HLA-DQA1*04: 01 is related to a higher multiple sclerosis lesion load on T2/Flair MRI sequences / O HLA-DQA1*04: 01 está relacionado com uma alta carga lesional na ressonância magnética em T2/Flair nos pacientes com esclerose múltipla

ABSTRACT Background: The genetic predisposition to multiple sclerosis (MS) is associated with HLA alleles, especially HLA-DRB1*15:01. Objective: To identify associations between findings in magnetic resonance imaging (MRI) and genetic features in a Brazilian cohort of patients with MS. Methods: We retrospectively studied data from 95 consecutive patients with MS. Two independent observers who were blinded to the clinical data identified black holes and enhanced lesions on T1 MRI sequences, and counted and measured contrast-enhanced lesions on T2 and Flair (fluid attenuation inversion recovery) sequences. Cases were classified according to lesion size, number, and volume. The HLA-DRB1, HLA-DQB1, and HLA-DQA1 alleles, and the rs4774, rs3087456, rs6897932, rs731236, and rs1033182 single nucleotide polymorphisms were identified by polymerase chain reaction amplification with sequence-specific primers using the One Lambda Inc. Kit, Canoga Park, CA, USA. Results: Patients with the HLA-DQA1*04:01 allele had lesion load (adjusted for age, sex, and MS duration) above median compared with patients with other HLA-DQA1 alleles (p=0.02). There were no differences among all the other HLA alleles and single nucleotide polymorphisms and lesion load. Conclusions: The correlation of the HLA-DQA1*04:01 allele with a higher lesion load on T2/Flair MRI sequences suggests that the presence of this allele is associated with the risk of greater MS severity.

RESUMO Antecedentes: A predisposição genética para a esclerose múltipla (EM) está associada a alelos HLA, principalmente o HLA-DRB1*15:01. Objetivo: Identificar associações entre lesões na ressonância magnética e características genéticas em uma coorte brasileira de pacientes com EM. Métodos: Estudamos retrospectivamente os dados de 95 pacientes consecutivos com EM. Dois observadores independentes que desconheciam os dados clínicos identificaram "black holes" e lesões realçadas pelo contraste nas sequências de ressonância magnética T1 e contaram e mediram as lesões nas sequências T2 e FLAIR (fluid attenuated inversion recovery). Os casos foram classificados de acordo com tamanho, número e volume da lesão. Os alelos HLA-DRB1, HLA-DQB1 e HLA-DQA1 e os polimorfismos de nucleotídeo único rs4774, rs3087456, rs6897932, rs731236 e rs1033182 foram identificados por amplificação de reação em cadeia da polimerase com iniciadores específicos de sequência usando o kit One Lambda Inc., Canoga Park, CA, EUA. Resultados: Os pacientes com alelo HLA-DQA1*04:01 apresentaram carga de lesão (ajustada para idade, sexo e duração da EM) acima da mediana em comparação com outros pacientes com demais alelos HLA-DQA1 (p=0,02). Não houve diferenças entre todos os outros alelos HLA e polimorfismos de nucleotídeo único e carga lesional. Conclusões: A correlação do alelo HLA-DQA1*04:01 com maior carga de lesão nas sequências de RM em T2 sugere que a presença desse alelo pode estar associada ao risco de maior gravidade da EM.

Polimorfismos do gene HLA-DRB1 em pacientes pediátricos com hepatite autoimune tipo 1 e hepatite autoimune associada à colangite autoimune / Hla-drb1 gene polymorphisms in pediatric patients with type 1 autoimmune hepatitis and type 1 autoimmune hepatitis overlap syndrome with autoimmune cholangitis

ABSTRACT BACKGROUND: Autoimmune hepatitis (AIH) is a rare chronic inflammatory liver disease associated with a loss of immunological tolerance to self-antigens. Susceptibility to AIH is partially determined by the presence of genes related to human leukocyte antigen (HLA), mainly allelic variants of DRB1. OBJECTIVE: The purpose of this study was to investigate the frequencies of the polymorphisms in HLA-DRB1 gene in children and adolescents with type 1 AIH and type 1 AIH overlap syndrome with autoimmune cholangitis (overlap syndrome, OS) in comparison to healthy sex and age-matched individuals (control group). METHODS: This is a cross-sectional study of 25 pediatric patients diagnosed with type 1 AIH and 18 with OS. Fifty-seven healthy individuals were included as controls. The polymorphisms of the HLA-DRB1 gene were evaluated by PCR and included HLA-DRB1*03, HLA-DRB1*04, HLA-DRB1*07, and HLA-DRB1*13. RESULTS: Our results showed that the presence of the allele HLA-DRB1*13 increased the chance of autoimmune cholangitis (OR=3.96, CI 1.07 to 14.61, P=0.04). The HLA-DRB1*04 and HLA- DRB1*07 have no association with the AIH and autoimmune cholangitis in a young sample. CONCLUSION: This work demonstrates an association of the main polymorphisms in the HLA-DRB1 gene to AIH with or without cholangitis in a Brazilian sample.

RESUMO CONTEXTO: Hepatite autoimune (HAI) é uma doença hepática inflamatória crônica, rara, associada à perda da tolerância imunológica aos auto-antígenos. A susceptibilidade à HAI é parcialmente determinada pela presença de genes relacionados ao antígeno leucocitário humano (HLA), principalmente variantes alélicas do DRB1. OBJETIVO: O objetivo deste estudo foi investigar a frequência de polimorfismos no gene HLA-DRB1 em crianças e adolescentes com HAI tipo 1 e HAI tipo 1 associada à colangite autoimune, em comparação com indivíduos saudáveis pareados por sexo e idade (grupo controle). MÉTODOS: Este é um estudo transversal de 25 pacientes pediátricos com diagnóstico de HAI tipo 1 e 18 com HAI associada à colangite autoimune. Cinquenta e sete indivíduos saudáveis foram incluídos como controles. Os polimorfismos do gene HLA-DRB1 foram avaliados por PCR e incluíram HLA-DRB1*03, HLA-DRB1*04, HLA-DRB1*07 e HLA-DRB1*13. RESULTADOS: Nossos resultados mostraram que a presença do alelo HLA-DRB1*13 aumentou a chance de colangite autoimune (OR=3,96; IC 1,07 a 14,61; P=0,04). O HLA-DRB1*04 e o HLA-DRB1*07 não apresentam associação com a HAI e colangite autoimune no grupo de pacientes mais jovens. CONCLUSÃO: Este trabalho demonstra uma associação dos principais polimorfismos no gene HLA-DRB1 à HAI com ou sem colangite na população brasileira.

Association analysis between HLA-DRB1 alleles and pemphigus vulgaris in a Han population in Sichuan / 中华皮肤科杂志

Objective To investigate the association between HLA-DRB1 alleles and pemphigus vulgaris (PV) in a Han population in Sichuan.Methods Polymerase chain reaction with sequencespecific primer (PCR-SSP) method was used for low-resolution and high-resolution typing of HLA-DRB1 alleles in 19 patients of Han nationality with PV and 25 healthy controls in Sichuan.Allele frequencies were calculated,and differences in the allele frequency between the above two groups were compared by using chisquare test.Results Totally,9 kinds of DRB 1 low-resolution alleles and 19 kinds of DRB 1 high-resolution alleles were identified in the PV patients and healthy controls.Frequencies of the DRB1* 14 allele (39.47％[15/38] vs.8.00％[4/50],x2 =17.43,P ＜ 0.05) and DRB1*1405 allele (15.79％[6/38] vs.2.00％[1/50],x2 =4.25,P ＜ 0.05) were significantly higher in the PV patients than in the healthy controls.Conclusion The HLA-DRB1*14 allele may be a common susceptibility gene for PV in the Han population in Sichuan,and the HLA-DRB1* 1405 allele may be most closely associated with PV.

The role of KIR2DL3/HLA-C*0802 in Brazilian patients with rheumatoid vasculitis

OBJECTIVES: Rheumatoid arthritis is a polygenically controlled systemic autoimmune disease. Rheumatoid vasculitis is an important extra-articular phenotype of rheumatoid arthritis that can result in deep cutaneous ulcers. The objective of this study was to establish a correlation between the frequency of major histocompatibility complex class I/II alleles and killer immunoglobulin-like receptor genotypes in patients with cutaneous rheumatoid vasculitis. METHODS: Using the Scott & Bacon 1984 criteria to diagnose rheumatoid vasculitis and after excluding any other causes such as diabetes, atherosclerosis, adverse drug reactions, infection, and smoking, patients who met the criteria were selected. All of the selected rheumatoid vasculitis patients presented deep cutaneous ulcers. Identification of the major histocompatibility complex class I/II and killer immunoglobulin-like receptor genotypes was performed by polymerase chain reaction assays of samples collected from the 23 rheumatoid vasculitis patients as well as from 80 controls (40 non-rheumatoid vasculitis RA control patients and 40 healthy volunteers). RESULTS: An association between the presence of the HLA-DRB1*1402 and HLA-DRB1*0101 alleles and cutaneous lesions in rheumatoid vasculitis patients and a correlation between the inhibitor KIR2DL3 and the HLA-C*0802 ligand in rheumatoid vasculitis patients were found. CONCLUSION: An association was found between the presence of the HLA-DRB1*1402 and HLA-DRB1*0101 alleles and the development of cutaneous lesions in rheumatoid vasculitis patients. Additionally, the HLA-C*0802 ligand protects these individuals from developing cutaneous lesions. .

Interaction between HLA-DRB1 gene polymorphism and environmental risk factors in the development of gestational diabetes mellitus / 中华妇产科杂志

Objective To explore the interactions between human leukocyte antigen ( HLA)-DRB1 gene polymorphism and environmental risk factors in gestational diabetes mellitus ( GDM ) pathogenesis.Methods Pregnant women who had prenatal cares in Obstetric Department , West China Second Hospital of Sichuan University were recruited from January 1st to December 31st in 2011.A prospective cohort study was conducted in the women who had a glucose challenge test ( GCT) or 75 g oral glucose tolerance test ( OGTT) during 24-28 gestational weeks.A total of 104 women diagnosed with GDM were randomly included in GDM group while another 103 normal women fell into the control group.The HLA-DRB1 polymorphism was detected by Polymerase Chain Reaction -Sequence Specific Primers ( PCR-SSP) method in both groups.The interactions between HLA-DRB1 polymorphism and environmental risk factors were analyzed based on the simple-case-study method.Results ( 1 ) There were 712 pregnant women with complete perinatal information during January 1st to December 31st, 2011, among whom 175 (24.6%) women were diagnosed with GDM.A logistic regression analysis showed that advanced maternal age (OR=1.081, 95%CI:1.027-1.138), imbalanced diet (OR=3.329, 95%CI:2.167 -5.116), high body mass index (BMI≥24.0 kg/m2) before pregnancy (OR=1.095, 95%CI:1.008 -1.190), HBsAg carrier status (OR=3.173, 95%CI:1.387-7.260) and family history of diabetes mellitus (DM) (OR=1.798, 95%CI:1.063 -3.041) were risk factors of GDM.(2) There were 49 HLA-DRB1 genotypes and 51 HLA-DRB1 genotypes in GDM group and the control group , respectively.We further compared the genotypes that occurred in over 3 cases in either group and found that HLA-DRB1*12,16 was only detected in 5 cases (5/103, 4.9%) in control group,and the difference was significant between the two groups (P=0.029).HLA-DRB1*11,16 and HLA-DRB1*09,09 were only detected in 4 cases (3.8%,4/104) and 5 cases (4.8%, 5/104) in GDM group respectively , but without significant differences between the two groups ( P >0.05 ).No significant difference was found in other genotype frequencies between the two groups ( P>0.05 ).( 3 ) Thirteen types of HLA-DRB1 allele were detected but no significant differences were observed in their frequencies between two groups ( P>0.05).(4) A positive interaction was detected between HLA-DRB1*07 polymorphism and advanced maternal ages (OR=5.952, 95%CI:1.314-26.970, P=0.022), while no interaction was found between HLA-DRB polymorphisms to other risk factors such as imbalanced diet , high body mass index ( BMI≥24.0 kg/m2 ) , HBsAg carrier status or DM family history.Conclusions Advanced maternal age, unbalanced diet, high body mass index (BMI≥24.0 kg/m2), HBsAg carrier status and DM family history are environmental risk factors of GDM in Chengdu.While HLA-DRB1*12,16 genotype may be a protective genotype for GDM.There is a positive interaction between HLA-DRB1*07 polymorphism and advanced maternal age which may play a critic role in GDM development.

The correlation between human leukocyte antigen-DRB1 alleles and anti-neutrophil cytoplasmatic antibodies in Han and Uygur ulcerative colitis patients in Xinjiang region / 中华消化杂志

Objective To study the correlation between human leukocyte antigen (HLA)-DRB1 alleles and anti neutrophil cytoplasmatic antibodies (ANCA) in Han and Uygur ulcerative colitis (UC)patients in Xinjiang region.Methods The serum ANCA was determined by indirect immunofluorescence assay in 62 Uygur UC patients,58 Han UC patients,188 Uygur and 184 Han healthy control individuals.HLA-DRB1 typing was performed by polymerase chain reaction-sequence based typing (PCR-SBT).The allele frequency of HLA-DRB1 was compared in ANCA positive and negative Han and Uygur patients as well as healthy controls.Stratified analysis was performed according to UC clinical type,severity and involvement.SPSS 17.0 software was applied for x2 test.Once P＜0.05,the odds ratio (OR) and 95％ confidence intervals (95％CI) was calculated.Results The positive rate of ANCA in Uygur UC patients (53.2％,33/62) was significantly higher than that of Han patients (34.5％,20/58) and the difference was statistically significant (x2=4.269,P =0.045).In Uygur,the gene frequency of HLA-DRB1 * 13 in ANCA positive UC patients (0.202)was significantly higher than that of ANCA negative patients (0.017) (x2 =10.092,P=0.016,OR=16.000,95％CI:2.892 to 88.524) and healthy controls (0.075) (x2=9.351,P＝0.040,OR=3.407,95％CI:1.666 to 6.971).The gene frequency of HLA-DRB1 * 13 in ANCA positive pancolitis type UC patients (9/15) was significantly higher than that of ANCA negative pancolitis type UC patients (1/14) and the difference was statistically significant (x2=8.955,P =0.040,OR =19.500,95％CI:2.787 to 136.461).However,in Han patients,there were no significant differences of HLA-DRB1 alleles frequencies among ANCA positive patients,ANCA negative patients and healthy controls (all P＞0.05),and the results of stratified analysis were same.Conclusions In Uygur UC patients of Xinjiang region,HLA-DRB1 * 13 may correlated with ANCA and with ANCA of pancolitis type UC patients.There is no such correlation in Han patients of Xinjiang region.