Association Between the MUC5B Promoter Polymorphism and Survival in Patients With Idiopathic Pulmonary Fibrosis

Peljto, Anna L.; Zhang, Yingze; Fingerlin, Tasha E.; Ma, Shwu‐Fan; Garcia, Joe G.N.; Richards, Thomas J.; Silveira, Lori; Lindell, Kathleen O.; Steele, Mark P.; Loyd, James E.; Gibson, Kevin F.; Seibold, Max A.; Brown, Kevin K.; Talbert, Janet; Markin, Cheryl; Kossen, Karl; Seiwert, Scott D.; Murphy, Elissa; Noth, Imre; Schwarz, Marvin I.; Kaminski, Naftali; Schwartz, David A.

doi:10.1001/jama.2013.5827

Cited by 397 publications

(323 citation statements)

References 30 publications

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“…In this case there is a clear increase in the frequency of a genetic variant in patients with disease. However, carriers of this common "risk" polymorphism have improved survival (67). We did not observe appreciable differences in age, sex, disease subgroup, or index hemodynamics based on N104ES carrier status ( Table E6) to suggest that lead-time bias contributed to the differences in outcomes; however, this remains a potential limitation.…”

Section: Discussionmentioning

confidence: 66%

Serum Endostatin Is a Genetically Determined Predictor of Survival in Pulmonary Arterial Hypertension

Damico

Kolb

Valera

et al. 2015

Am J Respir Crit Care Med

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102

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Rationale: Pulmonary arterial hypertension (PAH) is a medically incurable disease resulting in death from right ventricular (RV) failure. Both pulmonary vascular and RV remodeling are linked to dynamic changes in the microvasculature. Therefore, we hypothesized that circulating angiostatic factors could be linked to outcomes and represent novel biomarkers of disease severity in PAH.Objectives: We sought to determine the relationship of a potent angiostatic factor, endostatin (ES), with disease severity and mortality in PAH. Furthermore, we assessed genetic predictors of ES expression and/or function and their association with outcomes in PAH.Methods: We measured levels of serum ES in two independent cohorts of patients with PAH. Contemporaneous clinical data included New York Heart Association functional class, 6-minutewalk distance, invasive hemodynamics, and laboratory chemistries.Measurements and Main Results: Serum ES correlated with poor functional status, decreased exercise tolerance, and invasive hemodynamics variables. Furthermore, serum ES was a strong predictor of mortality. A loss-of-function, missense variant in the gene encoding ES, Col18a1, was linked to lower circulating protein and was independently associated with reduced mortality.Conclusions: Our data link increased expression of ES to disease severity in PAH and demonstrate a significant relationship with adverse outcomes. Circulating ES levels can be genetically influenced, implicating ES as a genetically determined modifier of disease severity impacting on survival. These observations support serum ES as a potential biomarker in PAH with the capacity to predict poor outcomes. More importantly, this study implicates Col18a1/ES as a potential new therapeutic target in PAH.

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Section: Discussionmentioning

confidence: 66%

Serum Endostatin Is a Genetically Determined Predictor of Survival in Pulmonary Arterial Hypertension

Damico

Kolb

Valera

et al. 2015

Am J Respir Crit Care Med

Self Cite

102

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“…The association between the minor allele of the MUC5B promoter polymorphism (rs35705950) and IPF is among the most well-replicated findings of genetic association in pulmonary medicine (18). Somewhat unexpectedly, increasing copies of the minor allele of rs35705950 have also been associated with reduced mortality among patients with IPF, suggesting that the MUC5B variant defines a mild subtype of IPF (19). Our findings demonstrate that there is an increased mortality rate associated with progressive imaging abnormalities, which are also associated with increasing copies of the MUC5B promoter genotype (findings consistent with our prior association between MUC5B and ILA in cross-sectional analyses) (2).…”

Section: Discussionmentioning

confidence: 93%

Development and Progression of Interstitial Lung Abnormalities in the Framingham Heart Study

Araki¹,

Putman

Hatabu³

et al. 2016

Am J Respir Crit Care Med

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261

218

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Rationale: The relationship between the development and/or progression of interstitial lung abnormalities (ILA) and clinical outcomes has not been previously investigated.Objectives: To determine the risk factors for, and the clinical consequences of, having ILA progression in participants from the Framingham Heart Study.Methods: ILA were assessed in 1,867 participants who had serial chest computed tomography (CT) scans approximately 6 years apart. Mixed effect regression (and Cox) models were used to assess the association between ILA progression and pulmonary function decline (and mortality).Measurements and Main Results: During the follow-up period 660 (35%) participants did not have ILA on either CT scan, 37 (2%) had stable to improving ILA, and 118 (6%) had ILA with progression (the remaining participants without ILA were noted to be indeterminate on at least one CT scan). Increasing age and increasing copies of the MUC5B promoter polymorphism were associated with ILA progression. After adjustment for covariates, ILA progression was associated with a greater FVC decline when compared with participants without ILA (20 ml; SE, 66 ml; P = 0.0005) and with those with ILA without progression (25 ml; SE, 611 ml; P = 0.03). Over a median follow-up time of approximately 4 years, after adjustment, ILA progression was associated with an increase in the risk of death (hazard ratio, 3.9; 95% confidence interval, 1.3-10.9; P = 0.01) when compared with those without ILA.Conclusions: These findings demonstrate that ILA progression in the Framingham Heart Study is associated with an increased rate of pulmonary function decline and increased risk of death.

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“…The common variant rs35705950 in the promoter region of MUC5B is carried by 9% of the European population and is the strongest risk factor for developing IPF accounting for 30–35% of the risk and also predicting asymptomatic mild fibrosis 68, 77, 78, 79. There are multiple potential explanations for how this polymorphism could lead to fibrosis (for a discussion, Evans et al 68…”

Section: Oxidative and Er Stress In Chronic Inflammatory And Mucopurumentioning

confidence: 99%

Oxidative and endoplasmic reticulum stress in respiratory disease

2018

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Oxidative stress and endoplasmic reticulum (ER) stress are related states that can occur in cells as part of normal physiology but occur frequently in diseases involving inflammation. In this article, we review recent findings relating to the role of oxidative and ER stress in the pathophysiology of acute and chronic nonmalignant diseases of the lung, including infections, cystic fibrosis, idiopathic pulmonary fibrosis and asthma. We also explore the potential of drugs targeting oxidative and ER stress pathways to alleviate disease.

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Association Between the MUC5B Promoter Polymorphism and Survival in Patients With Idiopathic Pulmonary Fibrosis

Cited by 397 publications

References 30 publications

Serum Endostatin Is a Genetically Determined Predictor of Survival in Pulmonary Arterial Hypertension

Serum Endostatin Is a Genetically Determined Predictor of Survival in Pulmonary Arterial Hypertension

Development and Progression of Interstitial Lung Abnormalities in the Framingham Heart Study

Oxidative and endoplasmic reticulum stress in respiratory disease

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