101 (0.0% vs. 12.5%; RR = 0.0; Pc < 0.05). A high female to male ratio of Graves' disease, 25 :1, was observed. Other associated autoimmune diseases were rare and no significant HLA class II associations were found with clinical markers of disease. CONCLUSIONS: Jamaican patients with Graves' disease share the DRB3 *0101 susceptible allele and the DRB4 *01 protective allele but not the susceptible haplotype DRB1 *0301, DRB3*0101, DQA1*0501 with Caucasians.     

HLA-DRB1 polymorphism is associated with Kell immunisation

K immunisation is observed in some polytransfused patients and pregnant women but does not occur in all cases of K incompatibility. This study analysed the role of genetic background in this selective response to K antigen by investigating HLA-DRB1 alleles associated with K immunisation in a southern European population. HLA-DRB1 genotyping was performed by polymerase chain reaction sequence-specific oligonucleotide/sequence-specific primer procedures in 54 K immunised patients and 200 healthy controls. The frequency of HLA-DRB1*11 was significantly higher in K immunised patients than healthy controls: 31 of 54 (57%) vs. 56 of 200 (28%) (P(c) < 0.001). In the remaining K immunised HLA-DRB1*11-negative patients, the frequency of HLA-DRB1*13 was increased: 14 of 23 (61%) vs. 49 of 144 in healthy controls (34%) (P < 0.02). The combined frequency of the two HLA-DRB1 alleles (HLA-DRB1*11 and HLA-DRB1*13) was 83% in K immunised patients when compared with 52% in healthy controls (P(c) < 0.001). K and k differ by a single amino acid T193 (M). The DRB1*11 and DRB1*13 alleles share a HLA-DRB1 gene sequence containing S in position 13, D in 70 and A in 74, and coding for the P4 pocket within the HLA-DR binding groove. This feature of the HLA-DRB1 gene could be involved in the K peptide presentation through a polymorphism ligand specific for the T193 (M) of K. In conclusion, this study demonstrated a high frequency of HLA-DRB1*11 or HLA-DRB1*13 alleles in K immunised patients, which could be due to specific K peptide presentation by HLA-DR molecules.     

Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2

OBJECTIVE: Susceptibility to autoimmune hepatitis (AIH) type 1 has been associated with DRB1*03, DRB1*04, and DRB3 alleles in European and North-American whites, with DRB1*04 in Japan, and with DRB1*04 and DRB1*13 in Latin America. Very few studies have been performed on AIH type 2. The aim of the present study was to evaluate the association of AIH types 1 and 2 with HLA-DR and DQ loci. METHODS: We performed HLA-DRB and -DQB1 typing by polymerase chain reaction amplification with sequence-specific primers (PCR-SSP) in 139 AIH patients. Most had AIH type 1 associated with circulating anti-smooth muscle antibody with F-actin specificity or antinuclear antibody. Twenty-eight patients presented AIH type 2 with anti-liver/kidney microsome type 1 or anti-liver cytosol type 1 antibodies. RESULTS: We observed a significant increase of DRB1*13 (70% vs 26% of controls, p < 0.00001) and DRB3 (93% vs 69% of controls, p < 0.00001) in AIH type 1 patients. Analysis of patients without DRB1*13 disclosed a secondary association with DRB1*03 (70% vs 30% of controls, p = 0.0001) and either the DRB1*13 or the DRB1*03 alleles were present in the majority of these patients (91% vs 48% of controls, p = 0.001). Comparison of DRB1*13- and DRB1*03-positive subjects revealed that the former alleles conferred susceptibility to younger patients with AIH type 1. DQB1 typing showed a significant increase in DQB1*06 (68% vs 41% of controls, p = 0.00007) in strong linkage disequilibrium with DRB1*13, and a decrease in DQB1*0301 (8% vs 47% of controls, p(c) = 0.0003). On the other hand, HLA typing of patients with AIH type 2 disclosed a significant increase in the DRB1*07 (68% vs 20% of controls, p(c) < 0.00014), DRB4 (79% vs 43% of controls, p(c) = 0.004), and DQB1*02 (86% vs 42%, p = 0.00002) alleles. After exclusion of DRB1*07, a secondary association with HLA-DRB1*03 was further observed in these patients (78% vs 30%, p = 0.007) and most of them had either DRB1*07 or DRB1*03 (93% vs 44% of controls, p(c) < 0.0001). CONCLUSIONS: Our data indicate that predisposition to AIH types 1 and 2 is associated, respectively, with the DRB1*13 or DRB1*03 and DRB1*07 or DRB1*03 alleles, and suggest that protection against type 1 disease may be conferred by DQB1*0301. In addition, the cluster of DRB1*13 in children with AIH type 1 also supports the concept that different HLA alleles might influence the onset of the disease.     

The role of human leukocyte antigens as predisposing and/or protective factors in patients with idiopathic thrombotic thrombocytopenic purpura

Fifty-four adult German patients suffering from idiopathic thrombotic thrombocytopenic purpura (TTP) have been examined for HLA class II. All patients presented autoantibodies against ADAMTS13 and ADAMTS13 activity levels <5%. Blood samples have been analyzed for HLA-DRB1 and DQB1 alleles using sequence-specific primer PCR and sequence-specific oligonucleotide PCR. Reference data of German bone marrow and blood donors were obtained from . The results were evaluated employing two-sided binomial tests, and p values were corrected using the Benjamini–Hochberg procedure. A significant accumulation for DQB1*02:02 (p < 0.001) and DRB1*11 (p = 0.003) was found within the patient group. Twenty percent (DQB1*02:02) or 48.1% (DRB1*11) of TTP patients were tested positive for the particular HLA antigen compared to 1.2% (DQB1*02:02) or 23.5% (DRB1*11) in the control group. A tendency for a reduced occurrence of HLA-DRB1*04 was revealed (7.4% in patients compared to 24.6% in controls). An association between the HLA antigens DQB1*02:02 and DRB1*11 and disease susceptibility for idiopathic TTP has been found. A higher risk for disease outbreak within persons carrying the mentioned alleles can be assumed. The reduced occurrence of HLA-DRB1*04 in TTP patients indicates a possible protective effect of this HLA allele in disease development.     

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.     

Molecular subtypes of the HLA-DR antigens in pulmonary tuberculosis.

OBJECTIVE: The aim of this study was to analyze association between HLA-DRB1 alleles and pulmonary tuberculosis (PTB) in the Polish population. METHODS: The HLA-DRB1 typing was performed using sequence-specific amplification (polymerase chain reaction with sequence specific primer [PCR-SSP] in 31 patients and 58 healthy volunteers. The DRB1 primers were supplied by DYNAL in the standard kit DYNAL DR "low-resolution"-SSP. RESULTS: The study showed that the DRB1*16 alleles frequency was higher in patients with PTB than in the tested group of healthy controls (P < 0.01). When HLA-DR2 alleles were combined (i.e., the DRB1*15 with DRB1*16 alleles), their frequency was comparable with that in the healthy individuals. The highest relative risk (RR) of tuberculosis was associated with DRB1*16 alleles (RR = 9.7). When HLA-DR6 alleles were combined (i.e., the DRB1*13 with DRB1*14 alleles), only a trend for higher frequency in patients with PTB was found. Frequency of DRB1*13 alleles of HLA-DR6 was significantly lower in PTB than in the healthy individuals (P < 0.001; RR = 0.04). CONCLUSIONS: Results suggest that the presence of HLA-DRB1*16 alleles may increase the risk of development of PTB, whereas HLA-DRB1*13 alleles may be resistant to tuberculosis.     

HLA-DR.DQ基因与骨关节结核的易感性研究

目的 探讨HLA-DR.DQ基因多态性与骨关节结核的遗传关联性,比较骨关节结核与肺结核之间易感基因的差异。方法 采用聚合酶链反应-序列特异性引物 (PCR-SSP)方法,对86例骨关节结核,88例正常人及34例肺结核的HLA-DR.DQ等位基因进行分析。结果 骨关节结核组与正常人比较,骨关节结核组DRB109、DQB10301基因频率增高 (38.99%比8.24%　PC ＜0.0001　RR =8.92;18.27%比2.66%　PC ＜0.05　RR =2.21),DRB113.2基因频率显著低于对照组 (4.76%比20.50%　PC ＜0.001　RR =0.18)。骨关节结核组与肺结核比较,DRB109、DQB10301基因频率增高 (38.99%比9.2%　PC ＜0.0001;18.15%比1.85%　PC ＜0.001),而DRB115基因频率低于肺结核组 (17.17%比36.3%　PC ＜0.01)。结论 HLA-DRB109、DQB10301可能是我国骨关节结核的易感基因,DRB113.2为保护基因。骨关节结核与肺结核之间易感基因存在差异。     

HLA-DMA*0103 and HLA-DMB*0104 alleles as novel prognostic factors in rheumatoid arthritis

OBJECTIVE: To evaluate HLA-DM alleles as markers for disease severity in rheumatoid arthritis (RA). METHODS: Two distinct cohorts of patients with RA were oligotyped for HLA-DB1 and HLA-DM genes using PCR amplified genomic DNA with sequence specific oligonucleotide probes. Cohort 1 comprised 199 unselected patients with RA (mean (SD) age 45.5 (13.5) years; disease duration 11.9(8.8) years), whose disease severity was assessed using Larsen score on hand and foot radiographs. Cohort 2 comprised 95 patients with severe RA and 70 patients with benign RA according to the Larsen method. RESULTS: In cohort 1, after stratification according to DRB1 genotypes, patients positive for HLA-DMA*0103 and negative for HLA-DRB1*04 tended to have greater articular damage on hands and wrists (p = 0.07 by Mann-Whitney U test) and reached statistical significance for the Larsen score per year (p = 0.05). This association between HLA-DMA*0103 and articular damage was especially observed in patients with HLA-DRB1*01. Similarly, HLA-DMB*0104 positive patients had higher Larsen score on hands and wrists (p = 0.02). This association was even stronger in DRB1*04 positive patients (p = 0.005). In cohort 2, HLA-DMA*0103 was associated with severe RA in patients negative for HLA-DRB1*04 (OD = 5.4; p = 0.014). HLA-DMB*0104 allele frequency tended to be higher in patients with severe RA but without reaching significance. CONCLUSION: This is the first study evaluating the role of HLA-DM genes in the severity of RA. Our results suggest that HLA-DMA*0103 and HLA-DMB*0104 alleles may represent new genetic markers of RA severity. The HLA-DMA*0103 allele tends to be associated with patients with RA negative for DRB1*04 and could predict a more severe form of disease especially in HLA-DRB1*01 positive patients. The HLA-DMB*0104 allele could have an additive effect in HLA-DRB1*04 patients. Combined determination of HLA-DM and HLA-DRB1 alleles could facilitate identification of patients likely to have a poor disease course.     

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.     

Major histocompatility complex haplotypic associations in Felty's syndrome and large granular lymphocyte syndrome are secondary to allelic association with HLA-DRB1 *0401

OBJECTIVE: To investigate the role of HLA class I in susceptibility to Felty's syndrome (FS) and large granular lymphocyte (LGL) syndrome. METHODS: Fifty caucasoid FS patients, and 55 patients with LGL syndrome, of whom 26 had arthritis and 29 did not, were studied. Complete HLA class I and HLA-DR typing including, where relevant, DRB1*04 subtyping was carried out by molecular methods. Comparison was made with 78 unselected healthy caucasoid controls and a further 29 DRB1*0401+ individuals. RESULTS: A significant association was found between HLA-A*02 and FS [odds ratio (OR) 3.9, 95% confidence interval (95% CI) 1.8-8.4, P = 0.0004]. At the B locus, there was an association between B*44 and LGL with arthritis [OR 3.5 (1.3-9.2), P = 0.01]. For HLA-Cw*0501, there was an association with FS [OR 4 (1. 7-9.2) P = 0.0008]. For both FS and LGL with arthritis, the extended haplotype HLA-A*02;B*44;Cw*0501;DRB1*0401 was significantly associated [OR 9.5 (2.6-35), P = 0.0001; OR 4.6 (1-22.4), P = 0.05, respectively]. There was no association between HLA class I or II and LGL without arthritis. All the allelic and haplotypic associations were lost on comparison with HLA-DRB1*0401+ controls. The strongest HLA association was with HLA-DRB1*0401 for FS [OR 27.9 (10.3-75.5), P = 10(-13)], and LGL with arthritis [OR 35.4 (9.6-131. 3), P = 10(-10)]. CONCLUSIONS: The major histocompatibility locus (MHC) associations with FS reported here are due to linkage disequilibrium with HLA-DRB1*0401. LGL syndrome with arthritis shows identical class II associations with FS, although there may be subtle immunogenetic differences between the two in the class I region. One of the extended haplotypes reported in a number of studies for FS and rheumatoid arthritis (summarized as HLA-A*02;Cw*0501; B*44;TNFb5;TNFa6;TNFd4;C4A*3;C4BQ*0;DRB1*0 401;DQB1*0301) is likely to be attributable to strong primary association with HLA-DRB1*0401, rather than to epistatic interaction between these loci.     

Up-regulated expression of HLA-DRB5 transcripts and high frequency of the HLA-DRB5*01:05 allele in scleroderma patients with interstitial lung disease

Objective. Interstitial lung disease (ILD) is a serious complication of SSc. We aimed to identify markers associated with SSc-related ILD. Methods. RNA was prepared from the peripheral blood mononuclear cells of 14 SSc patients, divided into four different RNA pools according to the presence or absence of ILD and to the treatment, and subjected to microarray analysis. Real-time quantitative PCR was used to confirm the microarray results in 43 SSc patients, 42 autoimmune controls and 10 healthy controls. Genomic DNA samples were collected from 149 patients with SSc (70 in Hokkaido and 79 in Tokyo) who underwent a high-resolution CT for the evaluation of ILD and from 230 healthy controls. Genotyping was performed using sequence-specific primers. Results. The microarray analysis revealed HLA-DRB5 to be the only gene commonly up-regulated in patients with ILD compared with those without ILD in both comparison groups. High expression levels of HLA-DRB5 in SSc patients with ILD were confirmed by real-time quantitative PCR. The prevalence of HLA-DRB5 gene carriers increased in the SSc patients with ILD relative to those without ILD or to healthy controls in both cohorts. Among the four detected alleles, the HLA-DRB5*01:05 allele was significantly more frequent in SSc patients with ILD than in SSc patients without ILD or in healthy controls. These associations were confirmed in the second cohort. Conclusion. HLA-DRB5 was highly expressed in PBMCs from patients with SSc-related ILD. The HLA-DRB5*01:05 allele is a risk factor for ILD in patients with SSc.     

广西壮族系统性硬皮病与人类白细胞抗原-DRB1等位基因关联性研究

目的 探讨广西壮族系统性硬皮病(SSc)与人类白细胞抗原(HLA)-DRB1基因的关联性.方法 用聚合酶链反应-序列特异性引物(PCR-SSP)方法.对58例壮族SSc患者和50名壮族健康人的HLA-DRB1基因进行研究.组间差异比较采用χ2检验或四格表确切概率法.结果 16种等位基因中SSc患者组检出14种,对照组中检出16种,SSc患者HLA-DRB1*1301、HLA-DRB1*1305和HLADRB1 * 15等位基因出现频率(分别为7.760%,11.207%,26.724%)较对照组升高(分别为1.000%,4.000%,15.000%),组间差异均有统计学意义(OR值分别为9.000、3.322、2.679,χ2值分别为4.341、4.206、6.038,P值分别为0.037、0.040、0.014).结论 提示HLA-DRB1*1301、HLA-DRB1*1305及HLA-DRB1*15等位基因可能是广西壮族SSc患者的易感基因.

Abstract：

Objective To explore the potential association between HLA-DRB1 Alleles and systemic scleroderma (SSc) of the Zhuang Nationality in Guangxi region. Methods Polymerase chain reaction-special sequence primers (PCR-SSP) was used to study the HLA-DRB1 alleles in 58 patients with SSc and 50 healthy controls of the Zhuang Nationalty in Guangxi Province. Comparisons between groups were performed with χ2 test or exact probabilities. Results Sixteen HLA-DRB1 alleles were discovered from the specimens,including 14 in the SSc specimens, and 16 in the control specimens. Among them,the allele frequencies of HLA-DRB1 * 1301 (7.760%, OR=9.000, χ2=4.341, P=0.037), HLA-DRB1 * 1305 (11.207%, OR=3.322,χ2=4.206, P=0.040) and DRB1 * 15 (26.724%, OR=2.679, χ2=6.038, P=0.014) were significantly higher in SSc patients than those of the controls (respectively for 1.000%, 4.000%, 15.000%). Conclusion Our data suggest that the HLA-DRB1 * 1301, HLA-DRB1 * 1305 and HLA-DRB1 * 15 may be the susceptible genes of SSc in Zhuang nationality population.