Association of MUC1 rs4072037 Polymorphism with the Progression and Prognosis of Connective Tissue Disease-associated Interstitial Lung Disease

doi:10.12114/j.issn.1007-9572.2020.00.584

Abstract

Abstract: Background　Interstitial lung disease seriously affects the prognosis of patients with connective tissue disease（CTD）.Recent studies have suggested that Krebs von den Lungen-6（KL-6）secreted by human typeⅡ alveolar epithelial cells is a sensitive biomarker of interstitial lung disease.MUC1 rs4072037 polymorphism is related to individual differences in KL-6 levels，but there are no rs4072037 of MUC1 gene related data in patients with connective tissue disease-associated interstitial lung disease（CTD-ILD），and the relationship of rs4072037 of MUC1 gene with serum KL-6 levels is not clear.Objective　This study was aimed at investigating the correlation of MUC1 rs4072037 polymorphism with serum KL-6 and pulmonary function and its prognostic value in patients with CTD-ILD.Methods　We retrospectively studied 48 CTD-ILD inpatients（CTD-ILD group）and 13 inpatients with CTD（CTD group）recruited from Department of Rheumatology and Immunology，the First Affiliated Hospital of University of South China，and 30 healthy volunteers（control group）recruited from outpatient health examinees of the hospital from January 2015 to December 2018.We collected their lung function parameters〔FVC%pred，FEV1%pred，TLC%pred，diffusing capacity for carbon monoxide（DLCO%pred），PaO2，alveolar-arterial oxygenation gradient（A-aDO2）〕，and serum KL-6，LDH and MUC1 rs4072037 polymorphism.Kaplan Meier method was used to draw survival curves， and log rank test was used to evaluate the difference between survival curves.Cox proportional hazards model was used to explore factors independently associated with CTD-ILD.C- statistics analysis was used to analyze the testing power of the predictive model.Results　Compared with the control group，CTD and CTD-ILD groups had much lower FVC%pred，FEV1%pred and PaO2 and higher A-aDO2，serum KL-6 and LDH（P<0.05）.The DLCO%pred of the CTD-ILD group was lower than that of other two groups（P<0.05）.A-aDO2 in CTD-ILD group was higher than that in CTD group（P<0.05）.In CTD-ILD group，there were 22 cases with A/A genotype and 26 with A/G genotype，while in control group，there were 9 with A/A genotype，12 with A/G genotype，and 9 with G/G genotype，indicating significant intergroup difference in MUC1 rs4072037 polymorphism（χ2=16.325，P<0.001）.CTD-ILD patients with A/A genotype had higher serum KL-6 level〔（8.09±1.68）U/L vs（2.40±4.64） U/L〕（t=3.748，P=0.007）and LDH〔（372±40 ）U/L vs（266±23 ）U/L〕（t=2.124，P=0.030）than those with A/G genotype.CTD-ILD patients with A/G genotype had lower A-aDO2〔（35±3）mm Hg vs（45±4）mm Hg〕and but higher DLCO%pred〔（58%±3%）vs（40%±6%）〕than those with A/A genotype（t=2.377，2.778，P=0.027，0.012）.The cumulative disease progression rate of CTD-ILD patients with A/A genotype and those with A/G genotype was different（χ2=9.242，P=0.008）.Multivariate analysis with Cox proportional hazards model showed that，MUC1 rs4072037（G）was an influencing factor of the remission rate 〔HR=5.43，95%CI（1.2，25.6），P=0.025〕.C-statistics indicated that rs4072037（G）could predict the clinical remission rate in a model with covariates（P=0.021）.Conclusion　MUC1 rs4072037 polymorphism may be closely associated with serum KL-6，pulmonary function and prognosis in patients with CTD-ILD，and can predicte the clinical remission rate.

Key words: Connective tissue disease；Lung diseases, interstitial；Interstitial lung disease；Mucin-1；KL-6；Pulmonary function；Correlation analysis

摘要： 背景　间质性肺炎（ILD）严重影响结缔组织疾病（CTD）患者预后，近年来研究提示人Ⅱ型肺泡上皮细胞分泌的表面抗原6（KL-6）是ILD的敏感生物学标志物。黏蛋白1（MUC1） rs4072037基因多态性与KL-6水平的个体差异有关，但目前并没有结缔组织病相关间质性肺疾病（CTD-ILD）患者中MUC1 rs4072037基因相关数据，其与血清KL-6水平的关系尚不明确。目的　研究MUC1 rs4072037基因多态性与血清KL-6水平、肺功能之间的关系，及其对CTD-ILD患者预后的预测价值。方法　选取2015年1月—2018年12月南华大学附属第一医院风湿免疫科住院诊治的CTD-ILD患者48例（CTD-ILD组）、单纯CTD患者13例（CTD组）及同期本院门诊自愿参与本研究的健康体检者30例（对照组）为研究对象。检测其肺功能〔用力肺活量占预计值百分比（FVC%pred）、第1 秒用力呼气末容积占预计值百分比（FEV1%pred）、肺总容量占预计值百分比（TLC%pred）、一氧化碳弥散量占预计值百分比（DLCO%pred）、动脉血氧分压（PaO2）、肺泡-动脉氧分压差（A-aDO2）〕、血清KL-6、乳酸脱氢酶（LDH）以及MUC1 rs4072037的基因型。采用Kaplan-Meier法绘制生存曲线，并通过 Log-rank检验评估生存曲线之间的差异；采用Cox比例风险回归模型分析CTD-ILD的独立影响因素，采用C统计量分析预测模型的检验效能。结果　CTD组与CTD-ILD组的FVC%pred、FEV1%pred、PaO2低于对照组，A-aDO2、血清KL-6、血清LDH水平高于对照组，CTD-ILD组的DLCO%pred低于对照组与CTD组，CTD-ILD组的A-aDO2高于CTD组（P<0.05）。CTD-ILD组患者A/A基因型22例、A/G基因型26例；对照组A/A基因型9例、A/G基因型12例、G/G基因型9例；两组间MUC1 rs4072037基因频率比较，差异有统计学意义（χ2=16.325，P<0.001）。CTD-ILD组A/A基因型患者血清KL-6水平〔（8.09±1.68）U/L〕、LDH水平〔（372±40）U/L〕均高于A/G基因型〔（2.40±4.64）U/L、（266±23）U/L〕（t=3.748、2.124，P=0.007、0.030）。A/G基因型CTD-ILD患者的A-aDO2〔（35±3）mm Hg〕低于A/A基因型〔（45±4）mm Hg〕，DLCO%pred（58%±3%）高于A/A基因型（40%±6%）（t=2.377、2.778，P=0.027、0.012）。A/A基因型CTD-ILD患者与A/G基因型CTD-ILD患者CTD-ILD患者的累积疾病进展率不同（χ2=9.242，P=0.008）。多因素Cox比例风险回归模型分析结果显示，MUC1 rs4072037（G）是疾病缓解率的影响因素〔HR=5.43，95%CI（1.2，25.6），P=0.025〕。C统计结果显示，rs4072037（G）在具有协变量的模型中可以预测临床缓解率（P=0.021）。结论　CTD-ILD患者MUC1 rs4072037基因型与血清KL-6水平、肺功能及疾病预后存在显著相关性，且可以预测其临床缓解率。

关键词: 结缔组织病, 肺疾病, 间质性, 黏蛋白-1, KL-6, 肺功能, 相关性分析

LONG Xiaoping，TANG Yanhua，XU Lihui，WANG Weizhong，LI Jianmin，XIE Lihu. Association of MUC1 rs4072037 Polymorphism with the Progression and Prognosis of Connective Tissue Disease-associated Interstitial Lung Disease　[J]. Chinese General Practice, 2020, 23(35): 4448-4453.

龙小平，唐艳华，许丽慧，王卫忠1李建民，谢立虎. 黏蛋白1基因单核苷酸rs4072037多态性对结缔组织病相关间质性肺疾病的影响及预测价值研究[J]. 中国全科医学, 2020, 23(35): 4448-4453.

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