Association Of HLA-DRB1 Alleles Research Articles

Association of HLA-DRB1 Alleles in Juvenile-onset Systemic Lupus Erythematosus (SLE) in Iranian Children

Introduction Systemic Lupus Erythematosus (SLE) is a complex autoimmune and inflammatory disease. Many studies show HLA alleles can be associated with SLE. The aim of this study was to determine the association of HLA-DRB1 alleles with juvenile- onset in Iranian children. Materials and Methods At a case – control study, 31 children with systemic lupus erythematosus (case group) who referred to Mofid Children’s Hospital, Shahid Behehsti University of Medical Sciences, Tehran, and 56 healthy children (control group) were participant. Genomic DNA was extracted and HLA typing was performed by Polymerase Chain Reaction (PCR) with Sequence - Specific Primers (SSP) technique. Results HLA- DRB1*01, HLA- DRB1*04, HLA- DRB1*11 and HLA- DRB1*13 were detected to as most frequent alleles associated with SLE in Iranian children. The frequency of HLA DRB1*08 was not significantly different in both groups (P>0.05(. HLA- DRB1*07 had a higher rate of repetition in the control group than patients with SLE. Conclusion There was a significant difference in the frequency of some alleles between patients and controls group, which could be related to susceptibility to SLE. These differences between frequencies of some alleles in both groups may help to determine the onset of lupus in children.

Associations of HLA DRB1 Alleles with Igg Oligoclonal Bands and Their Influence on Multiple Sclerosis Course and Disability Status

Background: Oligoclonal 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). Aim: To evaluate the importance of the associations between HLA DRB1 alleles and oligoclonal bands (OCB) in the multiple sclerosis (MS) patients disease course and disability. Metods: This 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 analysed using isoelectric focusing and IgG specific immunofixation to test for the presence of intrathecal specific OCB and compared directly with the serum samples. Results: HLA DRB1*08 allele be related to lower degree of disability, while the other HLA DRB1 alleles irrespective of the presence or absence of OCBs did not influence disability status. Oligoclonal bands were an indepedent and significant factor that influenced disability status irrespective of HLA DRB1* 04, *07, *08, *, *13, *15 and *16 alleles. Age at the onset of the first symptoms 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. In the model with *08 allele immunological factors had no impact on MS progression. Detection of OCBs in the CF was associated with the higher possibility of RR MS progression in all cases, except then the *08 allele was present. Conclusions: OCBs 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

The association of HLA-DRB1 alleles and drug use with HIV infection in a Chinese Han Cohort

ObjectiveTo investigate the relationship between the polymorphism of human leukocyte antigen (HLA)-DRB1 and the susceptibility and repellency of drug use combined with HIV infection in Chinese. MethodsA total of 213 unrelated healthy people, 41 HIV-infected drug users, 24 HIV-uninfected drug users, and 64 HIV-infected non-drug users were recruited. Their HLA-DRB1 allele frequencies were analyzed by PCR-SSP and allele distribution was analyzed. ResultsCompared with healthy controls, in drug users, the frequencies of HLA-DRB1 *0401-041, *1001 were significantly higher; in HIV-infected patients, the frequencies of HLA-DRB1 *0101-0103, *0401-0411, *1001 were significantly higher, while the frequencies of DRB1 *1501-1502, *1101-1105, *1301-1302, DRB4, DRB5 were significantly lower; in HIV-infected drug users, the frequencies of HLA-DRB1 *0101-0103, *0401-0411, *0801-0806, *1001, *1401/1404/1405 were significantly higher, while the frequencies of DRB1 *1301/1302, 1501-1502, DRB5 were significantly lower. ConclusionThere is close relationship between the polymorphism of HLA-DRB1 alleles and drug use with HIV infection, which plays an important role in elucidating the pathogenesis and providing the basis for therapeutics and prophylaxis of patients with drug use and HIV infection.

The importance of HLA DRB1 gene allele to clinical features and disability in patients with multiple sclerosis in Lithuania.

BackgroundThe association of HLA DRB1 alleles with susceptibility to multiple sclerosis (MS) has been consistently reported although its effect on the clinical features and disability is still unclear probably due to diversity in ethnicity and geographic location of the studied populations. The aim of the present study was to investigate the influence of HLA DRB1 alleles on the clinical features and disability of the patients with MS in Lithuania.MethodsThis was a prospective study of 120 patients with MS. HLA DRB1 alleles were genotyped using the polymerase chain reaction.ResultsThe first symptoms of MS in patients with HLA DRB1*15 allele manifested at younger age than in those without this allele (28.32 +/− 5.49 yrs vs. 30.94 +/− 8.43 yrs, respectively, p = 0.043). HLA DRB1*08 allele was more prevalent among relapsing-remitting (RR) MS patients than among patients with progressive course of MS (25.0% vs. 8.3%, respectively, chi^2 = 6.000, p = 0.05). MS patients with this allele had lower relapse rate than those without this allele (1.00 +/− 0.97 and 1.44 +/− 0.85, respectively, p = 0.043). Degree of disability during the last visit was lower among the patients with HLA DRB1*08 allele (EDSS score 3.15 +/− 1.95 vs. 4.49 +/− 1.96, p = 0.006), and higher among those with HLA DRB1*15 allele (EDSS score 4.60 +/− 2.10 vs.4.05 +/− 1.94, p = 0.047) compared to patients without these alleles but there were no significant associations between these alleles and the duration of the disease to disability. HLA DRB1*08 allele (OR = 0.18, 95% CI 0,039-0,8, p = 0.029) was demonstradet to be independent factor to take a longer time to reach an EDSS of 6, while HLA DRB1*01 allele (OR = 5.92, 95% CI 1,30-26,8, p = 0.021) was related in a shorter time to reach and EDSS of 6. Patients with HLA DRB1*08 allele had lower IgG index compared to patients without this allele (0.58 +/− 0.17 and 0.73 +/− 0.31, respectively, p = 0.04), and HLA DRB1*15 allele was more often found among MS patients with oligoclonal bands (OCBs) in cerebrospinal fluid than among those without OCBs (OR 2.3, CI 95% 1.017-5.301; p = 0.043).ConclusionsHLA DRB1*15 allele was related with an earlier manifestation of the first MS symptoms, progressive course of the disease and higher degree of disability. HLA DRB1*08 allele was more prevalent among the RR MS patients and was associated with the lower rate of relapse, degree of disability and IgG index.

Associação do alelo HLA-DRB1 com suscetibilidade a artrite reumatoide e gravidade da doença na Síria

INTRODUCAO: A artrite reumatoide (AR) e uma doenca cronica multifatorial complexa. A importância do sistema de antigenos leucocitarios humanos (HLA) como fator significativo de risco genetico para AR foi estudada no mundo. Embora amplamente distribuidos em diferentes areas na Siria, faltam estudos sobre o papel dos HLA. OBJETIVO: O objetivo de nosso estudo foi determinar a associacao dos alelos HLA-DRB1 com a suscetibilidade a AR e sua gravidade na Siria. PACIENTES E METODOS: Foram genotipados 86 pacientes com AR e 200 controles normais, usando-se reacao em cadeia da polimerase com sequencia de primer especifico (PCR-SSP). Anticorpos anti-CCP foram determinados por ELISA. Fator reumatoide (FR), proteina C-reativa (PCR), velocidade de hemossedimentacao (VHS) e o indice de atividade da doenca (DAS-28) foram obtidos nos registros medicos e utilizados para avaliar a gravidade clinica dos pacientes. RESULTADOS: Os alelos HLA-DRB1 *01, *04 e *10 mostraram forte associacao com suscetibilidade a doenca (OR = 2,29, IC 95% = 1,11-4,75, P = 0,022; OR = 3,16, IC 95% = 2,08-4,8, P < 0,0001; e OR = 2,43, IC 95% = 1,07-5,51, P = 0,029, respectivamente), enquanto a frequencia dos alelos HLA-DRB1 *11 e *13 foi significativamente mais baixa nos pacientes com AR do que nos controles (OR = 0,49, IC 95% = 0,3-0,8, P = 0,004; OR = 0,32, IC 95% = 0,15-0,69, P = 0,002, respectivamente). Os outros alelos HLA-DRB1 mostraram diferenca significativa. A frequencia dos anticorpos anti-CCP foi maior em pacientes epitopo compartilhado (EC) positivos do que em pacientes EC-negativos (OR = 5,5, IC 95% = 2-15,1, P = 0,00054). O indice DAS-28 de pacientes com AR nao mostrou diferenca significativa entre os grupos EC-negativo e EC-positivo. CONCLUSAO: Nossos resultados indicam que os alelos HLA-DRB1 *01, *04 e *10 estao relacionados com AR, enquanto os alelos HLA-DRB1 *11 e *13 protegem a populacao siria contra a AR.

HLA-DRB1 allele association with rheumatoid arthritis susceptibility and severity in Syria

IntroductionRheumatoid arthritis (RA) is a complex multifactorial chronic disease. The importance of human leukocyte antigen as a major genetic risk factor for RA was studied worldwide. Although it is widely distributed in different Syrian areas, studies of human leukocyte antigen (HLA) alleles’ role are absent. ObjectiveThe aim of our study was to determine the association of HLA-DRB1 alleles with the susceptibility and severity of RA in Syria. Patients and methodsEightysix RA patients and 200 healthy controls from Syria were genotyped using polymerase chain reaction with sequencespecific primer (PCR-SSP). Anti-CCP antibodies were measured by ELISA. Rheumatoid factor (RF), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and disease activity score 28 (DAS-28) values were obtained from patients’ medical records. DAS-28 was used to assess the clinical severity of the patients. ResultsThe HLA-DRB1*01, *04, and *10 frequencies showed a strong association with the disease susceptibility (OR=2.29, 95% CI=1.11–4.75, P=0.022; OR=3.16, 95% CI=2.08–4.8, P<0.0001; OR=2.43, 95% CI=1.07–5.51, P=0.029 respectively), while the frequencies of HLA-DRB1*11, and *13 were significantly lower in RA patients than in controls (OR=0.49, 95% CI=0.3–0.8, P=0.004; OR=0.32, 95% CI=0.15–0.69, P=0.002, respectively). The other HLA-DRB1 alleles showed no significant difference. The frequency of anti-CCP antibodies was higher in shared epitope (SE) positive patients compared with SE-negative patients (OR=5.5, 95% CI=2–15.1, P=0.00054). DAS-28 of RA patients didn’t show significant difference between the SE negative and the SE positive groups. ConclusionOur results indicate that HLA-DRB1*01, *04, and *10 alleles are related with RA, while HLA-DRB1*11 and *13 protect against RA in the Syrian population.

Association of HLA-DRB1 alleles and neuropsychological function in autism

Evidence suggests an association between autism and immune dysfunction. The associations between human lymphocyte antigen (HLA)-A2, B44, DRβ1*04 (DR4), C4B, and haplotype B44-SC30-DR4 and autism have been reported in western countries but there is a lack of such information in Asian population. This study aimed to assess the association between HLA-DRB1 allele frequencies and the clinical phenomenology of autism. The sample included 141 participants (male, 87.2%), who were diagnosed with autistic disorder based on clinical assessments and structured interviews using the Chinese version of the Autism Diagnostic Interview-Revised, and 156 healthy controls (male, 38.6%). The HLA-DRB1 alleles were determined by sequencing-based typing method. A subsample of patients (n=39) were assessed for intelligence and neuropsychological functions. The results showed that the pattern of DRB1 allele frequencies was significantly different between patients with autism and the controls (P=0.047). After adjusting for sex by haplotype regression, the frequencies of DR4, DR11, and DR14 were significantly different between patients with autism and healthy controls. In addition, patients with autism and DR4, DR11, or DR14 had different performance on intelligence and neuropsychology tests. Despite a relatively small sample size and a case-control association design, the findings suggest HLA-DRB1 gene might be associated with autism in Han Chinese. The true functional variants associated with autism in our samples remain to be further clarified. It warrants a replication study of a larger family sample and to validate the HLA genetic association with autism and its influence on neuropsychological function.

Genetic Susceptibility to Juvenile Idiopathic Arthritis in Iranian Children

This study was comprised of Iranian children with oligoarthritis and rheumatoid factor negative (RF) polyarthritis subtypes of juvenile idiopathic arthritis (JIA) to determine the association of HLA-DRB1 alleles in Iran. HLA-DRB1 alleles were investigated in 33 Iranian children with oligoarthritis and RF negative polyarthritis JIA and compared with 45 healthy controls. HLA typing was performed by PCR with sequence specific primers in either of the two groups and followed by direct detection of HLA polymorphism by sequence analysis in patient group. HLA-DRB1*11 was found to be the most frequent allele associated with oligoarthritis and RF negative polyarthritis JIA in Iran followed by HLA-DRB1*8. The frequencies of HLA-DRB1*04 and *13 were not significantly different in both groups. We concluded that there was a significant difference in allele frequencies between patients and control group that may help in predicting the susceptibility to oligoarthritis and rheumatic factor negative polyarthritis JIA.

Associations of HLA-DRB1 alleles with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in northern east part of Turkey

The aim of this study was to investigate the associations between human leukocyte antigen (HLA)-DRB1 alleles with genetic susceptibility to rheumatoid arthritis (RA) and production of antibodies against cyclic citrullinated peptide (anti-CCP antibody) and rheumatoid factor (RF) in Turkish RA patients. We studied 291 RA patients and 253 controls. Genotyping was performed by polymerase chain reaction with sequence-specific oligonucleotide probes hybridization method. Serum levels of anti-CCP antibody, IgM-RF and high sensitive C-reactive protein titers were measured by commercial kits using immunological methods. We found that HLA-DRB1*04 and *09 alleles were associated in anti-CCP+ and anti-CCP+ RA patients (P < 0.0001 and P < 0.001, respectively), while DRB1*01 and *04 were determined to be higher in RF+ RA patients (P < 0.001 and P < 0.0001, respectively). Moreover, DRB1*11 and DRB1*13 alleles were determined to be lower in RF and anti-CCP/RF+ RA patients (P < 0.001 for both). HLA-DRB1*04 was identified as a common responsible allele for susceptibility to the disease in anti-CCP, RF and anti-CCP/RF- RA patients (P = 0.0018, P = 0.0004 and P = 0.0023, respectively). HLA-DRB1*13 allele alone was found to be protective against to anti-CCP+ and RF- RA (P = 0.0003 and P = 0.006, respectively). On the contrary, there was no protective allele in anti-CCP/RF- RA as well as anti-CCP- RA patients. This study indicates that associate and protective HLA-DRB1 allele distributions are different in autoantibody (anti-CCP or RF or anti-CCP/RF)+ RA and autoantibody- RA patients, with exceptions of DRB1*04 and DRB1*13.

Peptides Presented by HLA-DR Molecules in Synovia of Patients with Rheumatoid Arthritis or Antibiotic-Refractory Lyme Arthritis

Disease-associated HLA-DR molecules, which may present autoantigens, constitute the greatest genetic risk factor for rheumatoid arthritis (RA) and antibiotic-refractory Lyme arthritis (LA). The peptides presented by HLA-DR molecules in synovia have not previously been defined. Using tandem mass spectrometry, rigorous database searches, and manual spectral interpretation, we identified 1,427 HLA-DR-presented peptides (220-464 per patient) from the synovia of four patients, two diagnosed with RA and two diagnosed with LA. The peptides were derived from 166 source proteins, including a wide range of intracellular and plasma proteins. A few epitopes were found only in RA or LA patients. However, two patients with different diseases who had the same HLA allele had the largest number of epitopes in common. In one RA patient, peptides were identified as originating from source proteins that have been reported to undergo citrullination under other circumstances, yet neither this post-translational modification nor anti-cyclic citrullinated peptide antibodies were detected. Instead, peptides with the post-translational modification of S-cysteinylation were identified. We conclude that a wide range of proteins enter the HLA-DR pathway of antigen-presenting cells in the patients' synovial tissue, and their HLA-DR genotype, not the disease type, appears to be the primary determinant of their HLA-DR-peptide repertoire. New insights into the naturally presented HLA-DR epitope repertoire in target tissues may allow the identification of pathogenic T cell epitopes, and this could lead to innovative therapeutic interventions.

The association of HLA-DRB1 alleles with antineutrophil cytoplasmic antibody-associated systemic vasculitis in Chinese patients

Antineutrophil cytoplasmic antibody (ANCA)–associated systemic vasculitis (AASV) is a group of autoimmune diseases. The human leukocyte antigen (HLA) system is devoted to the pathogenesis of these autoimmune diseases. The present study aimed to investigate the distribution of HLA-DRB1 alleles in Chinese AASV patients and its potential association with clinical and pathologic characteristics. This study included 152 Chinese patients with AASV and 200 healthy controls. Typing of HLA-DRB1 alleles was performed by bidirectional sequencing of exon 2. Compared with normal controls, DRB1*1454 was significantly less prevalent in AASV patients (0/304 vs 14/400, p = 4.6 × 10 −4, p corrected ( p c) = 0.017), whereas DRB1*1101 was significantly more frequent in patients with MPA (32/214 vs 26/400, p = 6.4 × 10 −4, p c = 0.023). In patients with Wegener's granulomatosis (WG) who were PR3-ANCA positive, DRB1*1202 (8/38 vs 20/400, p = 1.3 × 10 −3, p c = 0.047) was more prevalent than in normal controls. Compared with normal controls, HLA-DRB1*1454 was less prevalent in AASV patients, whereas DRB1*1101 was significantly more frequent in patients with microscopic polyangiitis. HLA-DRB1*1202 was prevalent among patients with PR3-ANCA-positive WG.

Association of HLA-DRB1 alleles with keloids in Chinese Han individuals

Keloids are common abnormal raised fibroproliferative lesions that can occur following even minor cutaneous trauma. There is strong evidence suggesting a genetic susceptibility in individuals affected by keloids including familial heritability, common occurrence in twins, and high prevalence in certain ethnic populations. Human leukocyte antigens (HLAs) have been proposed to modulate the immune response to keloids. HLA class II molecules are critical to the development of CD4(+) T-lymphocyte responses through their role in antigen presentation. No report has been published on HLA-DRB1 association with keloids in Chinese Han individuals. To investigate the etiology of keloids, the polymerase chain reaction sequence-specific primer method was used to analyze the distribution of HLA-DRB1 alleles in 192 patients with keloids and 273 healthy control individuals. Controls were matched by sex, age, and race. The HLA-DRB1*15 allele [19.01% vs 12.09%, odds ratio(OR) = 2.10, Pc = 0.024] was significantly more prevalent among keloid patients than healthy controls, whereas the frequency of the HLA-DRB1*03 allele (1.04% vs 4.95%, OR = 0.19, Pc = 0.022) was lower among keloid patients. Furthermore, through stratified analysis, we found that the HLA-DRB1*15 allele is related to the multiple-site group, severe group, and family history of keloids. This study supports an association between HLA-DRB1 alleles and susceptibility or resistance to keloids in Chinese Han individuals. The association of certain HLA alleles with susceptibility or resistance to keloids provides clues to choosing proper preventive strategies against keloid disease.

HLA in Portuguese Systemic Lupus Erythematosus Patients and Their Relation to Clinical Features

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease translating the different genetic and environmental factors involved. Polymorphisms at several loci, including the major histocompatibility complex (MHC), have been associated worldwide with SLE, although inconsistencies exist among these studies mainly due to genetic heterogeneity between populations and sample characteristics. The aim of the present study was to investigate in Portuguese SLE the association of HLA-DRB1 alleles with clinical patterns of the disease and severity. Two hundred eighteen Portuguese patients with SLE--42% of whom had kidney involvement--were studied for HLA-DRB1. Clinical and laboratory manifestations were correlated with HLA allele frequencies. HLA-DRB1 * 03 allele frequency was significantly higher in SLE patients--as a whole and as either with or without renal involvement--compared to controls, while HLA-DRB1 * 09 and DRB1 * 13 allele frequencies were decreased. Regarding the relationship with the presence or absence of specific clinical manifestations, it was only found that HLA-DRB1 * 08 allele frequency was increased in patients with neurological involvement. No association with the presence or absence of anti-dsDNA, anti-sm or antiphospholipid antibodies, or antiphospholipid syndrome, was observed. These results were reproducible when analysis was repeated only with patients with more than 5 years of evolution. As in other populations HLA-DRB1 * 03 is a susceptibility allele in Portuguese SLE patients, while HLA-DRB1 * 09 and DRB1 * 13 alleles may be protective alleles, not only for the disease, but for the development of nephritis. No correlations with the different clinical manifestations were found, except with the neurological system.

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

The association of HLA-DRB1 alleles with anti-citrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA) suggests the potential involvement of T lymphocytes in ACPA-seropositive disease. The purpose of this study was to investigate this hypothesis by systematic histologic and molecular analyses of synovial T cells in ACPA+ versus ACPA- RA patients. Synovial biopsy samples were obtained from 158 RA patients. Inflammation was determined histologically and immunohistochemically. RNA was extracted from peripheral blood mononuclear cells and synovial tissues obtained from 11 ACPA+ RA patients, 7 ACPA- RA patients, and 10 spondylarthritis (SpA) patients (arthritis controls). T lymphocyte clonality was studied by combined quantitative and qualitative T cell receptor CDR3 length distribution (LD) analysis and direct sequencing analysis. ACPA+ and ACPA- RA patients were similar at both the clinical and histologic levels. At the molecular level, however, patients with ACPA+ synovitis displayed a marked elevation of qualitative CDR3 LD alterations as compared with those with ACPA- synovitis and with the SpA controls. These differences in CDR3 LD were not observed in the peripheral blood, indicating a selective recruitment and/or local expansion of T cells in the synovial compartment. The CDR3 LD alterations reflected true monoclonal or oligoclonal expansions, as confirmed by direct sequencing of the T cell receptor. The CDR3 LD alterations in RA synovium did not correlate with B cell clonal expansions but were inversely associated with synovial lymphoid neogenesis. The T cell repertoire is specifically restricted in RA patients with ACPA+ synovitis. Whereas the origin and role of these clonal alterations remain to be determined, our data suggest the preferential involvement of T lymphocytes in ACPA-seropositive RA.

Molecular analysis of HLA-DRB1 allelic associations with systemic lupus erythematous and lupus nephritis in Taiwan

To evaluate the association of human leukocyte antigen (HLA)-DRB1 alleles with systemic lupus erythematosus (SLE) and lupus nephritis (LN) in the Taiwanese population, and to investigate the possible association of HLA-DRB1 alleles with disease severity in LN. HLA-DRB1 alleles were studied in 105 SLE patients (82 patients with LN, 23 patients without LN) and 855 healthy controls by polymerase chain reaction and sequence-based typing assays. The frequency of the HLA class II alleles DRB1*0301 (Odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.31-3.10, Pc = 0.02) and DRB1*1501 (OR = 2.06, 95% CI = 1.36-3.13, Pc = 0.01) were both increased in SLE patients, compared to healthy controls. The frequency of DRB1*1202 was significantly lower in LN patients than in SLE patients without nephritis (OR = 0.23, 95% CI = 0.09-0.57, Pc = 0.01). No specific allele was significantly associated with an increased or decreased risk for severity of LN in this sample. In Taiwanese people, the DRB1*0301 and DRB1*1501 alleles are significant risk factors for SLE, while the DRB1*1202 allele is protective for LN.

Association of DRB1 shared epitope genotypes with early mortality in rheumatoid arthritis: Results of eighteen years of followup from the early rheumatoid arthritis study

To determine whether the HLA-DRB1 shared epitope (SE) is associated with early mortality and specific causes of death in rheumatoid arthritis (RA). HLA-DRB1 genotyping was carried out on blood samples from 767 patients recruited for the Early RA Study (ERAS), a multicenter, inception cohort study with followup over 18 years. Dates and causes of death (n = 186) were obtained from the Office of National Statistics. The association of HLA-DRB1 alleles with risk of mortality was assessed using Cox proportional hazards regression analyses. Multivariate stepwise models were used to assess the predictive value of HLA-DRB1 genotypes compared with other potential baseline risk factors. The SE was not significantly associated with overall mortality. However, the presence of 2 SE alleles was associated with risk of mortality from ischemic heart disease (hazard ratio [HR] 2.02 [95% confidence interval 1.04-3.94], P = 0.04), and malignancy (HR 2.18 [95% confidence interval 1.17-4.08], P = 0.01). Analysis of specific SE genotypes (corrected for age and sex) revealed that the HLA-DRB1*0101/*0401 and 0404/*0404 genotypes were the strongest predictors of mortality from ischemic heart disease (HR 5.11 and HR 7.55, respectively), and DRB1*0101/*0401 showed a possible interaction with smoking. Male sex, erythrocyte sedimentation rate, and Carstairs Deprivation Index were also predictive, but the Health Assessment Questionnaire score, rheumatoid factor, nodules, and swollen joint counts were not. Mortality due to malignancy was particularly associated with DRB1*0101 genotypes. The risk of mortality due to ischemic heart disease or cancer in RA is increased in patients carrying HLA-DRB1 genotypes with particular homozygous and compound heterozygous SE combinations.

The association of HLA-DRB1 alleles with rheumatoid arthritis in the Chinese Shantou population: a follow-up studyThis paper is one of a selection of papers in this Special Issue, entitled International Symposium on Recent Advances in Molecular, Clinical, and Social Medicine, and has undergone the Journal's usual peer-review process.

We investigated the distribution of HLA-DRB1 alleles in a sample of the Chinese Shantou population, and explored the relationship between HLA-DRB1 alleles and the susceptibility and clinical features of rheumatoid arthritis (RA). We studied 117 consecutive patients with RA and control groups, including 38 cases of systemic lupus erythematosus and 100 healthy individuals. HLA-DRB1 genotyping was performed using PCR with sequence-specific primers. HLA-DRB1*04 subtypes were detected using spot hybridization of PCR products with sequence-specific oligonucleotide probes. We compared the frequency of HLA-DRB1 alleles in healthy control patients with that in patients with RA. Patients with RA were evaluated for sex, age at disease onset, disease duration, extra-articular involvement, presence of autoantibodies, global functional status, and radiographic damage. The frequency of HLA-DRB1*04 was found to be significantly higher in RA patients than in healthy individuals (49.6% vs 18.0%, odds ratio = 4.478, P < 0.001). HLA-DRB1*0405 was the most prominently associated subtype in RA patients (62.1% vs 27.8%, odds ratio = 4.255, P = 0.011). Compared with the HLA-DRB1*04-negative RA group, the mean duration of RA in the HLA-DRB1*04-positive RA group was longer, and the mean age at disease onset was lower. A 2-9 year follow-up study was performed, and the risk factors associated with the radiographic progression of RA were determined. Logistic regression analysis revealed that only HLA-DRB1*04 alleles were significantly associated with the radiographic progression of RA (B = 2.652, P = 0.018, Exp(B) = 14.182). Our observations indicated that the HLA-DRB1*04 alleles, especially the subtype HLA-DRB1*0405, were significantly associated with RA susceptibility in the Chinese Shantou population. The HLA-DRB1*04 alleles may be associated with the severity of RA.

Association of HLA-DR3 and HLA-DR4 with sinonasal polyposis in Mexican Mestizos

The pathogenesis of sinonasal polyposis (SNP) is not clear; it has been suggested that it is polygenic and multifactorial. The major histocompatibility complex is a useful tool to predict genetic susceptibility to diseases, especially to autoimmune diseases. Since such susceptibility is influenced by ethnicity, it is necessary to have a wide knowledge of the structure of the population to which the patient belongs. The purpose of the study was to determine the association of HLA-DRB1 alleles with sinonasal polyposis in the Mexican Mestizo population. We studied the HLA-DR alleles in 34 adult Mexican Mestizo patients with SNP and compared them to those present in 99 healthy controls. Genomic DNA from mononuclear cells was obtained by using the "salting out" technique and high-resolution DNA typing of the HLA-DRB1 alleles was performed after PCR amplification. We found a statistically significant increased frequency of the HLA-DRB1*03 allele (P = 0.03, odds ratio [OR] = 2.9, 95% confidence interval [CI]: 1.0-7.8) and of the HLA-DRB1*04 allele (P = 0.009, OR = 2.2, 95% CI: 1.2-4.2) in patients with SNP as compared to controls, and a statistically significant decreased frequency of the HLA-DRB1*08 allele (P = 0.01, OR = 0.2, 95% CI: 0.05-0.8). The HLA-DR locus seems to be associated with the genetic susceptibility to develop SNP in Mexicans. B-2b.

Association of HLA-DRB1*13 with susceptibility to uveitis in juvenile idiopathic arthritis in two independent data sets

Juvenile idiopathic arthritis (JIA) is the commonest rheumatic disease of childhood. Uveitis is the commonest eye complication of JIA, potentially leading to eye surgery and/or visual loss. JIA is a complex genetic trait with well-established HLA-DRB1 associations. The aim of this study was to investigate the involvement of HLA-DRB1 in JIA-associated uveitis. A set of 130 UK Caucasian simplex families consisting of healthy parent(s) and a child affected with juvenile oligoarticular idiopathic arthritis (of which 31 had developed uveitis) had previously been screened for multiple markers in the major histocompatibility complex region. Associations with uveitis were investigated through haplotype pattern mining (HPM) and the extended transmission disequilibrium test (ETDT). A further set of 228 UK Caucasian patients with long-standing JIA were fully genotyped for HLA-DRB1 using PCR with sequence-specific primers. Associations of HLA-DRB1 alleles in patients with uveitis (n = 50) were examined individually using the chi 2 test. In the first cohort, HPM identified significant associations of HLA-DRB1*13 with uveitis in juvenile oligoarthritis (P = 0.002). The ETDT confirmed overtransmission of this allele in the families (empirical global P = 0.018). In the second cohort, the significant association of uveitis with HLA-DRB1*13 was replicated (P = 0.0002, odds ratio 3.4, 95% confidence interval 1.7-6.5). This study has established the HLA-DRB1*13 association with uveitis in JIA. Further work is necessary in order to explore the prognostic potential of this marker.

HLA-DRB1 Alleles May Influence Disease Phenotype in Patients With Inflammatory Bowel Disease: A Critical Reappraisal With Review of the Literature

The HLA region has been implicated in determining the disease susceptibility or the clinical phenotype of inflammatory bowel disease. The aim of this study was to assess the relation between HLA-DRB1 alleles with the clinical features of Crohn's disease and ulcerative colitis and the presence of anti-neutrophil cytoplasmic and anti-Saccharomyces cerevisiae antibodies. Blood samples were obtained from 102 Crohn's disease patients, 114 ulcerative colitis patients, and 264 unrelated healthy controls. Anti-neutrophil cytoplasmics were detected by a standard immunofluorescence method, and anti-Saccharomyces cerevisiaes were examined by an enzyme-linked immunosorbent assay immunoglobulin G/immunoglobulin A commercial assay. HLA-DRB1 typing of 26 alleles was performed by polymerase chain reaction sequence-specific primes. Patients were phenotyped according to gender, disease location, extent, and behavior, surgical resection, need of steroid, and anti-neutrophil cytoplasmic/anti-Saccharomyces cerevisiae status. As a whole, after applying Bonferroni's correction for multiple comparisons, no significant association of HLA-DRB1 alleles with Crohn's disease or ulcerative colitis was found. After stratifying HLA-DRB1 alleles by clinical phenotypes of patients with ulcerative colitis, an excess of DRB1*1309*1320*1325*1329 allele (DR13) was found in conjunction with pancolitis (P < 0.0001), surgical resection (P < 0.0003), and extraintestinal manifestations (P < 0.0001). In Crohn's disease patients, an excess of DRB1*0304*0305*0307*0309 allele (DR3) was found in those with colonic disease (P < 0.0001) and patients with extraintestinal manifestations (P = 0.0003). This statistical association, however, emerged in only 3 of 114 patients with ulcerative colitis and in 3 of 102 patients with Crohn's disease. We found no association with the presence of anti-Saccharomyces cerevisiae or anti-neutrophil cytoplasmic. Some clinical features of Crohn's disease and ulcerative colitis may be influenced by specific HLA-DR alleles; in particular, in ulcerative colitis some alleles appear to segregate with more aggressive disease, whereas in Crohn's disease different alleles cosegregate in patients with colonic disease and extraintestinal manifestations.