Chest
Volume 152, Issue 4, October 2017, Pages 780-791
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Original Research: Diffuse Lung Disease
Clinical and Genetic Associations of Objectively Identified Interstitial Changes in Smokers

https://doi.org/10.1016/j.chest.2017.04.185Get rights and content

Background

Smoking-related lung injury may manifest on CT scans as both emphysema and interstitial changes. We have developed an automated method to quantify interstitial changes and hypothesized that this measurement would be associated with lung function, quality of life, mortality, and a mucin 5B (MUC5B) polymorphism.

Methods

Using CT scans from the Genetic Epidemiology of COPD Study, we objectively labeled lung parenchyma as a tissue subtype. We calculated the percentage of the lung occupied by interstitial subtypes.

Results

A total of 8,345 participants had clinical and CT scanning data available. A 5% absolute increase in interstitial changes was associated with an absolute decrease in FVC % predicted of 2.47% (P < .001) and a 1.36-point higher St. George’s Respiratory Questionnaire score (P < .001). Among the 6,827 participants with mortality data, a 5% increase in interstitial changes was associated with a 29% increased risk of death (P < .001). These associations were present in a subgroup without visually defined interstitial lung abnormalities, as well as in those with normal spirometric test results, and in those without chronic respiratory symptoms. In non-Hispanic whites, for each copy of the minor allele of the MUC5B promoter polymorphism, there was a 0.64% (P < .001) absolute increase in the percentage of lung with interstitial changes.

Conclusions

Objective interstitial changes on CT scans were associated with impaired lung function, worse quality of life, increased mortality, and more copies of a MUC5B promoter polymorphism, suggesting that these changes may be a marker of susceptibility to smoking-related lung injury, detectable even in those who are healthy by other measures.

Section snippets

Methods

We performed our study by using CT scanning and clinical and genetic data from the Genetic Epidemiology of COPD (COPDGene) Study, which has been described in detail elsewhere.15, 16 Briefly, 10,300 smokers between the ages of 45 and 80 years, with a history of at least 10 pack-years, were enrolled and underwent baseline testing, including an extensive interview, volumetric high-resolution CT scanning of the chest, and spirometric testing. COPDGene excluded Hispanics from the study, and the only

Results

A total of 8,345 participants had both clinical and objective imaging data available for analysis. Baseline characteristics of the entire cohort and subgroups are shown in Table 1. The distributions of interstitial changes in the cohort by lung zone are shown in Figure 2.

As shown in Table 2, in both the adjusted and unadjusted analyses, increasing amounts of interstitial features were associated with lower FEV1 % predicted, lower FVC % predicted, higher FEV1/FVC ratio, and a worse quality of

Discussion

In a large cohort of current and former smokers, we found that objectively detected interstitial features were associated with reduced lung function, worse quality of life, and increased mortality. In addition, for each copy of the minor allele of the MUC5B promoter polymorphism (rs35705950), more of the lung was affected by interstitial features. These associations were present even in participants who did not have visually defined ILA, in those with normal lung function, and in those without

Conclusions

We have developed and applied an objective analysis tool that quantifies interstitial changes on CT scans to a large cohort of smokers without known interstitial disease. Objective interstitial changes defined by this method were associated with reduced lung function, worse quality of life, and higher mortality, as well as a higher number of copies of a specific polymorphism in the promoter region of MUC5B. Additional work is needed to replicate these findings in other cohorts to help define a

Acknowledgments

Author contributions: S. Y. A. and G. R. W. take full responsibility for the content of this manuscript including the data and analysis. S. Y. A., R. H., J. C. R., R. S. J. E., and G. R. W. contributed to the study concept and design. All authors contributed to the acquisition, analysis, or interpretation of data. All authors contributed to the drafting of the manuscript. All authors contributed to the intellectual content. S. Y. A., R. K. P., A. A. D., and G. R. W. contributed to the

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    Drs Ash and Harmouche contributed equally to this work.

    Drs San Jose Estepar and Washko contributed equally to this work.

    FUNDING/SUPPORT: This study was funded by the National Institutes of Health [Grants 5-T32-HL007633-30 (S. Y. A., R. K. P.), R01-HL107246 (R. H., J. O. O., R. S. J. E., G. R. W.), R01-HL116933 (R. H., J. C. R., J. O. O., R. S. J. E., G. R. W.), R01-HL111024 (G. M. H.), P01-HL114501 (A. M. C., I. O. R., G. R. W.), and R01-HL089856 (J. C. R., D. A. L., R. S. J. E., G. R. W.)]; and Boehringer Ingelheim Pharmaceuticals, Inc. (G. R. W.).

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