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.     

Genetics of the HLA Region in the Prediction of Type 1 Diabetes

Type 1 diabetes (T1D) is one of the most widely studied complex genetic disorders, and the genes in HLA are reported to account for approximately 40–50% of the familial aggregation of T1D. The major genetic determinants of this disease are polymorphisms of class II HLA genes encoding DQ and DR. The DR-DQ haplotypes conferring the highest risk are DRB1*03:01-DQA1*05:01-DQB1*02:01 (abbreviated “DR3”) and DRB1*04:01/02/04/05/08-DQA1*03:01-DQB1*03:02/04 (or DQB1*02; abbreviated “DR4”). The risk is much higher for the heterozygote formed by these two haplotypes (OR = 16.59; 95% CI, 13.7–20.1) than for either of the homozygotes (DR3/DR3, OR = 6.32; 95% CI, 5.12–7.80; DR4/DR4, OR = 5.68; 95% CI, 3.91). In addition, some haplotypes confer strong protection from disease, such as DRB1*15:01-DQA1*01:02-DQB1*06:02 (abbreviated “DR2”; OR = 0.03; 95% CI, 0.01–0.07). After adjusting for the genetic correlation with DR and DQ, significant associations can be seen for HLA class II DPB1 alleles, in particular, DPB1*04:02, DPB1*03:01, and DPB1*02:02. Outside of the class II region, the strongest susceptibility is conferred by class I allele B*39:06 (OR =10.31; 95% CI, 4.21–25.1) and other HLA-B alleles. In addition, several loci in the class III region are reported to be associated with T1D, as are some loci telomeric to class I. Not surprisingly, current approaches for the prediction of T1D in screening studies take advantage of genotyping HLA-DR and HLA-DQ loci, which is then combined with family history and screening for autoantibodies directed against islet-cell antigens. Inclusion of additional moderate HLA risk haplotypes may help identify the majority of children with T1D before the onset of the disease.     

An association analysis of the HLA gene region in latent autoimmune diabetes in adults

Aims/hypothesis Pathophysiological similarities between latent autoimmune diabetes in adults (LADA) and type 1 diabetes indicate an overlap in genetic susceptibility. HLA-DRB1 and HLA-DQB1 are major susceptibility genes for type 1 diabetes but studies of these genes in LADA have been limited. Our aim was to define patterns of HLA-encoded susceptibility/protection in a large, well characterised LADA cohort, and to establish association with disease and age at diagnosis. Materials and methods Patients with LADA (n = 387, including 211 patients from the UK Prospective Diabetes Study) and non-diabetic control subjects (n = 327) were of British/Irish European origin. The HLA-DRB1 and -DQB1 genes were genotyped by sequence-specific PCR. Results As in type 1 diabetes mellitus, DRB1*0301_DQB1*0201 (odds ratio [OR] = 3.08, 95% CI 2.32–4.12, p = 1.2 × 10⁻¹⁶) and DRB1*0401_DQB1*0302 (OR = 2.57, 95% CI 1.80–3.73, p = 4.5 × 10⁻⁸) were the main susceptibility haplotypes in LADA, and DRB1*1501_DQB1*0602 was protective (OR = 0.21, 95% CI 0.13–0.34, p = 4.2 × 10⁻¹³). Differential susceptibility was conferred by DR4 subtypes: DRB1*0401 was predisposing (OR = 1.79, 95% CI 1.35–2.38, p = 2.7 × 10⁻⁵) whereas DRB1*0403 was protective (OR = 0.37, 95% CI 0.13–0.97, p = 0.033). The highest-risk genotypes were DRB1*0301/DRB1*0401 and DQB1*0201/DQB1*0302 (OR = 5.14, 95% CI 2.68–10.69, p = 1.3 × 10⁻⁸; and OR = 6.88, 95% CI 3.54–14.68, p = 1.2 × 10⁻¹¹, respectively). These genotypes and those containing DRB1*0401 and DQB1*0302 associated with a younger age at diagnosis in LADA, whereas genotypes containing DRB1*1501 and DQB1*0602 associated with an older age at diagnosis. Conclusions/interpretation Patterns of susceptibility at the HLA-DRB1 and HLA-DQB1 loci in LADA are similar to those reported for type 1 diabetes, supporting the hypothesis that autoimmune diabetes occurring in adults is an age-related extension of the pathophysiological process presenting as childhood-onset type 1 diabetes. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible to authorised users.     

Molecular analysis of major histocompatibility complex allelic associations with systemic lupus erythematosus in Taiwan

Objective. To investigate the association of HLA class II alleles/haplotypes, type I C2 deficiency gene, and tumor necrosis factor α gene promoter allele (TNF2) with systemic lupus erythematosus (SLE) in the Chinese population in Taiwan. Methods. The HLA-DRB1 and DQB1 alleles were studied in 105 SLE patients and 115 controls by the polymerase chain reaction (PCR)/sequence-specific oligonucleotide probe method, the subtyping of DRB1*15/16 and DRB5 by PCR with sequence-specific primers, type I C2 deficiency gene by PCR, and TNF2 by PCR-Nco I restriction fragment length polymorphism. Results. The frequencies of the HLA class II alleles DRB1*02, DRB1*1502, DRB5*0102, DQB1*0501, and DQB1*0602 and DR2-associated haplotypes DRB1* 1501,DRB5*0101,DQB1*0602 and DRB1*1502,DRB5* 0102,DQB1*0501 were higher among SLE patients than among controls; however, only DQB1*0501 was statistically significantly associated with SLE. No specific allele/haplotype was significantly associated with lupus nephritis. No subject had type I C2 deficiency. SLE patients had a marginally higher percentage of TNF2, which was in linkage disequilibrium with DR3. Since DR3 was not associated with SLE in this Taiwanese Chinese population, TNF2 might play a role in the immunopathogenesis of SLE. Conclusion. Although no HLA-DRB1 allele was found to be significantly associated with SLE, the associations with DQB1*0501 and TNF2 suggest that DQB1 and tumor necrosis factor α may be important genetic factors in SLE susceptibility in the Chinese population in Taiwan.     

HLA-DRB1/DQB1 susceptibility for autoimmune polyglandular syndrome type II and III in south of Tunisia

Objectives

The aim of our study was to investigate the association of HLA-DRB1 and HLA-DQB1 alleles with autoimmune polyglandular syndromes (APS) type II and III in a southern Tunisian population.

Patients and methods

Sixty-two unrelated patients with APSII (n = 20) and APSIII (n = 42) and 146 healthy controls were genotyped for HLA class II alleles (DRB1*, DQB1*) by PCR-SSP technique.

Results

An increased frequencies of HLA-DQB1*03:02 (P = 0,02; OR = 2.98) in APSII patients, HLA-DRB1*03 (P = 3 10⁻⁶; OR = 4.28) and HLA-DQB1*02:01 (P = 0.04; OR = 1.95) in APSIII patients were found compared to healthy controls. Study of the HLA-DRB1*;DQB1* haplotype frequencies showed a higher occurrence of DRB1*04;DQB1*03:02 and DRB1*03;DQB1*02:01 in APSII patients (P = 4 10⁻³; OR = 3.31 and P = 0.03; OR = 2.74 respectively) whereas APSIII was only associated with DRB1*03;DQB1*02:01 (P = 7.2 10⁻⁸, OR = 4.71).

Conclusion

Our data suggest that the variation in class II HLA alleles and haplotypes could be a genetic factor involved in the susceptibility of APS syndrome.     

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.     

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.     

Relationship between HLA-DQ and -DR genotypes and clinical characteristics in a French population of Type 1 diabetic patients.

AIMS: The present study was designed to look for a heterogeneity in the association between Type 1 diabetes mellitus (DM) and class II alleles of major histocompatibility complex (MHC) according to clinical presentation and C-peptide secretion during the first year of the disease, in a population living in south of France. METHODS: HLA DRB1 and DQB1 genotypes were determined in 129 Caucasoid patients with Type 1 DM and compared to a control group (n = 88). In a subgroup of 46 young adult diabetic patients, basal and postglucagon C-peptide secretion was followed during the first year of the disease (at 0, 1, 3, 6, 9 and 12 months). RESULTS: The two main haplotypes associated with Type 1 DM were DRB1*04DQB1*0302 and DRB1*03DQB1*02. The genotypes DRB1* 04DQB1 *0302/DRB1*04DQB1*0302 and DRB1 *03DQB1*02/DRB1*04DQB1* 0302 were associated with an early onset of diabetes, while homozygosity for DRB1*03DQB1*02 was characterized by later onset. Levels of residual insulin secretion in patients genotyped DRB1*03DQA1*0501DQB1* 02/DRB1* 04DQA1*0301DQB1*0302 were higher than in patients genotyped DRB1* 3DQA1*0501DQB1*02/DRB1*XDQA1*XDQB1*X or DRB1* XDQA1* XDQB1*X/DRB1*XDQA1*XDQB1*X. CONCLUSIONS: This study confirms some clinical heterogeneity of Type 1 DM linked to HLA DR and DQ genotypes, and leads to a paradoxical finding: DQB1*02/ DQB1*0302 combination predisposes to an early onset in the whole population but residual secretion of insulin disappears more slowly in a subgroup of young adults with recently diagnosed diabetes. These data suggest that interrelations between MHC genotype and diabetogenic process could be different at various ages of life.     

Class II HLA genotype in fulminant type 1 diabetes: A nationwide survey with reference to glutamic acid decarboxylase antibodies

Aims/Introduction: Fulminant type 1 diabetes is a subtype of type 1 diabetes characterized by a remarkably abrupt onset of insulin‐deficient hyperglycemia within a few days. The aim of the present study was to clarify characteristic class II HLA genotypes in a large number of patients with fulminant type 1 diabetes to date. Materials and Methods: We analyzed the HLA‐DRB1 and DQB1 genotypes, and their haplotypes in 207 patients with fulminant type 1 diabetes and 325 control subjects in the Japanese population. Results: The frequencies of the DRB1*04:05‐DQB1*04:01 and DRB1*09:01‐DQB1*03:03 haplotypes were significantly higher, and those of the DRB1*01:01‐DQB1*05:01, DRB1*15:02‐DQB1*06:01 and DRB1*08:03‐DQB1*06:01 haplotypes were significantly lower in patients with fulminant type 1 diabetes than in the control subjects. Combination analysis showed that the frequencies of homozygotes with DRB1*04:05‐DQB1*04:01 [odds ratio (OR) 7.0] and DRB1*09:01‐DQB1*03:03 (OR 9.5) were significantly higher in patients with fulminant type 1 diabetes. Within a limited portion of patients with fulminant type 1 diabetes with antibodies to glutamic acid decarboxylase (GADab; n = 25), the frequency of DRB1*09:01‐DQB1*03:03, but not DRB1*04:05‐DQB1*04:01, was significantly higher than in control subjects (44.0% vs 13.7%; Pc < 0.05, OR 5.0). [Correction to last line of Results, added after online publication 29 July 2011: “OR 5.1” is changed to “OR 5.0”.] Conclusions: Our large‐scale study showed the characteristic class II HLA genotypes in fulminant type 1 diabetes, and implicated that genetic contribution to disease susceptibility is distinct between GADab‐positive and GADab‐negative fulminant type 1 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00139.x, 2012)     

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.     

Trends in the Frequency of HLA DR-DQ Haplotypes Among Children and Adolescents with Type 1 Diabetes Mellitus in the Southeast Region of Turkey

Objective: The aim of this study was to determine the frequency of HLA DR-DQ haplotypes in children with type 1 diabetes mellitus (T1DM) in the Southeast Region of Turkey.Methods: Eighty children and adolescents with T1DM and eighty control subjects participated in the study. HLA-DR, DQ was typed using polymerase chain reaction and sequence-specific priming technique.Results: HLA DRB1*03 allele was significantly more common in patients than in control subjects. HLA DRB1*11, HLA DRB1*13 and HLA DRB1*14 allele frequencies were significantly lower in patients than in controls. DQB1*02 allele was more common in patients, whereas DQB1*03 allele was more frequent in control subjects. HLA DRB1*03-DQB1*02 haplotype was more frequently observed among patients.Conclusion: These results confirm the similar potential trends in the frequency distribution of HLA susceptibility genes with T1DM previously observed in Turkey and in other Caucasian populations. Conflict of interest:None declared.     

Increase of HLA-DRB1*0408 and -DQB1*0301 in HLA-B27 positive reactive arthritis

OBJECTIVE—To study HLA class II association in reactive arthritis.
METHODS—63 patients with reactive arth-ritis and 46 with rheumatoid arthritis were included in the study. HLA-DR alleles were determined by using a sequence specific PCR method. Oligonucleotide hybridisation was used for definition of DRB1*04 subtypes and DQB1 alleles. HLA-B27 was determined by standard microcytotoxity test or by PCR. HLA-B27 subtyping was made by sequencing.
RESULTS—46 (73%) of 63 patients with reactive arthritis were HLA-B27 positive and 24 (38%) were HLA-DRB1*04 positive. When haplotypes were inferred according to the known associations between DRB1 and DQB1 alleles, the frequency of DRB1*04-DQB1*0301 haplotype was found to be 13% (12/92) in HLA-B27 positive reactive arthritis patients, in contrast to 0% in HLA-B27 negative reactive arthritis (P = 0.04) and 1% in random controls (P = 0.0009). However, this combination was also found in 5% of 84 HLA-B27 positive control haplotypes, showing a linkage disequilibrium between B27 and this particular class II haplotype. HLA-DRB1*0408 subtype was found in 8/24 (33%) of the HLA-DRB1*04 alleles in patients with reactive arthritis, accounting for most DQB1*0301 haplotypes, but only in 5/55 (9%) of the DRB1*04 alleles in random controls (P = 0.017). All reactive arthritis patients with this subtype were positive for HLA-B27. DRB1*04-DQB1*0302 haplotype was increased in patients with rheumatoid arthritis (28/92, 30%) compared with reactive arthritis (12/126, 10%) or with the controls (12/100, 12%; P = 0.003). HLA-B*2705 was by far the dominant B27 subtype both in reactive arthritis patients with the particular DRB1*0408-DQB1*0301 haplotype and in controls. It was found in 11 out of 12 DR analysed patients, as well as in 10 out of 11 randomly selected B27 positive controls.
CONCLUSIONS—Although no single class II allele was found to be increased among patients with reactive arthritis, HLA-B27, DRB1*0408, and DQB1*0301 might exert a haplotypic effect in the pathogenesis of reactive arthritis, or they may be markers of a subset of B27 haplotypes conferring susceptibility.

     

Susceptibility markers in Tunisian first-degree relatives of patients with type 1 diabetes

To identify the profile of anti-pancreas autoantibodies and elucidate the HLA DRB1, DQB1 polymorphism in Tunisian first-degree relatives of patients with type 1 diabetes, we recruited 96 relatives from 21 families with at least one diabetic child. Islet cell antibodies (ICA) were detected by immunofluorescence on monkey pancreas; glutamate decarboxylase (GADA), IA2 (IA2-A) and insulin (IAA) antibodies were measured by RIA. HLA class II DRB1 and DQB1 alleles were typed by PCR-SSP. ICA, GADA, IA2-A and IAA were found in respectively 11.5, 4.2, 5.2 and 8.3% of relatives. Twenty-two out of 96 had at least one antibody and 20 out of these 22 had a susceptibility allele (DRB1*03, DRB1*04, DQB1*02 or DQB1*0302) with or without protective allele (DRB1*11, DRB1*13, DRB1*15 or DQB1*06). All of the 5 relatives having 2 autoantibodies or more carried the DRB1*04-DQB1*0302 susceptible haplotype. In conclusion, this observational study confirms in a Tunisian population known epidemiological data and demonstrates the usefulness of follow-up to determine the predictive value of studied markers.     

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.     

HLA class II alleles associations of anticardiolipin and anti-beta2GPI antibodies in a large series of European patients with systemic lupus erythematosus

The objective of this study was to determine the HLA class II associations of the anticardiolipin (aCL) and anti-beta2GPI (abeta2GPI) antibodies in a large series of European patients with systemic lupus erythematosus (SLE). A cohort of 577 European SLE patients was enrolled. aCL and abeta2GPI were measured by ELISA methods. Molecular typing of HLA-DRB1, DRB3, DRB4, DRB5, DQA1 and DQB1 loci was performed by the polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP) method. aCL of IgG, IgM and IgA isotypes were detected in 22.8%, 14% and 13.9% of patients, respectively. IgG and IgM abeta2GPI were detected in 20% of patients. aCL showed positive association with HLA DRB1*04, DRB1*0402, DRB1*0403, DRB1*07, DRB3*0301, DQA1*0201, DQA1*0301, DQB1*0302, and negative association with DQA1*0501, DRB3*0202. abeta2GPI showed positive association with DRB1*0402, DRB1*0403, DQB1*0302. DRB1*0402 carried the highest relative risk for the presence of both aCL (RR=8. 1) and abeta2GPI (RR=4.6). Our results confirm the already described associations of aCL with HLA DR4 and DR7, but also demonstrate that, among the alleles at the DRB1*04 locus, the *0402 was most represented both in aCL and in abeta2GPI positive patients. In addition, HLA class II associations of abeta2GPI are for the first time extensively examined in a large cohort of European SLE patients.     

HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease

Drug-induced idiosyncratic liver disease (DIILD) depends largely on host susceptibility factors. Small studies support the genetic influence of human leukocyte antigen (HLA) class II molecules on the predisposition to DIILD. We sought associations between HLA-DRB and -DQB alleles and DIILD considered collectively or according to the biochemical expression of liver damage. We studied a total of 140 patients with a definitive or probable diagnosis of DIILD, as assessed with the Council for International Organizations of Medical Sciences scale, with 635 volunteer bone marrow and blood donors serving as controls. HLA-DRB1* and -DQB1* genotyping was performed by hybridization with sequence-specific oligonucleotides after genomic amplification. The group with DIILD did not differ from control subjects with regard to the distribution of HLA-DRB and -DQB antigens. The frequencies of alleles DRB1*15 (35.4% vs. 18.6% of controls; P =.002; odds ratio [OR] 2.31) and DQB1*06 (61.5% vs. 40.8%; P =.001; OR 2.32) were significantly increased in patients with the cholestatic/mixed type of liver damage in comparison to healthy subjects. By contrast, frequencies of alleles DRB1*07 (16.9% vs. 35.4%; P =.003; OR 0.37) and DQB1*02 (32.3% vs. 55.8%; P =.0003; OR 0.39) were significantly decreased. In conclusion, there is no association between any specific HLA allele and the propensity to develop DIILD. However, the genetic influence associated with HLA class II alleles appears to play a role in the biochemical expression of liver injury in cholestatic/mixed hepatotoxicity and may explain why a given drug may cause different patterns of liver damage.     

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.     

Allele frequency and the associations of HLA-DRB1 and HLA-DQB1 polymorphisms with pemphigus subtypes and disease severity

Pemphigus is a rare, devastating, bullous autoimmune disease that damages the skin and mucous membranes, and has high morbidity and mortality. Studies have shown associations of pemphigus vulgaris (PV) and pemphigus foliaceus (PF) with human leukocyte antigen (HLA) class II polymorphisms.This study examined the frequency of Major Histocompatibility Complex, Class II, DR Beta 1, a Protein Coding gene (HLA-DRB1) and Major Histocompatibility Complex, Class II, DQ Beta 1 (HLA-DQB1) alleles in Vietnamese PV and PF patients, and the association of these polymorphisms with pemphigus subtypes and disease severity.The study enrolled 31 unrelated Vietnamese who underwent HLA typing using Sanger sequencing.HLA-DRB1∗14:54 was the most frequent allele in both PV (20.5%) and PF (33.3%) patients. The percentage of HLA-DQB1∗03:02 was significantly higher in PF than PV patients, while the percentage of HLA-DQB1∗05:03 was approximately 10 times higher in PV patients. Pemphigus patients who have the HLA-DRB1∗04 alleles are more likely to have mild or moderate disease.The HLA-DRB1 and DQB1 alleles may influence susceptibility to pemphigus subtypes, with DQB1∗05:03 being specific for PV and DQB1∗03:02 for PF. Our findings suggest that the DRB1∗04 alleles are likely to be associated with mild and moderate disease.     

Contribution of HLA-DRB1*04 alleles and anti-cyclic citrullinated antibodies to development of resistance to disease-modifying antirheumatic drugs in early rheumatoid arthritis

This study was intended to evaluate HLA-DRB1 alleles and antibodies against anti-cyclic citrullinated peptides (anti-CCP Abs) for their value in predicting patient responses to treatment with disease-modifying antirheumatic drugs (DMARDs) in early rheumatoid arthritis (RA). The subjects were 124 Japanese patients who had received their first treatment with DMARDs, usually methotrexate, within 1 year of disease onset and who had been followed-up for 2 years subsequently. Approximately 40% of patients developed DMARD resistance and accordingly required anti-tumor necrosis factor α (TNFα) therapy during the 2-year period. DMARD resistance was strongly associated with the carriage of SE-positive HLA-DRB1*04 alleles, especially the *0405 allele (OR, 3.92; 95%CI, 1.83–8.41; p = 0.0003). In contrast, the SE-positive allele HLA-DRB1*0101 was less potent in contributing to DMARD resistance. The rate of anti-CCP Ab-positive patients was significantly higher in the DMARD-resistant group (OR, 6.62; 95%CI, 1.45–30.24; p = 0.008). Multivariate logistic regression analysis confirmed the strong association of DMARD resistance with the presence of SE-positive *04 alleles (OR, 2.89; 95%CI, 1.28–6.53; p = 0.011) and anti-CCP Abs (OR, 6.31; 95%CI, 1.23–32.34; p = 0.027), yielding an area under the receiver operating characteristic curve of 0.76 (95% CI, 0.68–0.84; p = 0.000). After stratification, the highest rate of DMARD resistance was observed in patients having both SE-positive *04 alleles and anti-CCP Abs. These observations show that the presence of SE-positive *04 alleles in combination with anti-CCP Abs is the strongest predictor for development of DMARD resistance and eventual need of anti-TNFα agents in patients with early RA.     

Tissue types as prognostic risk factor in hepatitis B virus infection.

OBJECTIVES: Outcome after acute hepatitis B virus (HBV) infection may be determined by the host immune system. We studied the distribution of major histocompatibility (MHC) antigens in patients who developed natural immunity against HBV and those with chronic hepatitis B. METHODS: Thirty patients positive for IgG anti-HBs and anti-HBc ('naturally immune'), 30 patients with HBsAg-positive chronic hepatitis and 30 subjects with no serological markers of HBV infection (controls) were studied. MHC class-I antigens were detected by the standard Terasaki microlymphocytotoxicity test and the MHC class-II antigens by a polymerase chain reaction using sequence-specific primers. RESULTS: In the naturally immune group, A11, B73, CW3, DRB1*16 and DQB1*05 antigens were significantly more frequent than in the control group, and B73, DRB1*04 and DRB1*13 antigens were more frequent than in the chronic hepatitis group. In the chronic hepatitis group, CW6, DRB5 and DQB1*05 antigens were significantly more frequent than in the control group, and B8, CW7, DRB1*03 and DQB1*02 antigens were more frequent than in the naturally immune group. CONCLUSIONS: Differences in alleleic frequencies of HLA among persons with natural immunity against HBV and those with chronic hepatitis B may suggest a genetic basis for persistence of HBV infection and occurrence of chronic liver disease.