PMC4156421_01
Histological demonstration of the NSIP pattern of IPF in the patient's lungs. Microscopic examination of the lungs.. (A) 40x; (B) 400x. Note uniform fibrotic thickening of the alveolar septae and type II pneumocyte hypertrophy. There was no histologic evidence of sarcoidosis, hypersensitivity pneumonitis, organizing pneumonia, or diffuse alveolar damage.
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Histologic examination of lung tissue revealed diffuse fibrous thickening of alveolar septae (Figure 1, Figure S1). One section from the right middle lobe contained changes of microscopic honeycombing in an area of subpleural fibrosis, where small cysts lined by respiratory epithelium are present and contain mucous and neutrophils (Figure S1).
Integrated Genomics Viewer (IGV) screenshot of the rs35705950 variant.
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One of these variants (Figure 2), rs35705950, is located within the promoter region of MUC5B and has a strong association with both familial and sporadic IPF, with odds ratio (OR) estimates ranging from 2.4-6.8 for heterozygote carriers. Figure S2). For this analysis we used a recently described approach, Combined Annotation-Dependent Depletion scoring system (CADD), which estimates the relative pathogenicity of variants based on a variety of predicted functional effects.
Sequencing coverage and variant distribution within the MUC5B locus.. (A) Sequence coverage of the MUC5B gene. (B) Rare variants neighboring the MUC5B promoter variant rs35705950. Variant track is colored by allele frequency (blue: AF<2%, red: AF<5%, black: AF<10%). No other rare variants in this region overlap with putative transcription factor binding sites, consistent with the hypothesis that the rs35705950 is causative of MUC5B dysregulation. Plots were generated using the UCSC genome browser (http://www.genome.ucsc.edu).
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We also investigated the region between the MUC5AC gene and the MUC5B start site for rare variants (AF<2%) that overlap with regions that may possibly influence expression (Figure 3b).