Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis.
Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis.
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DOI：
10.1001/jama.2013.5827
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发表时间：
2013-06-05
期刊：
影响因子：
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通讯作者：
Schwartz DA
中科院分区：
文献类型：
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作者：
Peljto AL;Zhang Y;Fingerlin TE;Ma SF;Garcia JG;Richards TJ;Silveira LJ;Lindell KO;Steele MP;Loyd JE;Gibson KF;Seibold MA;Brown KK;Talbert JL;Markin C;Kossen K;Seiwert SD;Murphy E;Noth I;Schwarz MI;Kaminski N;Schwartz DA
目前基于临床和生理参数的特发性肺纤维化（IPF）死亡率预测模型在预测哪些患者将进展方面具有适度的价值。除了改善预后模型的潜力外，识别与IPF死亡率相关的遗传和分子特征可能有助于深入了解疾病的潜在机制并为临床试验提供信息。确定先前报告与肺纤维化发生相关的MUC 5 B启动子多态性（rs35705950）是否与IPF患者的生存率相关。在2个独立的IPF患者队列中进行的生存期回顾性研究：INSPIRE队列，由入组干扰素-γ1b试验的患者组成（n=438; 2003年12月15日至2009年5月2日; 7个欧洲国家、美国和加拿大的81个中心）和芝加哥队列，包括从芝加哥大学间质性肺病诊所招募的IPF受试者（n=148; 2007-2010）。INSPIRE队列用于模拟MUC 5 B基因型与生存率的相关性，解释基质金属蛋白酶7（MMP-7）血液浓度和其他人口统计学和临床协变量的影响。芝加哥队列用于重复研究结果。主要终点为全因死亡率。INSPIRE队列中GG、GT和TT基因型组的患者数量分别为148例（34%）、259例（59%）和31例（7%），芝加哥队列中分别为41例（28%）、98例（66%）和9例（6%）。INSPIRE的中位随访期为1.6年，芝加哥的中位随访期为2.1年。随访期间，INSPIRE患者中有73例死亡（36例GG、35例GT和2例TT），芝加哥患者中有64例死亡（26例GG、36例GT和2例TT）。在INSPIRE队列和INSPIRE队列中，携带1个或多个IPF风险等位基因（T）拷贝的患者的未校正2年累积死亡发生率较低（GG为0.25 [95% CI，0.17-0.32]，GT为0.17 [95% CI，0.11-0.23]，TT为0.03 [95% CI，0.00-0.09]）和芝加哥队列（GG为0.50 [95% CI，0.31-0.63]，GT为0.22 [95% CI，0.13-0.31]，TT为0.11 [95% CI，0.00-0.28]）。在INSPIRE队列中，与GG相比，TT和GT基因型（IPF风险）与生存改善相关（风险比分别为0.23 [95%CI，0.10-0.52]和0.48 [95%CI，0.31-0.72]; P<.001）。这一发现在芝加哥队列中得到了重复（风险比分别为0.15 [95%CI，0.05-0.49]和0.39 [95%CI，0.21-0.70]; P<0.002）。所观察到的MUC 5 B与生存率的相关性与年龄、性别、用力肺活量、一氧化碳弥散量、MMP-7和治疗状态无关。将MUC 5 B基因型添加到生存模型中显著提高了模型在INSPIRE队列和对照组中的预测准确性。（C=0.71 [95% CI，0.64-0.75] vs C=0.68 [95% CI，0.61-0.73]; P<.001）和芝加哥队列（C=0.73 [95% CI，0.62-0.78] vs C=0.69 [95% CI，0.59-0.75]; P= 0.01）。在IPF患者中，MUC 5 B的常见风险多态性与生存率改善显著相关。进一步的研究是必要的，以完善的风险估计，并确定这些发现的临床意义。
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. 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. 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. The primary end point was all-cause mortality. 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 was1.6 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). 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.