Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus

Susceptibility to systemic lupus erythematosus is associated with major histocompatibility complex (MHC)--encoded genes. We have used nucleotide sequence analysis to better define the disease-associated MHC alleles. HLA-DR2, DQw1, and especially the rare allele DQ beta 1. AZH confer high relative risk (RR = 14) for lupus nephritis in a Caucasian population of patients. Pilot studies using historical controls suggest that these genes also confer a high risk in non-Caucasian ethnic groups (RR = 24-78). We have found that DR4 is significantly decreased in patients with lupus nephritis. Fifty percent of the patients with lupus nephritis had either the DQ beta 1.1, the DQ beta 1.AZH, or the DQ beta 1.9 alleles. These alleles share amino acid residues that have been predicted to be the contact points for antigen and the T cell receptor. These HLA alleles appear to have a direct role in the predisposition to lupus nephritis, whereas DR4 may have a "protective" effect.     

Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus in southern chinese

Objective. To investigate the predisposing role of major histocompatibility complex (MHC) genes to systemic lupus erythematosus (SLE) in a Chinese population. Methods. Polymorphism in the HLA-DRB, DQB, complement component C4, and 21-hydroxylase genes was analyzed by restriction fragment length polymorphism analysis and oligonucleotide probing of in vitro-amplified DNA from 88 Chinese patients with SLE and 69 matched control subjects. Results. HLA-DRw15 and DQw1 were significantly more frequent in patients (corrected P < 0.006, relative risk 5.2), but none of the 9 sequence variants of DQw1 were increased. The C4A gene deletion usually associated with SLE in Caucasoid and black patients was absent from all Chinese subjects, but possession of other C4 deletions and of DRw15 conferred the greatest risk (relative risk = 8.3). Conclusion. Different MHC haplotypes predispose to lupus in Chinese than in other ethnic groups. Our data suggest that the susceptibility lies at, or telomeric to, the DR locus, and that DRw15 and C4 deletions may act synergistically in conferring disease susceptibility.     

TNF-308A and HLA-DR3 alleles contribute independently to susceptibility to systemic lupus erythematosus

OBJECTIVE: To evaluate the respective contributions of tumor necrosis factor (TNF) promoter polymorphisms and HLA-DR alleles to susceptibility to systemic lupus erythematosus (SLE). METHODS: TNF-238G/A and 308G/A promoter polymorphisms and HLA-DRB1 alleles were determined in 99 consecutive Caucasian SLE patients and 177 Caucasian controls. Standard and Mantel-Haenszel odds ratios were calculated to assess the magnitude of the susceptibility factors. The presence or absence of the SLE classification criteria was determined and correlated with the TNF promoter and HLA-DRB1 genotypes. RESULTS: The frequency of the TNF-308A/A and 308G/A genotypes was significantly higher in SLE patients (odds ratio 5.0). Conversely, TNF-238G/A and 238A/A genotypes were equally prevalent in SLE patients and controls. The HLA-DR3 specificity (DRBI*0301 allele) was significantly more prevalent in the SLE population (odds ratio 4.4). Stratification to correct for interdependence of the 2 loci confirmed the association of both TNF-308A and HLA-DR3 with SLE (Mantel-Haenszel odds ratio 3.2 and 2.4, respectively). No correlation was found between TNF promoter and HLA-DRB1 genotypes and any SLE classification criterion or disease manifestation. CONCLUSION: TNF-308A and HLA-DR3 alleles are independent susceptibility factors for SLE.     

Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus in southern Chinese.

OBJECTIVE. To investigate the predisposing role of major histocompatibility complex (MHC) genes to systemic lupus erythematosus (SLE) in a Chinese population. METHODS. Polymorphism in the HLA-DRB, DQB, complement component C4, and 21-hydroxylase genes was analyzed by restriction fragment length polymorphism analysis and oligonucleotide probing of in vitro-amplified DNA from 88 Chinese patients with SLE and 69 matched control subjects. RESULTS. HLA-DRw15 and DQw1 were significantly more frequent in patients (corrected P less than 0.006, relative risk 5.2), but none of the 9 sequence variants of DQw1 were increased. The C4A gene deletion usually associated with SLE in Caucasoid and black patients was absent from all Chinese subjects, but possession of other C4 deletions and of DRw15 conferred the greatest risk (relative risk = 8.3). CONCLUSION. Different MHC haplotypes predispose to lupus in Chinese than in other ethnic groups. Our data suggest that the susceptibility lies at, or telomeric to, the DR locus, and that DRw15 and C4 deletions may act synergistically in conferring disease susceptibility.     

Strong association between the major histocompatibility complex and systemic lupus erythematosus in southern Chinese

The distribution of HLA-A, B, and DR alleles has been studied in 100 Chinese patients with systemic lupus erythematosus and in 100 healthy Chinese controls. Complement components factor B, C4A and C4B were studied in 72 patients and 61 controls. There was no significant difference between patients and controls in the distribution of HLA-A, HLA-B, factor B and C4B alleles, but there was a significant excess of HLA-DR2 and C4A null in the patients. An unusual variant of C4B was found in 6 patients and 1 control. The possible role of haplotypes is considered in interpreting these results and relating them to previous findings in Chinese.     

HLA-DRB1 and -DQB1 alleles and gene polymorphisms of selected cytokines in systemic lupus erythematosus

Objective The objective of this study was to evaluate the genetic profiles of selected cytokines (transforming growth factor beta 1, tumor necrosis factor alpha, interleukin-6, interferon gamma, and interleukin-10) in systemic lupus erythematosus and the contributions of human leukocyte antigen (HLA)-DRB1 and -DQB1 alleles to susceptibility for this disease.Patients and methods The study was carried out in 24 SLE patients and 36 healthy controls (from Upper Silesia) using polymerase chain reaction methods. All persons were of Caucasoid origin. Standard association analysis was used to compare the HLA alleles and frequency of cytokine gene polymorphisms between these groups.Results Only the frequency of HLA-DRB1*07 allele was higher in SLE patients than controls (odds ratio 2.92, 95% confidence interval 1.16–7.33), but the difference did not reach statistical significance when Bonferronis adjustment procedure was performed. No other significant associations were noted between class II alleles (DR1-DR6, DR8-DR10, DQ1-DQ4) and SLE. The frequency of the interleukin-6 GG and GC genotypes was significantly higher in SLE patients than in controls, and a significantly higher percentage of the G vs C alleles between patients and controls was revealed (odds ratio 2.53, 95% confidence interval 1.37–4.65, chi-squared test 8.16, P<0.05). The most significant association of increased frequency of the G allele with SLE was more commonly noted in HLA-DRB1*07-positive patients (odds ratio 10.29, 95% confidence interval 5.34–19.83, P<0.001). These data indicate that this combination could contribute toward determining the susceptibility to SLE, but its possible significance will require confirmation by further studies.     

HLA-DRB1 antigens in Taiwanese patients with juvenile-onset systemic lupus erythematosus

OBJECTIVE: This study was done to investigate the frequency of HLA-DRB1 antigens in juvenile-onset systemic lupus erythematosus (SLE) in the Taiwanese population. PATIENTS AND METHODS: Thirty-four Taiwanese patients with juvenile onset SLE and 200 unrelated healthy controls were studied. HLA-DRB1 typing was performed with polymerase chain reaction (PCR) and the sequence-specific oligonucleotide probe (SSO) typing method. RESULT: Among the 14 investigated DRB1 alleles, the frequency of HLA-DRB1*1602 was higher in juvenile onset SLE patients than the controls (15.15% vs 4.50%, odds ratio 3.66, 95% confidence interval 1.15-11.68, Pc = 0.04). Although there were differences in the frequencies of DRB1*0301, DRB1*0803, and DRB1*1501 between patients and controls, the associations were statistically insignificant. CONCLUSION: The frequency of HLA-DRB1*1602 was significantly higher in patients with juvenile onset SLE than in healthy controls. This finding differs from those in the previous studies in Caucasian and Japanese adult onset SLE patients.     

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

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

Allelic markers close to prolactin are associated with HLA-DRB1 susceptibility alleles among women with rheumatoid arthritis and systemic lupus erythematosus

Objective. To investigate linkage disequilibrium between HLA-DRB1 disease susceptibility alleles and microsatellite markers close to the prolactin gene, among women with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and normal controls. Methods. DNA from 89 women with RA, 76 women with SLE, and 94 controls was typed for HLA-DRB1 status and D6S422 and D6S285, 2 highly polymorphic microsatellite markers close to the prolactin gene. RA patients were stratified by DRB1*0401 status, and SLE patients were stratified by *0301 status. Results. There was an excess frequency of D6S422*1 among SLE patients with DRB1*0301 (odds ratio [OR] 3.1). The frequency of this allele was also slightly in excess among RA patients with DRB1*0401 (OR 1.9). D6S285*5 was also in excess among female RA patients with DRB1*0401 (OR 3.5), and was slightly increased among female SLE patients with DRB1*0301. None of these alleles were found to be increased among *0401-positive or *0301-positive controls. Conclusion. These data indicate that there may be linkage disequilibrium between HLA-DRB1 alleles and microsatellite marker alleles close to the prolactin gene among women with RA and SLE. This suggests the possibility of extended haplotypes encoding for HLA-DRB1 susceptibility and high prolactin production, which contribute to susceptibility to both RA and SLE.     

The role of socioeconomic status in the susceptibility to develop systemic lupus erythematosus in Mexican patients

Clinical Rheumatology - Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disorder for which Major Histocompatibility Complex (MHC) genes are well-identified as risk factors. SLE...     

The effect of ethnicity on major histocompatibility complex complement allotypes and extended haplotypes in patients with systemic lupus erythematosus

Previous studies of patients with systemic lupus erythematosus (SLE) have shown an increased frequency of certain major histocompatibility complex (MHC) markers, including HLA-DR2, DR3, and C4AQ0 (C4A-null), in Caucasian patients. However, most of these studies were of randomly selected, unrelated patients; families were not included, and haplotypes were not determined. In order to define more accurately the possible role of MHC genes in lupus susceptibility, HLA-A, B, C, and DR, as well as BF, C2, C4A, C4B, and GLO, markers were determined in 62 Caucasian patients of known ethnic background, and in the members of their families. The distributions of extended haplotypes (fixed combinations of HLA-B, DR, and complotype alleles), fragments thereof, and individual alleles were determined in SLE patients and controls. The MHC distributions in all patients were compared with haplotypes in a normal Caucasian population. There were no statistically significant differences between the frequencies of any MHC marker, fragment, or extended haplotype in the patients compared with the controls. The patients were categorized into 2 groups of European ancestry (English/Irish; other Europeans), and each group was compared with a group of ethnically matched controls. There was a statistically significantly increased frequency of the alleles C4AQ0 and DR3 and the complotype SC01 in SLE patients of English/Irish descent as compared with ethnically matched controls. The increase in C4AQ0 and DR3 could be accounted for by the fact that they were part of the extended haplotype [HLA-B8;SC01;DR3] and/or its fragment (SC01;DR3). No increase in any MHC marker was observed in the other patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

人系统性红斑狼疮遗传易感性研究进展

系统性红斑狼疮(SLE)是一种多因素疾病,其发病机制至今尚未明确.但越来越多的研究证据表明,遗传易感性在疾病发生中起重要作用.人类基因组研究显示约50多个基因座(loci)与SLE有关,独立队列研究证实至少有9个区域有明显相关性,包括lq23、lq31-32、lq41-42、2q35-37、4p16-15.2、6p21-11、11p13、12q24及16q12-13.对具体患者,多个不同位点的基因组合可引起疾病表型的多样性.近期研究进一步证实,遗传因素在决定疾病易感性及临床表型时起作用,不同种族、地域人群中所涉及的相关基因有所差异.     

Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor alpha: relevance to genetic predisposition to systemic lupus erythematosus.

We report on the production of tumor necrosis factor (TNF)-alpha and TNF-beta by mitogen-activated peripheral blood lymphocytes or enriched monocyte subpopulations from human leukocyte antigen (HLA)-typed healthy subjects. The results indicate that HLA-DR2- and DQw1-positive donors frequently exhibit low production of TNF-alpha, whereas DR3- and DR4-positive subjects show high levels of TNF-alpha production. No correlation between TNF-alpha levels and HLA-A, -B, and -C genotype was found. The relevance of this quantitative polymorphism to the genetic predisposition to lupus nephritis in systemic lupus erythematosus (SLE) patients was investigated. DR2, DQw1-positive SLE patients show low levels of TNF-alpha inducibility; this genotype is also associated with an increased incidence of lupus nephritis. DR3-positive SLE patients, on the other hand, are not predisposed to nephritis, and these patients have high TNF-alpha production. DR4 haplotype is associated with high TNF-alpha inducibility and is negatively correlated with lupus nephritis. These data may help explain the strong association between HLA-DR2, DQw1 in SLE patients and their susceptibility to nephritis.     

Association of PDCD1 with susceptibility to systemic lupus erythematosus

Objective

The A allele of the PD1.3 single‐nucleotide polymorphism (SNP) on the programmed cell death gene PDCD1 was markedly more frequent in patients with systemic lupus erythematosus (SLE) than in unaffected controls in a recent study involving large sets of Swedish, European American, and Mexican families. This study sought to determine the role of PDCD1 in susceptibility to SLE in the Spanish population.

Methods

Seven PDCD1 SNPs were studied in 518 SLE patients and 800 healthy control subjects who had been recruited in 5 distant towns spanning continental Spain. Patients and controls were of Spanish ancestry. The diagnosis of SLE was in accordance with the American College of Rheumatology updated classification criteria.

Results

The A allele of the PD1.3 polymorphism was significantly less frequent in Spanish female patients with SLE than in Spanish female controls (9.0% versus 13.0%, odds ratio 0.67, 95% confidence interval 0.50–0.89). This difference was consistent across the 5 sets of samples grouped by town of recruitment. The other PDCD1 SNPs were not associated with SLE susceptibility. The haplotype structure of PDCD1 in the Spanish controls was different from that reported in other healthy control populations.

Conclusion

Our results confirm the association of PDCD1 with susceptibility to SLE, but the findings show a lack of involvement of the PD1.3 SNP, which is contrary to the role of the PD1.3 A allele observed previously. These contradictory results probably reflect population differences in the haplotype structure of the PDCD1 locus. More research focusing on new polymorphisms and identifying associations in other populations will be needed to clarify the role of PDCD1 in SLE susceptibility.

     

Higher genetic susceptibility to inflammation in mild disease activity of systemic lupus erythematosus

In order to test the hypothesis that stratification of Mexican Modification of the Systemic Lupus Erythematosus Disease Activity Index (MEX-SLEDAI) simplifies the genetic study of SLE, we evaluated the genetic susceptibility to inflammation and defects in clearance of immune complexes among SLE patients in Taiwan. SLE phenotypes were stratified according to the MEX-SLEDAI scores into two subgroups (≤10 and >10), and then according to renal disorder and neurological disorder, aiming to minimize any loss of power associated with disease heterogeneity. Upon stratification, IL1-β polymorphism and LTA were significantly associated with SLE within the MEX-SLEDAI ≤10 subgroup. When SLE patients were classified into two subgroups with or without renal disorder to stratify the genetic study, we could find that the stratification with renal disorder could partially confirm the hypothesis that stratification of MEX-SLEDAI score simplifies the genetic study of complex diseases such as SLE. So we concluded that in the mild disease state of SLE, stratification of disease phenotypes, especially IL1-β and LTA, according to MEX-SLEDAI scores could reveal new associations between candidate genes and disease activity index of SLE. Li-Jen Tsai and Sheng-Hsiung Hsiao have contributed equally to this study.     

Influence of shared epitope-negative HLA-DRB1 alleles on genetic susceptibility to rheumatoid arthritis

OBJECTIVE: Most patients with rheumatoid arthritis (RA) express the shared epitope (SE). It is not known whether SE-negative HLA-DRB1 alleles influence the development of RA. This study examined the influence of SE-negative HLA-DR alleles (DRB1*X) on the development of RA in 3 different French populations. METHODS: HLA-DRB1 alleles were defined by polymerase chain reaction with sequence-specific oligonucleotide hybridization or sequence-specific primers. SE-negative alleles were classified according to the electric charge of their P4 pocket. HLA-DRB1 alleles *0103, *0402, *07, *08, *11 (except *1107), *12, and *13 have a neutral or negative P4 charge and are called DRB1*XP4n. HLA-DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16 have a positive P4 charge and are called DRB1*XP4p. RESULTS: Among the SE-negative subjects, DRB1 genotypes with 1 or 2 DRB1*XP4n alleles were significantly overrepresented in the control subjects compared with the RA patients, whereas DRB1*XP4p/XP4p genotypes were equally represented in the patients and controls. In single-dose SE-positive subjects, SE/XP4n genotypes were equally represented in the patients and controls. However, SE/XP4p genotypes were significantly overrepresented in the RA patients. CONCLUSION: The DRB1*X allele polymorphism influences susceptibility to RA. Alleles that have a neutral or negative electric charge in their P4 pocket (DRB1*XP4n), such as DRB1*0103, *0402, *07, *08, *11 (except *1107), *12, and *13, protect against RA. Alleles that have a positive electric charge in their P4 pocket (DRB1*XP4p), such as DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16, have no influence on the predisposition to RA.     

HLA-DRB1、-DQB1基因多态性与食管鳞癌遗传关联性

目的　从基因水平探讨食管鳞癌HLA DRB1 , DQB1等位基因的遗传易感性 ,以阐述其免疫遗传学特征。方法　运用序列特异性引物聚合酶链反应技术 ,检测无亲缘关系湖北汉族健康人 1 36例、食管鳞癌患者 42例的HLA DRB1 , DQB1等位基因。结果　湖北汉族人食管鳞癌患者与正常人比较 ,HLA DRB1 0 90 1等位基因分布频率显著增高 (0 .2 50 0比 0 .1 397,P =0 .0 2 8,OR =2 .0 53 ,病因分数 =0 .1 2 82 ) ,HLA DQB1 0 30 1基因分布频率显著增高 (0 .2 976比 0 .1 875 ,P =0 .0 4 6 ,OR =1 .835 ,病因分数 =0 .1 35 4)。两者间其余HLA DRB1、 DQB1等位基因分布频率差异均无显著性。结论　HLA DRB1 0 90 1及 DQB1 0 30 1等位基因均与食管鳞癌正关联 ,为其易感基因。该两等位基因测序结果与其基因库第 2外显子序列吻合。     

Lack of association between HLA-DRB1 alleles of the major histocompatibility complex and p-ANCA status or clinical characteristics in patients with ulcerative colitis

INTRODUCTION: An association between different HLA-subtypes and ulcerative colitis has been described in various study populations of different ethnic and geographic background. Moreover, a correlation between HLA-DR2 and ulcerative colitis, in particular p-ANCA-positive ulcerative colitis, was reported. Thus, the present study aimed on the correlation of HLA-DRB1* alleles with the presence of p-ANCA and clinical characteristics in individuals of southern german descent. PATIENTS AND METHODS: The study population comprised 56 patients with ulcerative colitis and 177 healthy controls. HLA-DRB1* alleles were assessed by use of the dot blot method. Autoanti-bodies were visualized by indirect immunofluorescence on ethanol-fixed neutrophils. RESULTS: The allele HLA-DRB1*12 was more frequent in patients with ulcerative colitis (p = 0.01). After correction for the number of alleles tested (n = 16) statistical significance was no longer preserved. A weak association between the presence of HLA-DR5 and the detection of p-ANCA in ulcerative colitis was found (p = 0.0375). After correction for the number of comparisons (n = 10) no associations between HLA-DR antigens and the presence of p-ANCA remained. Furthermore, no significant correlations between clinical characteristics of ulcerative colitis and HLA-DR antigens were detected. DISCUSSION: Genes encoding for HLA-DR antigens are unlikely to have an impact on the heredity and the presence of disease phenotypes of ulcerative colitis in a study population of southern german descent.     

抗SSA和SSB抗体与HLA-Ⅱ基因的相关性分析

目的：探讨云南汉族系统性红斑狼疮（SLE）患者抗SSA和SSB抗体与HLA－DRB1、DQA1、DQB1等位基因及单体型的相关性。方法：采用多聚酶链反应－序列特异性引物（PCR－SSP）技术对63例云南汉族SLE患者和54名同民族健康对照进行DRB1、DQA1、DQB1基因分型。结果：云南汉族SLE患者中DR15（P＜0．01）、DR16（P＜0．05）、DQA1＊0102（P＜0．05）、DQA1＊0103（P＜0．01）、DQB1＊0601（P＜0．05）等位基因频率明显增高；抗SSA和SSB抗性阳性的SLE病人中DQA1＊0103频率均显著增高（P＝0．042，P＝0．006）；抗SSB抗体阳性的SLE患者中的DQA1＊0501 频率均显著增高（P＝0．009）。结论：云南汉族SLE 抗SSA和SSB抗体的产生与DQA1＊0103等位基因相关；抗SSB抗体的产生还与DQA1＊0501相关。