Family-based association of HLA-DRB1 and DQB1 alleles and haplotypes in a group of Iranian Type 1 diabetes children.

This family-based study was conducted in a group of Iranians with Type 1 diabetes (T1D) to investigate the transmission from parents of risk and non-risk HLA alleles and haplotypes, and to estimate the genetic risk score for this disease within this population. A total of 240 T1D subjects including 111 parent-child trios (111 children with T1D, 133 siblings, and 222 parents) and 330 ethnically matched healthy individuals were recruited. High-resolution HLA typing for DRB1/DQB1 loci was performed for all study subjects (n = 925) using polymerase chain reaction-sequence-specific oligonucleotide probe method. The highest predisposing effect on developing T1D was conferred by the following haplotypes both in all subjects and in probands compared to controls: DRB1*04:05-DQB1*03:02 (Pc = 2.97e-06 and Pc = 6.04e-10, respectively), DRB1*04:02-DQB1*03:02 (Pc = 5.94e-17 and Pc = 3.86e-09, respectively), and DRB1*03:01-DQB1*02:01 (Pc = 8.26e-29 and Pc = 6.56e-16, respectively). Conversely, the major protective haplotypes included DRB1*13:01-DQB1*06:03 (Pc = 6.99e-08), DRB1*15:01-DQB1*06:02 (Pc = 2.97e-06) in the cases versus controls. Also, DRB1*03:01-DQB1*02:01/DRB1*04:02|05-DQB1*03:02 and DRB1*03:01-DQB1*02:01/DRB1*03:01-DQB1*02:01 diplotypes conferred the highest predisposing effect in the cases (Pc = 8.65e-17 and Pc = 6.26e-08, respectively) and in probands (Pc = 5.4e-15 and Pc = 0.001, respectively) compared to controls. Transmission disequilibrium test showed that the highest risk was conferred by DRB1*04:02-DQB1*03:02 (Pc = 3.26e-05) and DRB1*03:01-DQB1*02:01 (Pc = 1.78e-12) haplotypes and the highest protection by DRB1*14:01-DQB1*05:03 (Pc = 8.66e-05), DRB1*15:01-DQB1*06:02 (Pc = 0.002), and DRB1*11:01-DQB1*03:01 (Pc = 0.0003) haplotypes. Based on logistic regression analysis, carriage of risk haplotypes increased the risk of T1D development 24.5 times in the Iranian population (p = 5.61e-13). Also, receiver operating characteristic curve analysis revealed a high predictive power of those risk haplotypes in discrimination of susceptible from healthy individuals (area under curve: 0.88, p = 5.5e-32). Our study highlights the potential utility of genetic risk assessment based on HLA diplotypes for predicting T1D risk in individuals, particularly among family members of affected children in our population.

Influence of HLA Class II Alleles and DRB1-DQB1 Haplotypes on Rheumatoid Arthritis Susceptibility and Autoantibody Status in the Chinese Han Population.

Human leukocyte antigen (HLA) class II alleles are considered to play a key role in the progress of rheumatoid arthritis (RA). This study was carried out to investigate the presence of HLA class II alleles and their influence on disease risk and autoantibody status in Chinese Han patients with RA. Here, HLA-DRB1, DQB1 and DPB1 genotyping was performed in 125 RA patients and 120 healthy controls by using the next-generation sequencing (NGS). Strong positive associations were shown between high-resolution typed HLA-DRB1*04:05:01, DRB1*10:01:01, DQB1*04:01:01, DPB1*02:01:02 and RA patients. Moreover, the haplotypes HLA-DRB1*04:05:01~ DQB1*04:01:01 and HLA-DRB1*10:01:01~ DQB1*05:01:01 were found to be more frequent in RA populations than in healthy controls. These possible susceptible HLA alleles (HLA-DRB1*04:05:01, DRB1*10:01:01, DQB1*04:01:01 and DPB1*02:01:02) also showed higher frequencies in seropositive RA patients as compared to normal controls. The present study provided evidence that alleles HLA-DRB1*04:05:01, DRB1*10:01:01, DQB1*04:01:01 and DPB1*02:01:02 constituted RA risk alleles, and haplotypes HLA-DRB1*04:05:01~ DQB1*04:01:01, HLA-DRB1*10:01:01~ DQB1*05:01:01 also showed prevalence in Chinese Han patients with RA. Serological results preliminary demonstrated patients carrying RA-risk HLA alleles might elevate the serum level of anti-citrullinated protein antibodies and rheumatoid factor and affect RA progression.

Concentration and Subclass Distribution of Anti-ADAMTS13 IgG Autoantibodies in Different Stages of Acquired Idiopathic Thrombotic Thrombocytopenic Purpura.

BACKGROUND: The acquired form of idiopathic thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease, in which the underlying deficiency of the ADAMTS13 protease is caused by autoantibodies, predominantly of the IgG isotype. Certain HLA-DR-DQ haplotypes were associated with the risk of developing TTP. OBJECTIVES: To investigate the development of the ADAMTS13-specific antibody response during the course of the disease, we analyzed the concentration, subclass distribution, and inhibitory potential of anti-ADAMTS13 IgG autoantibodies in samples of TTP patients drawn during the first acute phase, in remission, and during relapse. Additionally, we compared the anti-ADAMTS13 IgG levels between patients carrying and not carrying risk and protective HLA-DR-DQ haplotypes. PATIENTS AND METHODS: We determined the anti-ADAMTS13 IgG concentration and subclass distribution in 101 antibody-positive samples of 81 acquired TTP patients by ELISA methods. The presence and semi-quantitative amount of anti-ADAMTS13 inhibitors were determined in 97 of 100 deficient samples, and the specific inhibitory potential of anti-ADAMTS13 autoantibodies was determined in 49 selected samples, by mixing ADAMTS13-activity assays. HLA-DR-DQ typing and haplotype prediction were performed in 70 of the above patients. RESULTS: We found that IgG1 and IgG4 were the predominant subclasses, present in almost all samples. While IgG1 was the dominant subclass in almost half of the samples taken during the first acute episode, IgG4 was dominant in all samples taken during or following a relapse. The inhibitory potential of the samples correlated with levels of the IgG4 subclass. Anti-ADAMTS13 antibodies of IgG4-dominant samples had higher specific inhibitory potentials than IgG1-dominant samples, independently of disease stage. Interestingly, we found that patients carrying the protective DR7-DQ2 and DR13-DQ6 haplotypes had higher anti-ADAMTS13 IgG levels. CONCLUSION: Our results indicate that IgG4 becomes the dominant subtype at some point of the disease course, apparently before the first relapse, parallel to the increase in inhibitory potential of the anti-ADAMTS13 autoantibodies. Furthermore, we found an association between the genetic background and the antibody response in TTP.

Association of HLA-DRB1/DQB1 polymorphism with high-risk HPV infection and cervical intraepithelial neoplasia women from Shanghai.

Persistent human papillomavirus (HPV) infection is the main causative agent for cervical intraepithelial neoplasia (CIN) and cancer. Variability in host immunogenetic factors is important in determining the overall cellular immune response to the HPV infection. This study was carried out to confirm the association of human leukocyte antigen (HLA) class II DRB1 and DQB1 alleles with CIN and HPV persistent infections in women from Shanghai in a case-controlled study. A total of 170 patients, including 105 HPV positive patients and 65 HPV negative women (control) participated in the study. HybriBio's proprietary flow-through hybridization technique was used to perform HPV genotyping. Low-resolution PCR-sequence specific priming (PCR-SSP) was used to genotype HLA class II for DRB1 and DQB1 loci. Binary and multivariate logistic regression analysis highlighted the association of specific alleles with CIN and HPV persistent infections after adjusting for the confounding factor of age. HLA-DQB1*02 and *06 is significantly associated with increased risk of HPV16 persistent infection (P c < 0.013). HLA-DRB1*09 is significantly associated with increased risk for CIN, whereas the -DRB1*16 exhibit protective to CIN (P < 0.05). Significant association is found for HLA-DQB1*04 and *06 with increased risk for CIN (P < 0.05). There were possible associations of specific HLA class II alleles either with risk of persistent HPV infection or with developing CIN.

The role of human leukocyte antigen DRB1-DQB1 haplotypes in the susceptibility to acquired idiopathic thrombotic thrombocytopenic purpura.

The acquired form of idiopathic thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease, in which the underlying ADAMTS13-deficiency is caused by inhibitory autoantibodies against the protease. Human leukocyte antigens (HLA), responsible for antigen presentation, play an important role in the development of antibodies. The loci coding HLA DR and DQ molecules are inherited in linkage as haplotypes. The c.1858C>T polymorphism of the PTPN22 gene, which codes a protein tyrosine phosphatase important in lymphocyte activation, predisposes to a number of autoimmune diseases. We determined the HLA-DRB1-DQB1 haplotypes and the PTPN22 c.1858C>T genotypes in 75 patients with acquired idiopathic TTP and in healthy controls, in order to assess the role of these genetic factors and their interactions in the susceptibility to TTP. We found that the carrier frequencies of the DRB1∗11-DQB1∗03 and DRB1∗15-DQB1∗06 haplotypes were higher, while those of the DRB1∗07-DQB1∗02 and DRB1∗13-DQB1∗06 haplotypes were lower in TTP patients. There was no difference in the overall frequency of the PTPN22 c.1858T allele between TTP patients and controls. In conclusion, we identified four HLA-DRB1-DQB1 haplotypes associated with an increased (DRB1∗11-DQB1∗03 and DRB1∗15-DQB1∗06) or a decreased (DRB1∗07-DQB1∗02 and DRB1∗13-DQB1∗06) susceptibility to acquired idiopathic TTP.

Análisis de la asociación de HLA DRB1-DQB1 y autoanticuerpos en familias con Síndrome Poliendocrino Autoinmune (APS) / An analysis of the relationship between HLA DRB1-DQB1 and autoantibodies, in families with autoinmune polyendocrine syndrome (APS)

El APS es la asociación de enfermedades endocrinas autoinmunes, con otros desórdenes autoinmunes no endocrinos, denominados componentes mayores y menores. Este síndrome se clasificó en 4 tipos. Las alteraciones de la respuesta inmune provocan fallas regulatorias de la misma; y polimorfismos de HLA, entre otros, sumado a factores adquiridos o permanentes, representan gatillos disparadores de la autoinmunidad. Nuestro objetivo fue buscar la asociación de HLA-DRB1*-DQB1* en individuos pertenecientes a dos familias, con diagnóstico en uno o más de ellos de APS, o con enfermedades autoinmunes aisladas. Determinar los anticuerpos séricos: a21-OH, aGAD y aTPO y observar la asociación con el haplotipo HLA. Estudiamos padres e hijos de dos familias, dos integrantes padecían APS tipo 2 y 3; y otros con enfermedades autoinmunes. Buscamos HLA-DRB1*-DQB1* y cuantificamos a21-OH, aTPO y aGAD. Los pacientes con APS 2 y 3 presentaron el HLA-DRB1*0301-DQB1*0201. De los individuos estudiados, 5/9 tenían este haplotipo HLA y al menos un autoanticuerpo positivo. Hallamos el factor genético en 2/3 de los integrantes con enfermedades autoinmunes correspondientes a componentes mayores. La relación observada, entre APS y HLA-DRB1*0301-DQB1*0201, aumenta la posibilidad de identificar personas en riesgo de contraer afecciones autoinmunes en grupos familiares, en los cuales algún integrante padece APS.

The APS is the association of autoimmune endocrine diseases, with other non-endocrine autoimmune disorders, named mayor and minor components. This syndrome was classified in 4 types. The alterations of the immune response cause regulatory faults; and HLA polymorphisms, among others; taken in conjunction with acquired or permanent factors, these represent triggers of autoimmunity. Our objective was to find out the association of HLA-DRB1*-DQB1* in individuals belonging to two families, with diagnosis in at least one of them APS, or with isolated autoimmune diseases. To determine serum antibodies: a21-OH, aGAD and aTPO and to observe the association with HLA haplotype. We have studied parents and offspring of two families, two members who suffered APS type 2 and 3, and others with autoimmune diseases. We have looked for HLA-DRB1*-DQB1* and quantified a21-OH, aTPO and aGAD. Patients with APS 2 and 3 showed HLA-DRB1*0301-DQB1*0201. Among the population we have studied, 5/9 had this HLA haplotype and at least one positive auto antibody. We have found the genetic factor in 2/3 of the members with autoimmune diseases corresponding to greater components. The observed relation between APS and HLA-DRB1*0301-DQB1*0201, increases the possibility of identifying people at risk of catching autoimmune affections in familiar groups in which at least one member suffers APS.

Research on genetic polymorphisms of HLA-DRB1 and DQB1 in the Hans of Zunyi / 中国免疫学杂志

Objective:To investigate frequencies and polymorphism of HLA-DRB1 and DQB1 allele in the Hans of Zunyi area.Methods:Polymerase chain reaction-sequence specific primers(PCR-SSP) were used to type HLA-DRB1 and DQB1 genes of 200 unrelated healthy Han individuals in Zunyi area.Results:13 HLA-DRB1 and 7 HLA-DQB1 alleles were obtained at low resolution level in all subjects.The allele DRB1*09,DRB1*08 and DQB1*05 were showed high distributing frequencies;The allele DRB1*10 and DQB1*04 were scarcely found with low distributing frequencies.Comparied with Northern and Southern Han people,it would seem that Han people in Zunyi are more closely related to the Southern ones.The allele B*07 was scarcely found in the Southern Han with a high distributing frequency(GF=2.0%).Conclusion:HLA-DRB1 and DQB1 of Han people in Zunyi have plenty of polymorphisms.They seem to distribute in line with the Southern Han's characteristics but have their own territory feature with a high B*07 frequency.