We measured two common single-nucleotide polymorphisms associated with IPF (MUC5Brs35705950 and TOLLIP rs5743890) and telomere length in peripheral blood leucocytes, and assessed their associations with chronic hypersensitivity pneumonitis risk, survival, and clinical, radiographic, and pathological features.
We have previously found that 1) a common gain-of-function promoter variant in MUC5Brs35705950 is the strongest risk factor (genetic and otherwise), accounting for 30-35% of the risk of developing IPF, a disease that was previously considered idiopathic; 2) the MUC5B promoter variant can potentially be used to identify individuals with preclinical pulmonary fibrosis and is predictive of radiologic progression of preclinical pulmonary fibrosis; and 3) MUC5B may be involved in the pathogenesis of pulmonary fibrosis with MUC5B message and protein expressed in bronchiolo-alveolar epithelia of IPF and the characteristic IPF honeycomb cysts.
This study demonstrated that the MUC5B polymorphism rs35705950 is associated with increased risk of idiopathic pulmonary fibrosis susceptibility, severity, and the decreased overall survival.
A polymorphism in the promoter of the MUC5B gene has been associated with both sporadic and familial forms of idiopathic pulmonary fibrosis; however, the impact of this association remains to be determined.
In aggregate, our findings indicate that the MUC5B promoter variant is associated with higher C3 expression and suggest that the complement system may contribute to the pathogenesis of IPF.
Analysis of protein-altering variants in telomerase genes and their association with MUC5B common variant status in patients with idiopathic pulmonary fibrosis: a candidate gene sequencing study.
Two genome-wide association studies and one sequencing study have coincidently reported significant associations of single nucleotide polymorphisms (SNPs) in the desmoplakin (DSP) gene with the risk of pulmonary fibrosis (mainly idiopathic pulmonary fibrosis).
However, in the candidate region analysis, rs2076295 in the DSP gene, previously associated with COPD, lung function and idiopathic pulmonary fibrosis, was associated with change in %LAA-950 (β (SE) = 0.09 (0.02), P = 3.79e-05) and in ALD (β (SE) = - 0.06 (0.02), P = 2.88e-03).
We identified a novel genome-wide significant signal of association with IPF susceptibility near A-kinase anchoring protein 13 (AKAP13; rs62025270, odds ratio [OR] 1·27 [95% CI 1·18-1·37], p=1·32 × 10<sup>-9</sup>) and confirmed previously reported signals, including in mucin 5B (MUC5B; rs35705950, OR 2·89 [2·56-3·26], p=1·12 × 10<sup>-66</sup>) and desmoplakin (DSP; rs2076295, OR 1·44 [1·35-1·54], p=7·81 × 10<sup>-28</sup>).
Rare protein-altering variants in TERT, PARN, TERC, and RTEL1 are enriched in patients with IPF compared with controls, and, in the case of TERT, particularly in individuals without a risk allele at the rs35705950 locus.
DNA sequence analyses of the surfactant protein C gene in children with nonspecific interstitial pneumonia and adults with usual interstitial pneumonia exhibit a common heterozygous mutation located in exon 5.
Mutations in telomerase complex genes (TERT or TERC) and short telomeres are genetic risk factors for the development of familial or sporadic idiopathic pulmonary fibrosis.
In individuals with familial interstitial pneumonia without SFTPC mutations and patients with sporadic IPF, we also found UPR activation selectively in AECs lining areas of fibrotic remodeling.
Owing to diverse clinical presentations, STSs pose a diagnostic challenge, with bone marrow failure and idiopathic pulmonary fibrosis being frequent manifestations, occurring in association with gene mutations involving DKC1 (for expansion of gene symbols, use search tool at www.genenames.org), TERT, TERC, and others.
Heterozygous mutations in four telomere-related genes have been linked to pulmonary fibrosis, but little is known about similarities or differences of affected individuals.115 patients with mutations in telomerase reverse transcriptase (TERT) (n=75), telomerase RNA component (TERC) (n=7), regulator of telomere elongation helicase 1 (RTEL1) (n=14) and poly(A)-specific ribonuclease (PARN) (n=19) were identified and clinical data were analysed.Approximately one-half (46%) had a multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF); others had unclassifiable lung fibrosis (20%), chronic hypersensitivity pneumonitis (12%), pleuroparenchymal fibroelastosis (10%), interstitial pneumonia with autoimmune features (7%), an idiopathic interstitial pneumonia (4%) and connective tissue disease-related interstitial fibrosis (3%).