Association Of HLA-DRB1 Alleles Research Articles

Association of HLA-DRB1 alleles with status of antibodies to hepatitis B surface and e antigen.

Antigen presentation by HLA class II molecules to CD4+ T cells is an essential step for generating antibodies to hepatitis B antigens. In this study, we investigated the association between the HLA-DRB1 gene and the status of antibodies to hepatitis B surface and e antigens. Our results revealed a significant association between the status of anti-HBsAg and HLA-DRB1*04:03 (OR = 4.11, 95% CI = 1.50-10.84, p = 0.005, Padj. = 0.05) as well as HLA-DRB1*15:01 (OR = 1.74, 95% CI = 1.20-2.50, p = 0.002, Padj. = 0.045). MHC II binding predictions and in silico docking demonstrated strong binding affinity of HBsAg peptides to these two HLA-DRB1 molecules. Conversely, the status of anti-HBeAg was inversely associated with HLA-DRB1*14:54 (OR = 0.34, 95% CI = 0.18-0.64, p = 0.001, Padj. = 0.011), and in silico analysis revealed weak binding affinity of HBeAg peptides to HLA-DRB1*14:54. In conclusion, these findings support the involvement of HLA-DRB1 in humoral immunity against HBV infection.

Association of HLA-DRB1 Alleles with Rheumatic Fever Among Senegalese Patients

Background: Acute rheumatic fever (ARF) is a systemic inflammatory disease resulting from an abnormal immune response to group A β-hemolytic streptococci. ARF is a major public health problem in developing countries, particularly in Senegal. The aim of this study was to evaluate the mutation penetrance and genetic diversity of exon 2 of the HLA-DRB1 gene in Senegalese patients with ARF. Results: DNA was extracted from the blood of patients with ARF. Exon 2 of the HLA-DRB1 gene was amplified by polymerase chain reaction and sequenced using the Sanger method. Bioinformatics software and databases (polyphen-2, SIFT and ProVean) were used to assess the pathogenicity of missense mutations. The results revealed a high level of polymorphism in exon 2 of the HLA-DRB1 gene, with 73 non-synonymous mutations between codons 21 and 89, which lie in the hypervariable region encoded by exon 2. Of the 73 variants tested, 44% were pathogenic, indicating their potential involvement in ARF onset. Conclusion: Our results indicate that the HLA-DRB1 mutations involvement in the onset of rheumatic fever.

Association of HLA-DRB1 alleles with anti-D alloimmunization in RhD negative pregnant women in India

BackgroundHuman leukocyte antigen (HLA) restriction plays an important role in the susceptibility to alloimmunization against red blood cell (RBC) antigens. The prevalence of anti-D alloimmunization in RhD negative pregnancy is still quite high in our population. Thus, we planned this study to determine the association of HLA-DRB1 alleles with anti-D alloimmunization in RhD negative pregnant women. Material and methodsRBC antibody screen (ABS) was performed for RhD negative pregnant women attending the antenatal clinic our institute. Those with a negative result were included in the ‘non-alloimmunized’ (NAL) group (‘Control’ group), while those with anti-D alloantibody on performing antibody identification were included in the alloimmunized (AL) group of the study (n = 50 each). ABS and identification were done using column agglutination technique. The HLA-DRB1 typing was done by Luminex based reverse sequence specific oligonucleotide probing (SSOP) using commercial kits. The HLA-DRB1 allele frequency was compared in both the groups. ResultsThere was a significant difference between the two groups in terms of gravida (p < 0.001) and history of anti-D immunoprophylaxis (p < 0.001). The frequency of HLA-DRB1*03 and HLA-DRB1*04 alleles was significantly higher in the AL group than the NAL group: 40 % versus 18 % [Odds Ratio (OR): 3.04, 95 % CI: 1.21–7.6; p = 0.015] for HLA-DRB1*03 alleles and 18 % versus 4 % (OR: 5.27, 95 % CI: 1.08–25.78, p = 0.025) for HLA-DRB1*04 alleles. ConclusionThe frequency of HLADRB1*03 and HLADRB1*04 alleles was significantly higher in RhD negative pregnant women alloimmunized with anti-D alloantibody.

The association of HLA-DRB1 alleles and MBL2 gene variant in pediatric acute lymphoblastic leukemia patients

IntroductionEpidemiologic studies on pediatric acute lymphoblastic leukemias (ALL) have been conducted to evaluate the possible risk factors including genetic, infectious and environmental factors with the objective of idenfying the etiology. Mannose-binding lectin 2 (MBL2) plays an important role in first-line immune defense. HLA DRB1 alleles play a role in presentation of peptides to T cells and in activation of the adaptive immune response. ObjectiveIn our study, we aimed to investigate both the MBL2 gene variant and HLA-DRB1 alleles in pediatric ALL patients. MaterialsIn this study, 86 high-risk ALL patients and 100 controls were included. Polymerase Chain Reaction (PCR)-Restriction Fragment Length Polymorphism (PCR-RFLP) and PCR-sequence specific primer (SSP) methods were used for detection of polymorphism of the MBL2 and HLA-DRB1 alleles, respectively. ResultsThe frequency of the MBL2 AB genotype was lower in female ALL patients, compared to male ALL patients (p = 0.034). An association was found between the MBL2 BB genotype and DRB1*07 and among patients with the MBL2 BB genotype; those who also carried the DRB1*07 and *04 alleles were significantly higher than those without the DRB1*07 and *04 alleles. (p = 0.048, p = 0.022, respectively). ConclusionThis is the first study suggesting that the MBL2 BB genotype in association with the DRB1*07 or co-inheritance of the HLA-DRB1*04 and HLA DRB1*07 may have an impact on the etiopathogenesis of the disease.

Association of HLA DRB1 Alleles with Asthma in Pakistani Population of Punjab Region

Association of HLA DRB1 Alleles with Asthma in Pakistani Population of Punjab Region

Association of HLA class II alleles with suicidal behavior in a Transylvanian population

Abstract Background: Suicide is a complex phenomenon determined by the interaction of various risk factors. The Major Histocompatibility Complex is the most polymorphic gene cluster of the entire human genome, being linked to both the regulation of the immune system and various psychiatric diseases. The aim of this study was to identify HLA-DQB1 and DRB1 alleles and genotypes susceptible to influence suicidal behavior. Methods: We explored the association of HLA-DQB1 alleles with the suicidal behavior on a sample of 427 individuals (including 110 suicide attempters) from Transylvania, as well as the association of HLA-DRB1 alleles with the suicidal behavior on a sample of 271 individuals (including 50 suicide attempters), using the single specific primer-PCR (SSP-PCR) technique. Results: We found that the HLA-DQB1*02, *03 and *06 alleles, the DQB1*02/*03, DQB1*02/*06, DRB1*12/*15 and DRB1*07/*13 genotypes, as well as the DQB1*06~DRB1*07 and DQB1*02~DRB1*13 haplotypes, were more frequent in suicide attempters. In contrast, the HLA-DQB1*04 and DQB1*13 alleles, the DQB1*02/*05 and DQB1*03/*05 genotypes and the DQB1*03~DRB1*13 haplotype were less frequent in the case group. Conclusion: HLA-DQB1*02, *03 and *06 alleles and the DQB1*02/*03 and *02/*06 genotypes are susceptible to favor a suicide behavior, while the HLA-DQB1*04 and *13 alleles and the DQB1*02/*05 and *03/*05 genotypes were protective against such behavior. A similar analysis regarding the HLA-DRB1 alleles detected a possible risk for suicidal behavior among individuals possessing either the DRB1*12/*15 or the DRB1*07/*13 genotypes. DQB1*06~DRB1*07 and DQB1*02~DRB1*13 haplotypes were found susceptible to favor a suicidal behavior, while DQB1*03~DRB1*13 exhibited a protective influence.

Olfatory HLA-associated mechanism of formation of married couples in the development of congenital heart diseases in children

Taking into account the significance of the HLA complex in the inflammatory and immune responses, we can assume that the potential for limiting or developing pathology in the next generation will be determined at the stage of selection of certain alleles in the spousal genotype.The aim. To study the role of HLA assortativity in couples with healthy children and couples with children with congenital heart diseases (CHD) through the prism of immunogenetic mechanisms of mutual olfactory choice.Materials and methods. We studied the distribution of HLA-DRB1 alleles in married couples with healthy children and with children having CHD. To identify the associations of HLA-DRB1 alleles with odor preferences, we also studied the group included young males and females. HLA-DRB1 gene typing was carried out in all participants.Results. The combination of HLA-DRB1 alleles in couples with healthy children was similar to the combination of these alleles in the mutual olfactory sympathy between unfamiliar young males and females. Allele combinations in the spouses from the experimental group differ from the group of random selection. The frequency of matches for HLA-DRB1 alleles in married couples with children having CHD without was significantly higher than in the control group.Conclusion. The first stage of selection, associated with olfactory selection, is aimed to the whole population, and it is significantly manifested in the control group (married couples with healthy children). At the same time, in the experimental group (couples with children having CHD), some deviations from the main selection were discovered. Generally, specific HLA-DRB1 allele combinations obtained on the basis of olfactory assessments, indicate the involvement of HLA molecules in pheromone reception.

HLA DRB1 alleles, IFN-γ and TGF-β Gene Variants in childhood ALL patients

Abstract Objectives Graft-versus-host disease (GvHD) is a complex clinical syndrome with organ dysfunction as a consequence of a severe immunological reaction mediated by mainly T cells after hematopoietic stem cell transplantation. Our aim is to evaluate the association of HLA-DRB1 alleles, IFN-γ and TGF-β gene variations, with childhood ALL (c-ALL) patients and with GvHD after transplantation. Methods This study included 30 high-risk c-ALL patients and 100 controls. HLA-DRB1 alleles were studied by the NGS method, and TGF-β and IFN-γ variations were studied by the PCR-RFLP method. Results The rates of HLA-DRB1*15 alleles and IFN-gamma CC genotype were significantly higher in c-ALL patients (p=0.004, p=0.036 respectively). Association of the HLA-DRB1*15 alleles with the TGF-β TC genotype was found with a higher rate in the patient group (p=0.031). Association of the DRB1*04 allele with the IFN-γ CC genotype was found with a higher rate in the patient group (p=0.028). Acute GvHD developed in eight of 19 patients who underwent transplantation. IFN-γ CT was found to have a protective role in occurrence of aGvHD (p=0.044). Association of the DRB1*15 allele with IFN-γ TT was found with a higher rate in a GvHD (p=0.050). Conclusions It is thought that polymorphism of HLA-DR15 and IFN-γ CC may contribute to the development of c-ALL, while IFN-γ CT might be protective for aGvHD.

Association of HLA-DRB1 alleles with rheumatoid arthritis in Split-Dalmatia County in southern Croatia.

The aim of this study was to investigate the distribution of HLA-DRB1 alleles in patients with rheumatoid arthritis (RA) in the Sinj Region (SR) and the rest of the Split-Dalmatia County (SDC) in Croatia and to determine their relationship with disease severity. Atotal of 74RA patients and 80healthy controls from the SR, and 74RA patients and 80healthy controls from the rest of the SDC were genotyped using sequence-specific oligonucleotide primed PCR. High-resolution typing of HLA-DRB1*04 alleles was performed using the single specific primed polymerase chain reaction (PCR-SSP) method. Serum anti-CCP, rheumatoid factor, C‑reactive protein, and erythrocyte sedimentation rate were measured in all RA patients, whereas disease activity was assessed by DAS-28 and functional status by the Health Assessment Questionnaire Disability Index. The HLA-DRB1*04 allele was more frequent in patients with RA from the SR than that in patients from the rest of the SDC (18.2% vs. 9.5%; P = 0.014), whereas the HLA-DRB1*15 allele was more frequent in patients with RA from the rest of the SDC than in patients from the SR (16.2% vs. 7.4%; P = 0.010). Shared epitope (SE) positive patients from the SR had significantly higher serum anti-CCP and RF antibody levels (P = 0.014 and P = 0.004, respectively), higher disease activity (P = 0.043), and worse functional status (P < 0.001), than SE-positive patients from the rest of the SDC. The observed higher incidence of more severe forms of RA in the SR in comparison to the rest of the SDC might be associated with the higher incidence of HLA-DRB1*04 allele in the SR.

Association of HLA-DRB1 Alleles with Rheumatic Fever and Rheumatic Heart Disease: A Meta-analysis

ABSTRACT Background Rheumatic fever (RF) and its sequel rheumatic heart disease (RHD) is an autoimmune disease caused by an abnormal host immune response to group A streptococcus (GAS) infection. The HLA class II molecules are entailed in immune-mediated infectious, inflammatory, and autoimmune diseases including RHD. However, HLA class II genes are reported to be associated with RF/RHD across different populations with a very little consistency. Objective The aim of the study is to investigate the association between HLA class II genes and RF/RHD by meta-analysis. Methods A comprehensive literature search was conducted to identify all relevant case-control studies published before December 31, 2019. The data were extracted using standardized form and pooled odds ratio (OR) with 95% confidence interval (CI) are calculated to assess the strength of the association between HLA class II genes and RF/RHD. Results Thirteen studies for HLA-DRB1 alleles (1065 patients and 1691 controls) and eight studies for HLA-DQB1 alleles (644 patients and 1088 controls) were finally included. The meta-analysis showed a significantly higher frequency of HLA-DRB1*07 allele (OR = 1.68, P < .0001) in RF/RHD patients when compared to controls, while the frequency of HLA-DRB1*15 allele (OR = 0.60, P = .03) was significantly lower in RF/RHD patients than in controls. However, there were no significant differences in the frequency of HLA-DQB1 alleles between RF/RHD patients and controls. Conclusions The results of the meta-analysis suggest that the differential presentation of autoimmune peptides by HLA-DRB1*07 (susceptible) and HLA-DRB1*15 (protective) alleles with different affinities may play a crucial role in the pathogenesis of RF/RHD.

No association of HLA-DRB1 and TNF alleles in Mexican patients with autoimmune hepatitis.

HLA-DRB1 alleles has been found implicated in susceptibility to autoimmune hepatitis (AIH) in populations from different genetic backgrounds. In Mexicans, HLA-DRB1*04:04 is recognized as a risk allele for AIH but, to date, there is no high-resolution data supporting this association. Also, the association of other nonclassical HLA genes, such as TNF-LTA locus, have not, to our knowledge, been evaluated in this population. The association of HLA-DRB1 alleles determined by sequence-based typing and two polymorphisms in the TNF locus with AIH in a sample of Mexican patients was evaluated. Fifty-six patients from Guadalajara, Mexico, diagnosed with AIH and 115 age-gender matched healthy volunteer blood donors, were genotyped for HLA-DRB1 by the sequencing exon 2 and for TNFA-308G>A and LTA + 252A>G polymorphisms. Increased frequencies of both HLA-DRB1*04:04:01 and *16:02:01:01 alleles (OR = 2.91; 95% CI = 1.08-7.84) and the haplotype (DRB1-TNFA-LTA) *04:04:01-G-A (OR = 5.33; 95% CI = 1.32-21.49) were observed in AIH patients. However, after corrections for multiple comparisons, associations were not significant. In conclusion, our study does not support the association of HLA-DRB1*04:04:01 with the susceptibility to AIH in Mexican population. More studies including patients from other Mexican regions and considering other genetic, immunological, and environmental factors should be performed.

Human leukocyte antigen (HLA)-DRB1 allele polymorphisms and systemic sclerosis

Objectives: Human leukocyteantigen (HLA) is the most important gene for immune system regulation. Although studies have evaluated the association between HLA-DRB1 allele polymorphisms and systemic sclerosis (SSc), their results are still controversial. We performed a meta-analysis to assess the association of HLA-DRB1 alleles with risk of SSc.Methods: Electronic database were systematically searched for articles, a total of 11 case–control studies including 3268 cases and 5548 controls were analyzed. Odds ratio (ORs) and 95% confidence intervals were used to assess the association of HLA-DRB1 alleles with SSc. The relationship between SSc-related autoantibodies and DRB1 alleles was also analyzed.Results: In the overall analysis, four alleles (DRB1*04:03, DRB1*08, DRB1*11, and DRB1*11:04) increased the risk of SSc; however, five alleles (DRB1*07, DRB1*11:01, DRB1*13, DRB1*13:01, and DRB1*14) had the opposite effect. Analysis of subgroups by ethnicity indicate that DRB1*11:01 and DRB1*13:01 confer a protective effect in Caucasians, while DRB1*11:04 was associated with a higher risk of SSc. For Asian, DRB1*13:02 was found to be a protective factor. In addition, the frequency of DRB1*11:04 alleles was significantly increased in ATA+ SSc patients compared with ATA− SSc patients.Conclusion: DRB1*04:03, DRB1*08, DRB1*11, and DRB1*11:04 were associated with the risk of SSc. Additionally, DRB1*11 and DRB1*11:04 were association with ATAs.

Association of HLA-DRB1 Alleles with Allergic Asthma and Total Serum IgE Levels in Iraqi Adults Patients

Association of HLA-DRB1 Alleles with Allergic Asthma and Total Serum IgE Levels in Iraqi Adults Patients

Lower Frequency of HLA-DRB1*01 in Southwestern Iranian Patients with Atherosclerosis.

Human leukocyte antigen (HLA) complex is a gene family involved in antigen presentation associated with protection or susceptibility to inflammatory, infectious and autoimmune diseases. Atherosclerosis is a chronic inflammatory disease in which HLA molecules play a role in the initiation and development of the disease through presentation of self or foreign antigens to T cells. To investigate the association of HLA-DRB1 alleles with atherosclerosis in a sample of southwestern Iranians. We performed an analytical cross-sectional study involving 96 patients with atherosclerosis and 72 controls. HLA-DRB1 genotyping was performed by PCR-SSP method. We observed a significantly lower frequency of DRB1*01 in patients with coronary artery atherosclerosis than in controls (4.68% vs. 13.1, P=0.0052, OR=3.09, CI 95%: 1.35-7.05). However, this allele showed a positive association with high blood pressure (P=0.009) in patients. Furthermore, DRB1*16 allele was associated with hyperlipidemia (P=0.008) in patients. Our results demonstrated that DRB1*01 may be a protective allele against atherosclerosis in individuals who live in southwest of Iran. The mechanism of this protection needs further investigation.

Epitope-Binding Characteristics for Risk versus Protective DRB1 Alleles for Visceral Leishmaniasis.

HLA-DRB1 is the major genetic risk factor for visceral leishmaniasis (VL). We used SNP2HLA to impute HLA-DRB1 alleles and SNPTEST to carry out association analyses in 889 human cases and 977 controls from India. NetMHCIIpan 2.1 was used to map epitopes and binding affinities across 49 Leishmania vaccine candidates, as well as across peptide epitopes captured from dendritic cells treated with crude Leishmania Ag and identified using mass spectrometry and alignment to amino acid sequences of a reference Leishmania genome. Cytokines were measured in peptide-stimulated whole blood from 26 cured VL cases and eight endemic healthy controls. HLA-DRB1*1501 and DRB1*1404/DRB1*1301 were the most significant protective and risk alleles, respectively, with specific residues at aa positions 11 and 13 unique to protective alleles. We observed greater peptide promiscuity in sequence motifs for 9-mer core epitopes predicted to bind to risk (*1404/*1301) compared with protective (*1501) DRB1 alleles. There was a higher frequency of basic amino acids in DRB1*1404/*1301-specific epitopes compared with hydrophobic and polar amino acids in DRB1*1501-specific epitopes at anchor residues pocket 4 and pocket 6, which interact with residues at DRB1 positions 11 and 13. Cured VL patients made variable, but robust, IFN-γ, TNF, and IL-10 responses to 20-mer peptides based on captured epitopes, with peptides based on DRB1*1501-captured epitopes resulting in a higher proportion (odds ratio 2.23, 95% confidence interval 1.17-4.25, p = 0.017) of patients with IFN-γ/IL-10 ratios > 2-fold compared with peptides based on DRB1*1301-captured epitopes. Our data provide insight into the molecular mechanisms underpinning the association of HLA-DRB1 alleles with risk versus protection in VL in humans.

HLA-DRB1 gene polymorphisms in Iranian children with Henoch-Schönlein purpura.

Background:People of all ages can suffer from Henoch-Schönlein purpura (HSP), but it is the most common vasculitis in childhood. The most important involving gene is located on chromosome 6p21.3, a region coding for human leukocyte antigens (HLAs). Among HLA genes, because of the high rate of polymorphisms, HLA-DRB1 is estimated to have a strong association with HSP. In this study, we aimed to assess the association of HLA-DRB1 alleles with HSP in Iranian children.Materials and Methods:This study consisted of thirty Iranian children with HSP and 35 healthy controls. Genomic DNA was extracted, and HLA typing was performed by polymerase chain reaction with sequence-specific primers technique.Results:The results have shown that HLA-DRB1*01 and HLA-DRB1*11 (P = 0.002, odds ratio [OR] = 7.579, confidence interval [CI] = 1.934–29.697 and P = 0.039, OR = 3.333, CI = 1.030–10.788), respectively, are the most frequent alleles associated with HSP in Iranian children population. The frequency of other alleles was not significantly different in both groups. The results also show no correlation between HLA types and disease manifestations.Conclusion:According to these results, there is an association between HLA-DRB1*01 and HLA-DRB1*11 gene polymorphisms and susceptibility to HSP in our study group.

Associations of Human Leukocyte Antigen-DRB1 Alleles with Nasopharyngeal Carcinoma and Its Clinical Significance in Xinjiang Uyghur Autonomous Region of China.

Background:Genetic susceptibility is one of the major etiological factors for nasopharyngeal carcinoma (NPC). Among the genetic predisposing factors, human leukocyte antigen (HLA) genes have been reported to be associated with NPC. This study aimed to investigate the associations of HLA-DRB1 alleles with NPC and the clinical significance of HLA-DRB1 alleles in NPC.Methods:From January 2009 to December 2013, 140 NPC patients (118 Han patients and 22 Uyghur patients) and 158 healthy controls (81 Han individuals and 77 Uyghur individuals) from Xinjiang Province were genotyped for HLA-DRB1 using the polymerase chain reaction-sequence specific primer technique. Chi-square analysis was used when comparing allele frequencies between groups. The clinical outcomes were evaluated by Kaplan-Meier method and Cox regression model.Results:Compared with healthy controls, the allele frequency of HLA-DRB1*0701 was increased in the Uyghur patients (P = 0.008) but not in the Han patients (P = 0.869). HLA-DRB1*0101 allele was presented with higher frequency in clinical Stage I + II group compared with clinical Stage III + IV group in the Han patients (P = 0.015) but not in the Uyghur patients (P = 1.000). Higher frequency of HLA-DRB1*1501 allele was observed in patients aged <45 years compared with those in patients aged ≥45 years (P = 0.002). Neither HLA-DRB1*0701 nor HLA-DRB1*0101 had a statistically significant association with 3-year survival.Conclusions:This study found HLA-DRB1*0701 in Uyghur population was associated with an increased risk of developing NPC. In Han population, we found HLA-DRB1*0101 was associated with protection from disease progression, and HLA-DRB1*1501 was associated with early age of onset. HLA-DRB1 could not be identified as a prognostic indicator for NPC in either Han or Uyghur patients.

Meta-Analysis of the Association of HLA-DRB1 with Anti-Citrullinated Protein Antibody-Positive and Anti-Citrullinated Protein Antibody-Negative Rheumatoid Arthritis

Because of genetic complex and variations of auto antibodies of rheumatoid arthritis (RA) in different populations, the data on the association of HLA-DRB1 alleles in anti-citrullinated protein antibody of (ACPA) RA were inconsistent. The purpose of the study is to systematically summarize results of published data through performing a meta-analysis using data in which HLA-DRB1 alleles are associated with ACPApositive RA and ACPA-negative RA. In this study, we collected data from 12 studies with 13,861 cases and 12,896 controls. Information in these studies included HLADRB1 typing and ACPA status from different countries. Odds ratios (ORs) and corresponding 95% confidence intervals (CI) were used to analyze the association of different HLA-DRB1 alleles with ACPA-positive RA or ACPA-negative RA. To correct skewing data, the analysis of ACPA-status was stratified by patient distribution. Our analyses indicate that in ACPA-positive RA, all patients with RA had significantly higher frequencies of HLA-DRB1*01, *04, *0401, *0405, *07, *11, *13 and *14 than controls. One of the HLA-DRB1*07, *11, *13 and *14 showed protective association with RA. In addition, HLA-DRB1*03, *10 and *12 had more influence than control to RA in European populations; the HLA-DRB1*03 and *12 alleles were associated with the protection. In ACPA-negative RA, only DRB1*07 was associated with the protection (OR 0.53 [95% CI 0.36 - 0.76]) among all HLA-DRB1 alleles in European populations. In ACPA-positive RA, currently available results indicate that *01, *04, *0401 and *0405 are susceptible, while HLA-DRB1*07, *11, *13 and *14 are protective in all populations. While the HLA-DRB1*10 is susceptible, HLA-DRB1*03 and *12 show protective association with RA in European populations. Additionally, regardless of the positive or negative ACPA, the DRB1*07 is always associated with protection in European populations.

Associations of HLA DRB1 alleles with IgG oligoclonal bands and their influence on multiple sclerosis course and disability status

Background and aimOligoclonal bands (OCB) may be associated with the genes of HLA complex, which allows to consider the possible interaction of genetic and immunological factors and its importance in the development and progression of multiple sclerosis (MS). The aim of this study was to evaluate the associations between HLA DRB1 alleles and oligoclonal bands (OCBs) in the disease course and disability of multiple sclerosis (MS) patients. Materials and methodsThis was a prospective study of 120 patients with MS. HLA DRB1 alleles were genotyped using the polymerase chain reaction. Matched cerebrospinal fluid (CSF) and plasma samples were analyzed using isoelectric focusing and IgG specific immunofixation to test for the presence of intrathecal specific OCB. ResultsHLA DRB1*08 allele was related to a lower degree of disability. Oligoclonal bands were an independent and significant factor that influenced disability status irrespective of HLA DRB1* 04, *07, *08, *13, *15 and *16 alleles. Age at the onset and duration of the disease were independent and significant factors for MS progression in all logistic regression models with each newly added HLA DRB1 allele. HLA DRB1*08 allele was related to 75% lower odds that relapsing remitting (RR) MS will change to a progressive course MS irrespective of the other factors investigated. Detection of OCBs in the CSF was associated with the higher possibility of RR MS progression in all cases, except when the *08 allele was present. ConclusionsOCBs had an influence on disability status, while HLA DRB1*08 allele was significantly associated with lower possibility that RR MS will change to progressive course MS.

An Association Between Amino Acid Position 74 of HLA–DRB1 and Anti–Citrullinated Protein Antibody Levels in Japanese Patients With Anti–Citrullinated Protein Antibody–Positive Rheumatoid Arthritis

Anti-citrullinated protein antibodies (ACPAs) are highly specific to rheumatoid arthritis (RA), and strong associations between HLA-DRB1 alleles and ACPA levels have been detected in RA patients. We undertook this study to elucidate the associations between particular amino acid positions in HLA-DRB1 and ACPA levels in patients with RA. We analyzed ACPA data on a total of 4,371 Japanese ACPA-positive RA patients in whom HLA-DRB1 allele genotyping had been performed. Generalized linear regression analysis and omnibus testing were carried out to determine associations of HLA-DRB1 alleles, amino acid residues, or amino acid positions with levels of ACPA. HLA-DRB1*09:01 and HLA-DR15 were confirmed to be associated with ACPA levels. HLA-DRB1*08:03 and DRB1*14:06 were associated with reduced and increased ACPA levels, respectively. We detected a strong association between ACPA levels and amino acid position 74 (P = 1.9 × 10(-51) ). The association was mainly conferred by alanine residue (P = 4.5 × 10(-51) ). After adjustment for position 74, amino acid positions 60 and 57 were found to be associated with ACPA levels. Amino acid positions 74 and 57 had previously been reported to be associated with susceptibility to ACPA-positive RA in Asians. Combinations of the amino acid residues at position 74 and position 60 or 57 could induce improvement in Akaike's information criterion comparable to that induced by the 5 significant HLA-DRB1 alleles (HLA-DRB1*08:03, DRB1*09:01, DRB1*14:06, DRB1*15:01, and DRB1*15:02). Amino acid position 74 in HLA-DRB1 is strongly associated with ACPA levels in ACPA-positive RA, as well as with RA susceptibility. The mechanisms of ACPA production and susceptibility to ACPA-positive RA seem to partly overlap.