美国学者的一项研究显示,粘蛋白基因启动子的常见多态性MUC5B rs35705950与特发性肺纤维化(IPF)患者的生存改善显著相关。相关论文2013年5月21日在线发表于《美国医学会杂志》(JAMA)。
该研究纳入438例参与一项为期3年的干扰素治疗研究的IPF患者。
结果显示,共37%的患者被检出携带MUC5B多态性。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。进一步校正患者的基质金属蛋白酶-7(MMP-7)血浆浓度后发现,高浓度的MMP-7与IPF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。
研究者表示,目前尚不知道MUC5B rs35705950多态性为什么有助于改善IPF患者的生存,但可能与黏膜宿主防御增强、感染性并发症降低、有益药物反应及伤口修复中的潜在双重作用相关。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。然而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的唯一选择。
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.
{nextpage}Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with a median survival of 3 years.1 The prognosis is variable; patients may remain stable for several years, slowly lose lung function, progress in an intermittent stair-step fashion, or experience precipitous acute exacerbations.2- 4 Although clinical and physiological parameters have modest value in predicting which patients will progress,5 serum biomarkers, including chemokine ligand 18, KL6, surfactant protein A (SFTPA), and SFTPD, are independently associated with outcome in IPF.6- 7 Recently, elevated plasma concentrations of matrix metalloproteinase 7 (MMP-7), intercellular adhesion molecule 1, and interleukin 8 have been shown to be associated with poor outcomes in IPF, and when combined with clinical features, these plasma proteins predict mortality in IPF.8
Rare mutations in SFTPC, SFTPA2, telomerase reverse transcriptase (TERT), and telomerase RNA component (TERC)9- 11 have been associated with development of pulmonary fibrosis. Recently, a common polymorphism in the promoter of a mucin gene (MUC5B) has been found to be associated with an increase in risk of developing both familial and sporadic IPF in an allele dose-dependent manner.12- 13 While MUC5B expression in the lung was 14.1 times higher in patients with IPF, the MUC5B promoter polymorphism was associated with up-regulation of this transcript only in unaffected participants.