日本人群中 HLA - DR 与进行性系统性硬化症的关联

Association of HLA-DR with progressive systemic sclerosis in Japanese.

作者信息

Takeuchi F, Nakano K, Yamada H, Hong G H, Nabeta H, Yoshida A, Matsuta K, Bannai M, Tokunaga K, Ito K

机构信息

Department of Medicine and Physical Therapy, Faculty of Medicine, University of Tokyo, Japan.

出版信息

J Rheumatol. 1994 May;21(5):857-63.

PMID:8064726

Abstract

OBJECTIVE

To clarify the contribution of HLA-DR genes to the susceptibility to progressive systemic sclerosis (PSS).

METHODS

HLA-DR typing was carried out in 36 Japanese patients with PSS, 42 with systemic lupus erythematosus and 104 healthy subjects by polymerase chain reaction (PCR) method using specific primers and by PCR-SSCP (single-standard DNA conformation polymorphism) method.

RESULTS

A haplotype DRB11502-DRB50102 was significantly increased in PSS (50.0%, p < 0.00004, pc < 0.001), especially in antitopoisomerase I antibody (a-Scl-70) positive patients (62.5%, p < 0.00003, pc < 0.001) and PSS with diffuse scleroderma (75.0%, p < 0.00001, pc < 0.0001). In addition, DRB10802 was also increased in DRB11502 negative patients with a-Scl-70, (50.0%, p = 0.033, pc = not significant) and in DRB11502 negative patients with diffuse scleroderma (75.0%, p = 0.008, pc = not significant). Thus, 81.3% of a-Scl-70 positive patients, and 93.8% of patients with PSS with diffuse scleroderma showed either HLA-DRB11502 or 0802.

CONCLUSIONS

Our observations show the extreme difference of genetic background of a-Scl-70 positive PSS, with regard to HLA-DR, between Japanese and other ethnic groups including Caucasian and American black persons. The increase in DRB11502-DRB50102 haplotype supported the hypothesis of Reveille, et al that uncharged polar amino acid residue at position 30 of HLA-DQB1 allele was important for a-Scl-70 positive PSS because close association of the haplotype with DQB10601 was well established in Japanese; listed as a hypothetical candidate of PSS susceptible DQB1 allele. DRB10802 were also associated with hypothetical candidates of DQ alleles. Furthermore, the sharing of the particular amino acid sequence: valine38 and phenylalanine67-lysine68-glutamic acid69-asparic acid70-arginine71, by DRB50102, DRB10802 and DR11 (associated with Caucasian PSS) also suggests a contribution of the sequence in HLA-DR molecules to the pathogenesis of PSS according to the shared epitope hypothesis.

摘要

目的

阐明HLA - DR基因对进行性系统性硬化症（PSS）易感性的影响。

方法

采用聚合酶链反应（PCR）法，使用特异性引物，并通过PCR - SSCP（单标准DNA构象多态性）法，对36例日本PSS患者、42例系统性红斑狼疮患者和104名健康受试者进行HLA - DR分型。

结果

单倍型DRB11502 - DRB50102在PSS患者中显著增加（50.0%，p < 0.00004，校正p < 0.001），尤其是在抗拓扑异构酶I抗体（抗Scl - 70）阳性患者中（62.5%，p < 0.00003，校正p < 0.001）以及弥漫性硬皮病的PSS患者中（75.0%，p < 0.00001，校正p < 0.0001）。此外，在抗Scl - 70的DRB11502阴性患者中DRB10802也增加（50.0%，p = 0.033，校正p无显著性），在弥漫性硬皮病的DRB11502阴性患者中也增加（75.0%，p = 0.008，校正p无显著性）。因此，81.3%的抗Scl - 70阳性患者以及93.8%的弥漫性硬皮病PSS患者显示为HLA - DRB11502或0802。

结论

我们的观察结果显示，在HLA - DR方面，抗Scl - 70阳性PSS的日本患者与包括白种人和美国黑人在内的其他种族之间存在极端的遗传背景差异。DRB11502 - DRB50102单倍型的增加支持了Reveille等人的假设，即HLA - DQB1等位基因第30位的不带电荷极性氨基酸残基对于抗Scl - 70阳性PSS很重要，因为在日本该单倍型与DQB10601的紧密关联已得到充分证实；DQB10601被列为PSS易感DQB1等位基因的假设候选者。DRB10802也与DQ等位基因的假设候选者相关。此外，DRB50102、DRB1*0802和DR11（与白种人PSS相关）共享特定氨基酸序列：缬氨酸38和苯丙氨酸6丁氨酸68 - 谷氨酸69 - 天冬氨酸70 - 精氨酸71，这也根据共享表位假说来表明HLA - DR分子中的该序列对PSS发病机制有影响。