The MUC5B promoter polymorphism is associated with specific interstitial lung abnormality subtypes

Abstract

The MUC5B promoter polymorphism (rs35705950) has been associated with interstitial lung abnormalities (ILA) in white participants from the general population; whether these findings are replicated and influenced by the ILA subtype is not known. We evaluated the associations between the MUC5B genotype and ILA in cohorts with extensive imaging characterisation.We performed ILA phenotyping and MUC5B promoter genotyping in 5308 and 9292 participants from the AGES-Reykjavik and COPDGene cohorts, respectively.We found that ILA was present in 7% of participants from the AGES-Reykjavik, 8% of non-Hispanic white participants from COPDGene and 7% of African-American participants from COPDGene. Although the MUC5B genotype was strongly associated (after correction for multiple testing) with ILA (OR 2.1, 95% CI 1.8-2.4, p=1×10^-26), there was evidence of significant heterogeneity between cohorts (I²=81%). When narrowed to specific radiologic subtypes, (e.g. subpleural ILA), the MUC5B genotype remained strongly associated (OR 2.6, 95% CI 2.2-3.1, p=1×10^-30) with minimal heterogeneity (I²=0%). Although there was no evidence that the MUC5B genotype influenced survival, there was evidence that MUC5B genotype improved risk prediction for possible usual interstitial pneumonia (UIP) or a UIP pattern in non-Hispanic white populations.The MUC5B promoter polymorphism is strongly associated with ILA and specific radiologic subtypes of ILA, with varying degrees of heterogeneity in the underlying populations.

Figure 1

Chest computed tomographic (CT) images depicting radiologic subtypes and the overlap between subtypes of interstitial lung abnormalities (ILA). In all panels the blue arrows point to areas of ILA without fibrosis, the red arrows point to areas of ILA with fibrosis, each panel (1–6) represents one participant. Panels 1–3 demonstrate patterns of ILA that are inconsistent with usual interstitial pneumonia (UIP), panels 4–5 demonstrate patterns of ILA that are possible UIP and panel 6 is a pattern of ILA that is consistent with UIP. Panel 1 represents non-fibrotic, centrilobular predominant ILA, with an area zoomed in to highlight the centrilobular ground glass nodules. Panel 2 is non-fibrotic, mixed pattern of ILA, in 2A the blue arrow points to subpleural reticulation; in 2B the arrows demonstrate both subpleural and centrilobular ground glass. Panel 3 is fibrotic (see the red arrows in 3B), radiologic interstitial lung disease (ILD), that is inconsistent with UIP due to the pleural plaque (blue arrow) in 3A. Panel 4 is non-fibrotic, subpleural predominant ILA, blue arrows pointing to subpleural reticulation. Panel 5 is fibrotic, subpleural predominant ILA, with red arrows in both panels pointing to traction bronchiectasis. Panel 6 is fibrotic, radiologic ILD; red arrows highlight traction bronchiectasis and honeycombing.

Figure 2

Receiver operator curves and bar graphs depicting interstitial lung abnormality (ILA), specifically possible and definite usual interstitial pneumonia (UIP) prediction, using baseline clinical information (age, sex and pack-years of smoking) and then with adding the MUC5B promoter polymorphism in each cohort. In the bar graphs the addition of MUC5B minor allele is for at least one copy of the minor allele.