MUC5B和TOLLIP基因多态性对特发性肺纤维化患者预后评估的临床研究

Clinical study of MUC5B and TOLLIP gene polymorphisms in evaluating the prognosis of patients with idiopathic pulmonary fibrosis

目的了解中国特发性肺纤维化(IPF)患者MUC5B和TOLLIP的基因多态性变异状况,探讨其能否作为IPF患者精确治疗和判断预后的基因生物标志物。方法纳入IPF患者126例,随访并采集患者基线特征、肺总量(TLC)、用力肺活量(FVC)、一氧化碳弥散功能(D_LCO)、影像学变化;采用化学发光酶免疫检测法和酶联免疫吸附法检测外周血血清涎液化糖链抗原-6(KL-6)和B淋巴细胞趋化因子CXCL13基线水平;聚合酶链反应测定基因MUC5B rs35705950及TOLLIP rs5743890、rs5743894单核苷酸多态性(SNP)。结果126例IPF患者TOLLIP SNP rs5743890和rs5743894均为AA型,占100.0%;MUC5B SNP rs35705950表达为GG型患者116例,占92.1%,GT型患者10例,占7.9%,未检测到TT型患者。GT型和GG型患者的年龄和未吸烟者的分布趋势无明显差异(P>0.05);与GG型患者比较,GT型患者的FVC、D_LCO和TLC年变化程度,KL-6和CXCL13水平,网格状和蜂窝状病变年变化程度,以及死亡率均明显降低,其中位生存时间明显高于GG型患者(P<0.05)。结论中国IPF患病人群存在基因多态性现象。MUC5B rs35705950和TOLLIP rs5743890、rs5743894基因亚型在中国IPF患病人群中突变率低。GT型较GG型患者肺功能减损和影像学病变进展慢,KL-6和CXCL13水平低,预后较好。

Objective To understand the genetic polymorphisms of MUC5 B and TOLLIP in Chinese patients with idiopathic pulmonary fibrosis(IPF),and to explore whether gene polymorphism variation in Chinese IPF patients can be used as a genetic biomarker for accurate treatment and prognosis judgment.Methods A total of one hundred and twenty-six patients with IPF were enrolled in this study.The baseline characteristics,total lung capacity(TLC),forced vital capacity(FVC),carbon monoxide diffusion function(D_LCO),imaging changes of the patients were followed up.The levels of serum sputum glycosylated antigen-6(Krebs Von den Lungen-6,KL-6)and B lymphocyte chemotactic factor C-X-C motif chemokine 13(CXCL13)were detected by chemiluminescent enzyme immunoassay and enzyme-linked immunosorbent assay.The gene MUC5 B rs35705950 and TOLLIP rs5743890,rs5743894 single nucleotide polymorphism(SNP)were determined by polymerase chain reaction.Results One hundred and twenty-six patients with IPF were found with AA type by TOLLIP rs5743890 and rs5743894 SNP,accounting for 100.0%;MUC5 B rs35705950 SNP was expressed as 116 patients(92.1%)with GG type,and 10 patients(7.9%)with GT type,no TT patients were detected.There was no significant difference in clinical characteristics between the two groups in age and non-smokers(P>0.05).Compared with group G,annual decrease of lung function(FVC,D_LCO,and TLC),serum biomarkers(KL-6 and CXCL13),annual increase of reticular and honeycombing lesions,and mortality were significantly lower in group T(P<0.05).The median survival time of IPF patients carrying the MUC5 B SNP rs35705950 minor allele(gene phenotype GT)heterozygous was significantly higher than that of homozygous IPF patients with a genetic phenotype of GG.Conclusions There are genetic polymorphisms in Chinese patients with IPF.MUC5 B rs35705950 and TOLLIP rs5743890,rs5743894 gene subtypes have low mutation rates in the cohort.Compared with homozygous patients of MUC5 B SNP rs35705950,heterozygous patients have smaller changes in lung function and radiological image,lower levels of serum KL-6 and CXCL13,and better prognosis.