The HLA–DRB1 shared epitope is associated with susceptibility to rheumatoid arthritis in African Americans through European genetic admixture

Objective

To determine whether shared epitope (SE)–containing HLA–DRB1 alleles are associated with rheumatoid arthritis (RA) in African Americans and whether their presence is associated with higher degrees of global (genome‐wide) genetic admixture from the European population.

Methods

In this multicenter cohort study, African Americans with early RA and matched control subjects were analyzed. In addition to measurement of serum anti–cyclic citrullinated peptide (anti‐CCP) antibodies and HLA–DRB1 genotyping, a panel of >1,200 ancestry‐informative markers was analyzed in patients with RA and control subjects, to estimate the proportion of European ancestry.

Results

The frequency of SE‐containing HLA–DRB1 alleles was 25.2% in African American patients with RA versus 13.6% in control subjects (P = 0.00005). Of 321 patients with RA, 42.1% had at least 1 SE‐containing allele, compared with 25.3% of 166 control subjects (P = 0.0004). The mean estimated percent European ancestry was associated with SE‐containing HLA–DRB1 alleles in African Americans, regardless of disease status (RA or control). As reported in RA patients of European ancestry, there was a significant association of the SE with the presence of the anti‐CCP antibody: 86 (48.9%) of 176 patients with anti‐CCP antibody–positive RA had at least 1 SE allele, compared with 36 (32.7%) of 110 patients with anti‐CCP antibody–negative RA (P = 0.01, by chi‐square test).

Conclusion

HLA–DRB1 alleles containing the SE are strongly associated with susceptibility to RA in African Americans. The absolute contribution is less than that reported in RA among populations of European ancestry, in which ∼50–70% of patients have at least 1 SE allele. As in Europeans with RA, the SE association was strongest in the subset of African American patients with anti‐CCP antibodies. The finding of a higher degree of European ancestry among African Americans with SE alleles suggests that a genetic risk factor for RA was introduced into the African American population through admixture, thus making these individuals more susceptible to subsequent environmental or unknown factors that trigger the disease.

     

Influence of HLA-DRB1 genes and the shared epitope on genetic susceptibility to rheumatoid arthritis in Taiwanese

OBJECTIVE:To investigate the association of predisposing and protective HLA-DRB1 alleles with rheumatoid arthritis (RA) and its clinical markers in a Taiwanese population. METHODS: A total of 273 patients with RA and 480 healthy controls, all of Taiwanese origin, were genotyped for HLA-DRB1 alleles by polymerase chain reaction and sequence-based typing assays. The associations between RA and HLA-DRB1 alleles and genotypes were investigated by chi-squared test. RESULTS: The DRB1*0405 and *1001 phenotypes showed the most significant associations with RA (OR 4.04, 95% CI 2.84-5.77, pc = 3.2 10(-14); OR 5.25, 95% CI 2.10-13.06, pc = 3.0 10(-3), respectively). Individuals carrying single or double doses of the shared epitope (SE/non-SE or SE/SE) had higher risks of RA. The compound heterozygote of DRB1*0405/*1001 showed the largest increase in RA risk (OR 15.8, 95% CI 2.48-100.7, pc = 0.004). Single or double doses of SE alleles were significantly associated with a higher bone erosion rate. Rheumatoid factor positivity and bone erosion were more frequent in patients with at least one copy of DRB1*0405. CONCLUSION: Our results show that SE-encoding HLA-DRB1*0405 and *1001 are associated with RA in a Taiwanese population; this is the first time DRB1*1001 has been described in persons of Asian ethnicity. Heterozygotes of DRB1*0405 and *1001 predicted the strongest susceptibility to RA, suggesting that this genotype enhances susceptibility to RA in Taiwanese.     

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.     

中国汉族类风湿关节炎患者HLA-DR4基因与抗环瓜氨酸肽抗体的相关性研究

目的：探讨中国汉族类风湿关节炎（RA）患者中抗环瓜氨酸肽抗体（ACCP）与人类白细胞抗原（HLA）-DR4基因的相关性。方法：入选RA104例、正常对照122名。ACCP检测采用酶联免疫吸附法（ELISA）,类风湿因子检测采用散色比浊法,HLA-DR4基因采用序列特异性引物-聚合酶链方法（PCR-SSP）检测。结果：RA患者中HLA-DR4基因携带率为34.6%,主要亚型为HLA-DRB1＊0405,正常对照组为17.2%,差异有统计学意义（P=0.01）。RA患者的共同表位（SE）携带率为30.9%,与国内相关研究结果（33.2%,36.8%）相似,但明显低于国外相关研究（78.5%,65.4%,85%,67%）,差异有统计学意义（P〈0.01）。RA患者中ACCP阳性率为76.5%,与国内外报道相符,正常对照组为0,两者差异有统计学意义。SE（＋）患者的ACCP阳性率为84%,SE（-）患者的ACCP阳性率73.2%,两者差异无统计学意义。RA患者中ACCP的滴度与X线分期相关（r=0.233,P〈0.05）。结论：我国汉族RA患者中ACCP与HLA-DR4或SE无明显的相关性。ACCP可能与关节破坏的严重程度相关。     

The HLA-DRB1 shared epitope is not associated with antibodies against cyclic citrullinated peptide in Chinese patients with rheumatoid arthritis

OBJECTIVE: Rheumatoid arthritis (RA) is a destructive autoimmune polyarthritis that has been associated with a group of human leucocyte antigen (HLA)-DRB1 alleles that share a common amino-acid sequence at residues 70-74 called the shared epitope (SE). Recently, anti-cyclic citrullinated peptide (CCP) antibodies have also been reported to be associated with HLA-DR4 and have gained wide acceptance as early diagnostic markers for RA in Caucasian patients. The current study was performed to investigate whether the association between the SE (HLA-DRB1 0401/04/05/10) and anti-CCP antibodies is also present in Chinese Han patients with RA. METHODS: One hundred and four RA patients and 122 healthy controls were recruited. HLA-DR4 was detected by the sequence-specific primer polymerase chain reaction (SSP-PCR) phototyping method. Anti-CCP antibodies and immunoglobulin M rheumatoid factor (IgM-RF) were measured by enzyme-linked immunosorbent assay (ELISA) and laser nephelometry, respectively. RESULTS: Of the Chinese patients with RA, 76.5% exhibited anti-CCP antibodies compared with none of the controls (76.5% vs. 0%, p<0.001). The prevalence of the SE was significantly higher in patients with RA compared with controls [p = 0.010, odds ratio (OR) = 2.42, 95% confidence interval (CI) = 1.16-5.07]. Among the HLA-DR4 alleles, the presence of HLA-DRB1 0401 was significantly higher in RA patients than in controls (p = 0.0118, OR = 9.68, 95% CI = 1.13-448.8). In our study we found that the SE was not associated with production of anti-CCP antibodies (p = 0.2899, OR = 1.920, 95% CI = 0.52-8.89). CONCLUSIONS: The prevalence of the SE is significantly lower in Chinese RA patients, as compared with previous reports of a study using a Caucasian cohort, indicating that distinct genetic risk factors might be associated with anti-CCP antibody production. These data emphasized the complexity of the genetic effects of the major histocompatibility complex on the RA phenotype.     

HLA-DRB1 alleles encoding the shared epitope associated with rheumatoid arthritis confer additional susceptibility to seronegative spondyloarthropathies in HLA-B27-positive Japanese individuals

Although the crucial role of HLA-B27 for the development of seronegative spondy-loarthropathies (SpA) has been established, family and twin studies indicated the presence of additional genetic factors. To determine whether HLA-DRB1 gene acts as an additional susceptibility factor for SpA in HLA-B27-positive Japanese individuals, complete HLA-DRB1 allele typing of 23 HLA-B27-positive patients (21 with ankylosing spondylitis, one with Reiter’s syndrome, and one with uveitis and sacroiliitis) and 17 HLA-B27-positive healthy individuals was performed using polymerase chain reaction-microtiter plate hybridization (PCR-MPH) assay. Twenty-two of patients’ 46 HLA-DRB1 alleles (47.8%) were those that encode the shared epitope associated with rheumatoid arthritis, as compared with eight of 34 DRB1 alleles of healthy HLA-B27-positive individuals (23.5%). This difference was statistically significant [odds ratio (OR)=2.98.P=0.036]. Seventeen of 23 patients were positive for one or two alleles coding for the shared epitope, as compared with seven of 17 healthy individuals (73.9 versus 41.2%, OR=4.04,P=0.053). These results suggest that HLA-DRB1 alleles encoding the shared epitope may act as an additional susceptibility factor for the development of SpA in HLA-B27-positive Japanese individuals.     

Particular HLA-DRB1 shared epitope genotypes are strongly associated with rheumatoid vasculitis

OBJECTIVE: To examine the relationship of the HLA-DRB1 shared epitope (SE) to rheumatoid vasculitis, using individual patient data (IPD) meta-analytic methods. METHODS: Published studies that enrolled adult patients with rheumatoid arthritis (RA) were identified by searches of Medline and Embase, and by manual searches of medical journals. All authors were contacted for IPD. Meta-analyses were performed to assess the association of SE presence, dose, and genotype with rheumatoid vasculitis. RESULTS: A total of 14 studies and 1,568 patients (129 with vasculitis) were included in the analysis. RA patients with vasculitis were significantly more likely to have rheumatoid nodules (odds ratio [OR] 2.5, 95% confidence interval [95% CI] 1.5-3.9], but there was no significant association with male sex, rheumatoid factor positivity, or erosive disease. No significant association was observed between the presence of the SE (i.e., 1 or 2 alleles versus 0 alleles) and rheumatoid vasculitis (summary OR 1.4, 95% CI 0.7-2.7). Analysis by SE genotype, however, demonstrated a striking relationship of vasculitis to 3 genotypes containing a double dose of the SE, specifically HLA-DRB1*0401/*0401 (OR 6.2, 95% CI 1.01-37.9), *0401/*0404 (OR 4.1, 95% CI 1.1-16.2), and *0101/*0401 (OR 4.0, 95% CI 1.4-11.6). CONCLUSION: The HLA-DRB1 SE genotypes *0401/*0401, *0401/*0404, and *0101/*0401 may be of particular importance to rheumatoid vasculitis. It is hoped that additional investigation of these and other SE genotypes will lead to improved insight into the mechanisms influencing the clinical expression of RA.     

Use of monoclonal antibodies to detect disease associated HLA-DRB1 alleles and the shared epitope in rheumatoid arthritis

OBJECTIVE—To use a panel of monoclonal antibodies (Mab) which recognise HLA class II alleles associated with rheumatoid arthritis for fluorescence activated cell sorter (FACS) analysis of peripheral blood mononuclear cells (PBMNC) from patients with early and established rheumatoid arthritis and to compare these results against DNA oligotyping of HLA class II molecules in the same patients.
METHODS—27 patients (18 from an early arthritis clinic, nine with established rheumatoid arthritis) were studied using both techniques. PBMNC were stained with Mab which recognise the shared epitope, the HLA-DRB1*04 molecule and its *0401, *0404 subtypes in the presence of bound peptide. Mab stained cells were analysed by FACS. Genomic DNA was prepared from PBMNC and used for DNA oligotyping and sequencing by standard methods.
RESULTS—FACS analysis of Mab stained PBMNC gave identical results to those obtained by DNA oligotyping in 26/27 patients. The antibodies identified the shared epitope in 14/14 cases and the presence of an HLA-DRB1*04 molecule in 12/12 cases. HLA-DRB1*0404 was identified in 4/4 cases. HLA-DRB1*0401 was identified in 5/6 cases. One patient oligotyped as HLA-DRB1*0401, but consistently failed to react with the *0401 Mab. DNA sequencing of the second exon of the HLA-DRB1*0401 allele in this patient confirmed a normal HLA-DRB1*0401 genotype.
CONCLUSIONS—FACS analysis of PBMNC stained with Mab recognising the shared epitope and rheumatoid arthritis associated HLA susceptibility molecules provides a rapid, reliable, and more accessible alternative to DNA oligotyping. The apparent discordance between phenotypic and genetic analysis of HLA-DRB1*0401 in one patient, may reflect variability in HLA-DRB1*0401 gene expression or in class II peptide presentation.

     

Mode of inheritance of HLA-DRB1 shared epitope in Japanese familial rheumatoid arthritis

OBJECTIVE: To clarify the mode of genetic contribution of the HLA-DR shared epitope (SE) to the pathogenesis of familial cases of Japanese rheumatoid arthritis (RA). METHODS: Fifty-three unrelated Japanese RA families that had more than 2 affected sibs were selected. The HLA-DR shared epitope typing was carried out by the PCR method and PCR-SSCP (single stranded DNA conformation polymorphism) method. Affected sib pair analysis was carried out using the MAPMAKER/SIB 2.0 program. The mode of inheritance was also calculated based on the sharing of genes identical by descent (IBD) between siblings in each of the 53 affected sib-pairs (propositus and the 2nd affected sib). RESULTS: The maximum LOD score of HLA-DR was 0.437, and the sharing of 2 IBDs, 1 IBD, and no IBDs between affected sibs were 0.330, 0.500, and 0.170, respectively. The sharing distribution of IBD was confirmed to be compatible with the dominant or additive mode since the observed gene frequency of SE was 0.255. CONCLUSION: The HLA-DR shared epitope participated in the pathogenesis of familial cases of Japanese RA. The SE contributes to this pathogenesis in either the dominant or additive mode of inheritance.     

The role of HLA-DRB1 shared epitope alleles in predicting short-term response to leflunomide in rheumatoid arthritis

OBJECTIVES: To investigate the role of shared epitope (SE) alleles in the short-term clinical response to leflunomide for the treatment of active RA. METHODS: In an open-label, multi-centre study of 16-weeks duration, 93 patients (82% female) fulfilling ARA 1987 RA criteria were treated with leflunomide (100 mg loading dose for 3 days, then 20 mg/day as the maintenance dose). The primary efficacy criterion was the response status according to the European League Against Rheumatism (EULAR) response criteria using Disease Activity Score-28 (DAS28) activity measure. SE determinations have been undertaken by polymerase chain reaction and sequence-specific oligonucleotide genotyping methods. RESULTS: The mean (s.d.) Disease Activity Score-28 (DAS28) was 5.1 (1.3) before the treatment, which was significantly decreased after 16 weeks [3.0 (1.1), P < 0.001]. According to the EULAR response criteria, 55 patients (59.1%) were classified as good responders. SE was positive in 51 (54.8%) of the patients, with 13 (13.9%) having SE homozygosity or carrying any two SE alleles. Among SE-positive patients, 68.6% (35/51) were good responders, compared with 47.6% (20/42) in SE negatives (P = 0.04). No difference was present according to SE hetero- or homozygosity (68.4 vs 69.2%). RF was also present significantly more frequently in the SE-positive group compared with negatives (78.4 vs 57.1%, P = 0.03). However, no significant difference was observed in the prevalence of RF positivity in patients with a good clinical response (72.7 vs 63.2%, P = 0.32). CONCLUSIONS: The results suggest that HLA-DRB1 SE presence may favourably affect the outcome of leflunomide monotherapy in an unselected group of RA patients with an active disease and naive to leflunomide.     

Independent association of rheumatoid factor and the HLA-DRB1 shared epitope with radiographic outcome in rheumatoid arthritis

OBJECTIVE: Findings of a recent study suggested that HLA-DRB1 alleles encoding the rheumatoid arthritis (RA) "shared epitope" (SE) were not predictive of erosive damage at 2 years in patients with early inflammatory arthritis who were rheumatoid factor (RF) positive, but were predictive in those who were RF negative. The present study was undertaken to determine whether RF status was also important in the association between the SE and radiographic outcome in patients with longstanding RA. METHODS: The association between radiographic outcome, HLA-DRBI, and RF status was examined in 299 RA patients with established disease (5-30 years). Radiographic outcome was measured by scoring radiographs of the hands and feet using the standard radiographs of Larsen. HLA-DRB1 typing was performed using polymerase chain reaction methodology. Results were stratified by RF status and analyzed by multiple regression. RESULTS: An association between radiographic severity and the SE was found in RF-, but not RF+, patients. RF- patients carrying an SE allele had higher Larsen scores than RF- patients lacking the SE, although there was no association with SE dosage. The mean Larsen score was significantly higher in RF+ patients than in RF- patients, but there were no differences between RF+ patients with 0, 1, or 2 SE alleles. Multiple regression analysis confirmed independent associations of RF and SE positivity with radiographic outcome. No significant associations were found between RF and the SE, or RF and individual SE alleles. CONCLUSION: Our data indicate that RF and the SE are independently associated with radiographic outcome in RA. In RF+ patients with longstanding RA, there is no apparent association between the presence of the SE and radiographic damage. However, in RF-patients, although radiographic outcome is generally less severe, there is an association between severity and presence of the SE.     

The presence of the HLA-DRB1 shared epitope correlates with erosive disease in Chilean patients with rheumatoid arthritis

OBJECTIVE: To assess the contribution of the HLA-DRB1 shared epitope (SE) to the radiological outcome of rheumatoid arthritis (RA) after 6 yr of follow-up in a reported series of 129 Chilean patients with established disease. METHODS: A prospective study was conducted between 1992 and 1998 using hand radiographs to assess disease outcome in a published series of patients in whom two doses of the SE were present in 20%, one dose was present in 34% and the SE was absent in 46%. At study entry, 29 of the 92 patients with hand radiographs were at Steinbrocker stages I or II (non-erosive), with a median disease duration of 2.8 yr (0.4-17). RESULTS: In 1998, 113 (87%) of the patients were alive. One hundred and eight patients underwent complete clinical evaluation. Their median age was 57 yr (range 30-81) and the median disease duration was 15 yr (6-50). We were able to study 25 of the 29 patients who had non-erosive disease at study entry in 1992. We found that 10 of 11 patients having one or two doses of the SE developed erosive disease compared with three of 14 without the SE (Yates' corrected P=0.0023, relative risk 4.24, 95% confidence interval 1.53-11.77). CONCLUSIONS: These observations support and extend the notion that the presence of the SE in one or two doses can predict the development of erosions even in RA populations in whom the SE is not as prevalent as in Caucasians.     

山东地区类风湿关节炎与HLA-DRB1基因共同表位的关联性研究

目的　探讨山东地区汉族人群类风湿关节炎 (RA)与HLA DRB1基因共同表位 (SE)的关联性。方法　采用特异性引物聚合酶链反应 (PCR SSP)方法对山东地区人群 1 32例RA患者及1 30名正常健康者的HLA DRB1 0 1、 0 4、 1 0的 1 7个等位基因进行检测。结果　山东地区RA患者中携带有SE的基因频率显著高于正常对照组 (5 0 0 %∶2 2 3% ,P <0 0 1 ) ,HLA DR4亚型 0 4 0 5是主要的易感基因 (2 2 8%∶1 0 0 % ,P <0 0 0 5 )。其他亚型包括DRB1 0 1 0 1 (3 8%∶3 1 % ) , 0 1 0 2 (2 3%∶2 3% ) , 0 1 0 3(3 8%∶3 1 % ) , 0 1 0 4 (3 0 %∶2 3% ) , 0 4 0 1 (1 0 6 %∶4 6 % ) , 0 4 0 4 (9 1 %∶4 6 % ) , 0 4 0 7(8 3%∶9 2 % ) , 0 4 0 3(6 8%∶3 1 % ) , 0 4 0 2 (6 8%∶4 6 % ) , 0 4 0 8(5 3%∶1 5 % ) , 0 4 0 9(2 3%∶0 ) , 0 4 0 6 (1 5 %∶0 ) , 0 4 1 0 (0 8%∶0 ) , 0 4 1 1 (0 8%∶0 )和 1 0 0 1 (1 1 4 %∶6 9% )的差别均无统计学意义。Logistic回归分析表明 :SE纯合子对RA的危害性要比其杂合子大 (P <0 0 0 1 )。结论　SE与山东地区汉族RA易感性及疾病严重性有关联     

Polymorphism in the immunoglobulin VH gene V1-69 affects susceptibility to rheumatoid arthritis in subjects lacking the HLA-DRB1 shared epitope

OBJECTIVE: To investigate the contribution of polymorphism in the immunoglobulin heavy chain variable region V1-69 gene set to genetic susceptibility to rheumatoid arthritis (RA) in Czech and British patients. METHODS: We used V1-69 gene sequence-specific polymerase chain reaction (PCR) and restriction enzyme digestion to study polymorphism in the V1-69 gene set in germline DNA of 109 Czech and 159 British RA patients and 164 ethnically matched controls. Polymorphism was further studied by nucleotide sequencing of the V1-69 gene locus in germline DNA. RESULTS: We found that all patients and controls had at least one V1-69 gene copy. In the Czech RA cohort, the dimorphic nucleotide in codon 73 of V1-69 (GAA or AAA) was present in the homozygous form 73(A/A) in 31 of 109 (28.4%) RA patients vs 12 of 79 (15.2%) controls [odds ratio (OR)=2.22, P<0.001]. When the RA patients and controls were classified according to HLA shared epitope (SE) status, 73(A/A) was found in 18 of 76 (23.7%) SE(+) patients compared with 13 of 38 (34.2%) SE(-) patients, four of 12 (18.2) SE(+) controls and eight of 57 (14%) SE(-) controls. This suggests that homozygosity for the dimorphic sequence 73(A) contributed to susceptibility to RA in SE(-) Czech individuals (OR=3.2, P<0.001). The most striking observation was that none of the 38 SE(-) Czech patients, compared with 11 of 76 (14.5%) SE(+) RA patients, three of 22 (13.6%) SE(+) and 11 of 57 (19.3%) SE(-) ethnically matched controls, were homozygous for the alternative dimorphic sequence 73(G/G) (OR=9.1, P<0.05). These data, however, were not replicated in a Caucasoid British RA population. CONCLUSION: The dimorphic sequence at codon 73 (73(A/A)) of the V1-69 gene contributes to genetic susceptibility in SE(-) Czech RA patients.     

Relationship among the HLA-DRB1 shared epitope,smoking, and rheumatoid factor production in rheumatoid arthritis

OBJECTIVE: Rheumatoid factor (RF) production in rheumatoid arthritis (RA) is generally associated with more severe disease. In some studies, RF production has been associated with carriage of HLA-DRB1 alleles encoding the RA-associated shared epitope (SE). Patients who smoke are also more likely to be RF positive. In this study, we investigated whether the association between RF production and smoking was influenced by carriage of the SE. METHODS: The smoking histories of 371 RA patients attending a hospital clinic were recorded. RF levels and SE status were determined for every patient, and the associations between the SE, smoking, and RF production were examined. HLA-DRB1 typing was performed using polymerase chain reaction. Results were analyzed using chi-square tests and logistic regression analysis. RESULTS: Patients who had ever smoked were significantly more likely to be RF positive than nonsmokers (odds ratio 2.2, P < 0.0001). This remained significant (P = 0.003) after correction for age, sex, and disease duration in a logistic regression model. An association was also found between RF positivity and carriage of the SE (P = 0.03, after correction for age, sex, and disease duration), but significance was reduced or lost after correction for previous or current smoking (P = 0.05 and 0.09, respectively). Examination of the major SE phenotypes in this RA population by multivariate logistic regression analysis revealed that only DRB1*0401 was associated with RF positivity, and that this was independent of the influence of smoking. CONCLUSION: Our data confirm that RF production in RA patients is associated with smoking. This does not appear to depend on an HLA-DR-restricted immune response. The association of the SE with RF positivity is primarily due to HLA-DRB1*0401. This appears to be independent of the association with smoking, although smoking further increases the likelihood of RF production in DRB1*0401 patients.     

内蒙古地区汉族类风湿关节炎与HLA-DRB1基因共同表位的相关性研究

目的探讨内蒙古地区汉族人群类风湿关节炎(RA)与HLA-DRB1基因共同表位(SE)的关联性。方法采用特异性引物聚合酶链反应(PCR-SSP)方法对内蒙古地区汉族人群80例RA患者及110名正常健康者的HLA-DRB1*01、*04、*10的17个等位基因进行检测。结果内蒙古地区RA患者中携带有SE的基因频率显著高于正常对照组(48．8％：20％,P＜0．01),HLA-DR4亚型*0405是主要的易感基因(28．8％：12％,P＜0．01),其他亚型包括DRB1*0101(2．5％：0．9％),*0102(2．5％：0),*0103(1．25％：0．9％),*0104(2．5％：0％),*0401(6．25％：1．8％),*0402(3．75％：0．9％),*0403(1．25％：1．8％),*0404(2．5％：1．8％),*0406(2．5％：2．7％),*0407(1．25％：0．9％),*0408(3．75％：0．9％),*0409(1．25％：0),*0410(2．5％：0．9％),*0411(0：0)和*001(8．75％：4．5％)的差异均无统计学意义。Logistic回归分析表明：SE纯合子对RA的危害性要比杂合子大(P＜0．01)。在RA患者中。SE纯合子和SE杂合子的病程、关节肿痛数、关节压痛数、血沉(ESR),C反应蛋白(CRP)、类风湿因子(RF)、X线(Ⅲ期 Ⅳ期)与SE阴性组比较,差异有统计学意义。SE纯合子与SE杂合子相比较,各观察指标差异均无统计学意义。结论SE与内蒙古地区汉族RA易感性及疾病严重性有关。