法国东部类风湿关节炎患者中HLA - DRB1等位基因及共享氨基酸序列与疾病易感性和严重程度的关系

HLA-DRB1 alleles and shared amino acid sequences in disease susceptibility and severity in patients from eastern France with rheumatoid arthritis.

作者信息

Toussirot E, Auge B, Tiberghien P, Chabod J, Cedoz J P, Wendling D

机构信息

Department of Rheumatology, University Hospital, Besançon, France.

出版信息

J Rheumatol. 1999 Jul;26(7):1446-51.

PMID:10405928

Abstract

OBJECTIVE

To examine the effects of HLA-DRB1 alleles and amino acid sequences that carry the shared epitope (SE) upon rheumatoid arthritis (RA) susceptibility and disease severity in patients from Eastern France.

METHODS

HLA-DRB1 alleles were determined in 120 patients and 104 healthy controls by polymerase chain reaction/sequence specific oligonucleotide probes. Subtyping of DRB1*01 and *04 were performed using sequence specific primers. Patients were retrospectively evaluated for disease duration, age at disease onset, presence of rheumatoid factors, subcutaneous nodules, vasculitis and other extraarticular diseases, for the need for arthroplasty and immunosuppressive/immunoregulatory agents, and for radiographic damage.

RESULTS

The prevalence of HLA-DRB104 was significantly higher in patients (46.6%) than in controls (17.3%) (Pcorr = 0.000003). HLA-DRB10101 and *0401 were the most prominently associated subtypes in patients with RA (33.3%, Pcorr = 0.011, and 28.3%, Pcorr = 0.00008, respectively). A significant fraction of patients (72.5%) expressed one or 2 copies of the SE (p < 0.0000001; OR 4.77, CI 2.61-8.78). The presence of double SE was associated with a higher risk of developing RA (OR 4.83, CI 1.91-12.71; p = 0.0001). No significant differences in the clinical records among patients expressing no RA linked alleles, one and 2 copies of the SE, were observed. However, analyzing the specific effect of each amino acid sequence, we observed a significant association of the QKRAA motif with vasculitis (p = 0.03) and history of joint replacement surgery (p = 0.05), suggesting a role for lysine in position 71 of the shared sequence.

CONCLUSION

These findings differ from those of previous HLA-DRB1 allele studies in patients with RA from other regions of France. Thus, the heterogeneity in both the expression of DRB1 alleles and the association of these alleles with disease severity could be relevant within a country such as France.

摘要

目的

研究HLA - DRB1等位基因及携带共同表位（SE）的氨基酸序列对法国东部类风湿关节炎（RA）患者易感性及疾病严重程度的影响。

方法

采用聚合酶链反应/序列特异性寡核苷酸探针法，对120例患者和104例健康对照者进行HLA - DRB1等位基因检测。使用序列特异性引物对DRB101和04进行亚型分型。回顾性评估患者的病程、发病年龄、类风湿因子、皮下结节、血管炎及其他关节外疾病的存在情况，是否需要进行关节成形术以及使用免疫抑制/免疫调节药物，以及影像学损伤情况。

结果

患者中HLA - DRB104的患病率（46.6%）显著高于对照组（17.3%）（校正P值 = 0.000003）。HLA - DRB10101和*0401是RA患者中最显著相关的亚型（分别为33.3%，校正P值 = 0.011；28.3%，校正P值 = 0.00008）。相当一部分患者（72.5%）表达1个或2个拷贝的SE（p < 0.0000001；比值比4.77，可信区间2.61 - 8.78）。双SE的存在与发生RA的较高风险相关（比值比4.83，可信区间1.91 - 12.71；p = 0.0001）。在未表达与RA相关等位基因、表达1个拷贝SE和2个拷贝SE的患者之间，临床记录未观察到显著差异。然而，分析每个氨基酸序列的具体作用时，我们观察到QKRAA基序与血管炎（p = 0.03）及关节置换手术史（p = 0.05）显著相关，提示共同序列第71位的赖氨酸起作用。