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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.

SUBMITTER: Putman RK

PROVIDER: S-EPMC5687883 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Putman Rachel K RK Gudmundsson Gunnar G Araki Tetsuro T Nishino Mizuki M Sigurdsson Sigurdur S Gudmundsson Elías F EF Eiríksdottír Gudny G Aspelund Thor T Ross James C JC San José Estépar Raúl R Miller Ezra R ER Yamada Yoshitake Y Yanagawa Masahiro M Tomiyama Noriyuki N Launer Lenore J LJ Harris Tamara B TB El-Chemaly Souheil S Raby Benjamin A BA Cho Michael H MH Rosas Ivan O IO Washko George R GR Schwartz David A DA Silverman Edwin K EK Gudnason Vilmundur V Hatabu Hiroto H Hunninghake Gary M GM

The European respiratory journal 20170911 3

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 C ...[more]

PMID: 28893869

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Project description:BACKGROUND:Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS:Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS:Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7×10-17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7×10-35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3×10-49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4×10-5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5×10-6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS:We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.).

Project description:BACKGROUND:The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk. METHODS:Using a genomewide linkage scan, we detected linkage between idiopathic interstitial pneumonia and a 3.4-Mb region of chromosome 11p15 in 82 families. We then evaluated genetic variation in this region in gel-forming mucin genes expressed in the lung among 83 subjects with familial interstitial pneumonia, 492 subjects with idiopathic pulmonary fibrosis, and 322 controls. MUC5B expression was assessed in lung tissue. RESULTS:Linkage and fine mapping were used to identify a region of interest on the p-terminus of chromosome 11 that included gel-forming mucin genes. The minor-allele of the single-nucleotide polymorphism (SNP) rs35705950, located 3 kb upstream of the MUC5B transcription start site, was present at a frequency of 34% among subjects with familial interstitial pneumonia, 38% among subjects with idiopathic pulmonary fibrosis, and 9% among controls (allelic association with familial interstitial pneumonia, P=1.2×10(-15); allelic association with idiopathic pulmonary fibrosis, P=2.5×10(-37)). The odds ratios for disease among subjects who were heterozygous and those who were homozygous for the minor allele of this SNP were 6.8 (95% confidence interval [CI], 3.9 to 12.0) and 20.8 (95% CI, 3.8 to 113.7), respectively, for familial interstitial pneumonia and 9.0 (95% CI, 6.2 to 13.1) and 21.8 (95% CI, 5.1 to 93.5), respectively, for idiopathic pulmonary fibrosis. MUC5B expression in the lung was 14.1 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not (P<0.001). The variant allele of rs35705950 was associated with up-regulation in MUC5B expression in the lung in unaffected subjects (expression was 37.4 times as high as in unaffected subjects homozygous for the wild-type allele, P<0.001). MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis. CONCLUSIONS:A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis. Our findings suggest that dysregulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis. (Funded by the National Heart, Lung, and Blood Institute and others.).

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

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The <i>MUC5B</i> promoter polymorphism is associated with specific interstitial lung abnormality subtypes.

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