人类白细胞抗原-DRB1等位基因与皮肌炎患者抗黑色素瘤分化相关蛋白5抗体表达的相关性研究

Association of human leucocyte antigen-DRB1 alleles and the development of anti-melanoma differenti-ation-associated gene 5 antibodies in patients with dermatomyositis

目的探讨PM/DM患者HLA-DRB1等位基因多态性与抗黑色素瘤分化相关蛋白5（MDA5）抗体表达的关系。方法共纳入70例PM患者、104例DM患者和400名健康对照。采用基于测序的基因分型法进行HLA-DRB1的基因分型，使用重组MDA5抗原通过ELISA法测定抗MDA5的水平。采用χ2检验或Fisher确切概率法比较病例组和对照组之间的HLA-DRB1等位基因频率。结果抗MDA5抗体阳性的PM/DM患者中DRB1＊04：01[分别为17.0%和1.3%；校正P值（Pc）=3.8×10-8；比值比（OR）= 16.2；95%可信区间（CI）=（6.6，39.7）]和DRB1＊12：02[分别为42.6%和19.3%；Pc=0.008；OR=3.1；95%CI（1.7，5.7）]高于对照组。抗MDA5抗体阳性DM-ILD患者中DRB1＊04：01[P=5.2×10-6；OR=17.1；95%CI（5.3，54.9）和＊12：02（P=3.8×10-4，OR=3.1；95%CI（1.7，5.7）]的频率也高于对照组。而抗MDA5阴性DM-ILD患者中DRB1＊04：01和＊12：02的频率与对照组相比差异无统计学意义。将DM患者按ILD和抗MDA5抗体的有无进行分层，除DRB1＊04：01以外的携带共享表位（SE）的DRB1等位基因组合（即DRB1＊01：01，＊01：02，＊04：05和＊10：01）的频率在患者和对照组之间差异无统计学意义。结论DRB1＊04：01和＊12：02是DM患者抗MDA5抗体产生的遗传易感基因，且该遗传易感性不能用SE假说来解释。

Objective To investigate the association of human leucocyte antigen （HLA-DRB1） with anti-melanoma differentiation-associated gene 5 （MDA5） expression in polymyositis/dermatomyositis （PM/DM）.Methods Seventy patients with PM, 104 patients with DM and 400 healthy controls were included. Genoty-ping of HLA-DRB1 was performed using the sequencing-based typing method. Levels of anti-MDA5 were measured by enzyme linked immunosorbent assay using recombinant MDA5 antigen. The frequencies of HLA-DRB1 alleles were compared between the patients and controls using a chi-square test or Fisher＇s exact test.Results Frequencies of DRB1＊04：01 [17.0% vs 1.3%, corrected P-value （Pc）=3.8×10-8; odds ratio （OR）=16.2;95% confidence interval （CI） （6.6, 39.7）] and DRB1＊12：02 [（42.6% vs 19.3%, Pc=0.008; OR=3.1; 95% CI（1.7, 5.7）] were significantly higher in anti-MDA5 positive PM/DM patients compared with the controls. The frequencies of DRB1＊04：01 [P=5.2×10-6, OR=17.1, 95%CI： （5.3, 54.9）／ and ＊12：02 [P=3.8×10-4, OR=3.1, 95%CI（1.7,5.7）] in anti-MDA5 positive DM-interstitial lung disease （ILD） patients were higher than those in the controls, whereas the frequencies of DRB1＊04：01 and ＊12：02 did not differ between the anti-MDA5 negative DM-ILD patients and the controls. No difference in the frequency of DRB1 alleles, other than ＊04：01, carrying the shared epitope （SE）, i.e.＊01：01,＊01：02,＊04：05 and＊10：01, was observed between the controls and DM patients stratified by the presence of anti-MDA5 and ILD.Conclusion DRB1＊04：01 and ＊12：02 confer susceptibility to anti-MDA5 antibody production in DM, which cannot be explained by the SE hypothesis.