ATS 2013：MUC5B基因多态性与特发性肺纤维化患者生存改善显著相关

《美国医学会杂志》5月21日在线发表的一项研究报告显示，粘蛋白基因MUC5B启动子的常见多态性 rs35705950与特发性肺纤维化(IPF)患者的生存改善显著相关。美国丹佛科罗拉多大学公共卫生学院流行病学部的Anna L. Peljto博士及其同事称，在一个纳入438例IPF患者的队列中，研究者发现那些携带1个或多个变异体拷贝的患者与那些不携带这一变异体的患者相比，2年累积死亡率更低。这一报道且同时在美国胸科学会(ATS)年会上发布。

与之相反的是，既往报道认为同一位点多态性与散发性IPF和家族性间质性肺炎强烈相关，并被认为是这两种疾病的危险等位基因。MUC5B rs35705950基因多态性是如何赋予晚期IPF生存获益的尚不清楚，研究者说，但“粘膜宿主防御功能提高、感染并发症的减少、有益的药物应答、以及潜在的创伤修复双重作用，都是应被考虑的可能因素。”他们指出，“上述机理之外，这些结果提示携带MUC5B 启动子基因多态性的IPF患者可能意味着一个特异的病理学进程，包含更高的疾病易感性和更长的生存期，两者都具有显著性特征。”

Peljto博士及其同事检验了438例参与一项为期3年的干扰素治疗研究的IPF患者。共37%的患者被检出携带MUC5B多态性。结果显示，携带1个或多个MUC5B多态性拷贝的患者，未校正2年累计死亡率低于未携带MUC5B多态性的患者。后来，研究者在第二个人群中对该多态性进行了评估。从21世纪头10年后半段开始，这一人群在芝加哥大学间质性肺病诊所接受治疗且随访1.6年(中位数)，共计148例患者。与第一列人群相似，该人群中携带MUC5B多态性的患者比例为39%，在这一人群中，携带MUC5B多态性的患者其未校正累积死亡率也显著低于未携带MUC5B多态性的患者。

研究者对两组患者的数据进行汇总分析，并校正患者年龄、性别、吸烟史、基线用力肺活量和基线一氧化碳扩散能力后，Peljto 医生及其同事说，“MUC5B多态性在统计学上仍是生存的显著预测因素。”进一步校正患者的基质金属蛋白酶-7(MMP-7)血浆浓度等数据后发现，高浓度的MMP-7与IPF患者预后不良相关。在该分析中，MUC5B多态性与生存改善之间的相关性维持不变。研究者说，“据我们所知，这一研究首次将遗传性变型与IPF患者的生存联系起来。”(JAMA 2013 May 21 [doi:10.1001/jama.2013.5827])

然而，“鉴于在患有已确认疾病的患者中，MUC5B的增加仅能够相对较小地提高预测准确性，”因此目前考虑在临床上常规对IPF患者进行基因分型为时尚早。对于患有亚临床或早期疾病的患者，在肺功能明显下降前，通过综合MUC5B及其他遗传和分子因素的预测能力来预测预后可能有所帮助，“因为目前美国尚无获准用于治疗IPF的药物疗法，早期遗传学咨询或肺移植可能是患者唯一的机会，”研究者说。

该研究由美国国立心肺血液研究所及匹兹堡大学Dorothy P. and Richard P. Simmons Endowed Chair for Pulmonary Research资助。Peljto博士声明无相关经济利益冲突，其同事报告与多家药企资助存在多项联系。

Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis.
IMPORTANCE
Current prediction models of mortality in idiopathic pulmonary fibrosis (IPF), which are based on clinical and physiological parameters, have modest value in predicting which patients will progress. In addition to the potential for improving prognostic models, identifying genetic and molecular features that are associated with IPF mortality may provide insight into the underlying mechanisms of disease and inform clinical trials.
OBJECTIVE
To determine whether the MUC5B promoter polymorphism (rs35705950), previously reported to be associated with the development of pulmonary fibrosis, is associated with survival in IPF.
DESIGN, SETTING, AND PARTICIPANTS
Retrospective study of survival in 2 independent cohorts of patients with IPF: the INSPIRE cohort, consisting of patients enrolled in the interferon-γ1b trial (n = 438; December 15, 2003-May 2, 2009; 81 centers in 7 European countries, the United States, and Canada), and the Chicago cohort, consisting of IPF participants recruited from the Interstitial Lung Disease Clinic at the University of Chicago (n = 148; 2007-2010). The INSPIRE cohort was used to model the association of the MUC5B genotype with survival, accounting for the effect of matrix metalloproteinase 7 (MMP-7) blood concentration and other demographic and clinical covariates. The Chicago cohort was used for replication of findings. MAIN OUTCOMES AND MEASURES: The primary end point was all-cause mortality.
RESULTS
The numbers of patients in the GG, GT, and TT genotype groups were 148 (34%), 259 (59%), and 31 (7%), respectively, in the INSPIRE cohort and 41 (28%), 98 (66%), and 9 (6%), respectively, in the Chicago cohort. The median follow-up period was 1.6 years for INSPIRE and 2.1 years for Chicago. During follow-up, there were 73 deaths (36 GG, 35 GT, and 2 TT) among INSPIRE patients and 64 deaths (26 GG, 36 GT, and 2 TT) among Chicago patients. The unadjusted 2-year cumulative incidence of death was lower among patients carrying 1 or more copies of the IPF risk allele (T) in both the INSPIRE cohort (0.25 [95% CI, 0.17-0.32] for GG, 0.17 [95% CI, 0.11-0.23] for GT, and 0.03 [95% CI, 0.00-0.09] for TT) and the Chicago cohort (0.50 [95% CI, 0.31-0.63] for GG, 0.22 [95% CI, 0.13-0.31] for GT, and 0.11 [95% CI, 0.00-0.28] for TT). In the INSPIRE cohort, the TT and GT genotypes (risk for IPF) were associated with improved survival compared with GG (hazard ratios, 0.23 [95% CI, 0.10-0.52] and 0.48 [95% CI, 0.31-0.72], respectively; P < .001). This finding was replicated in the Chicago cohort (hazard ratios, 0.15 [95% CI, 0.05-0.49] and 0.39 [95% CI, 0.21-0.70], respectively; P < .002). The observed association of MUC5B with survival was independent of age, sex, forced vital capacity, diffusing capacity of carbon monoxide, MMP-7, and treatment status. The addition of the MUC5B genotype to the survival models significantly improved the predictive accuracy of the model in both the INSPIRE cohort (C = 0.71 [95% CI, 0.64-0.75] vs C = 0.68 [95% CI, 0.61-0.73]; P < .001) and the Chicago cohort (C = 0.73 [95% CI, 0.62-0.78] vs C = 0.69 [95% CI, 0.59-0.75]; P = .01).
CONCLUSIONS AND RELEVANCE
Among patients with IPF, a common risk polymorphism in MUC5B was significantly associated with improved survival. Further research is necessary to refine the risk estimates and to determine the clinical implications of these findings.