Idiopathic pulmonary fibrosis (IPF) is an incurable complex genetic disorder that is associated with sequence changes in 7 genes (MUC5B, TERT, TERC, RTEL1, PARN, SFTPC, and SFTPA2) and with variants in at least 11 novel loci.
The mutation (p.Trp211Arg), which segregates with a disease phenotype characterized by either isolated IIP/IPF, or IPF associated with lung adenocarcinoma, is located in the carbohydrate recognition domain (CRD) of SP-A1 and involves a residue invariant throughout evolution, not only in SP-A1, but also in its close paralog SP-A2 and other CRD-containing proteins.
Serum SP-A levels were significantly higher in patients with IPF than in patients with non-IPF ILD (SMD: 1.108 [0.584, 1.632], P < .001), or pulmonary infection (SMD: 1.320 [0.999, 1.640], P < .001) and healthy controls (SMD: 2.802 [1.901, 3.702], P < .001).
Moreover, focusing on MUC5B may provide a unique opportunity to define the early molecular events that lead to, and potentially prevent, the development of IPF.
To determine whether single-nucleotide polymorphisms (SNPs) within TOLLIP and MUC5B modify the effect of interventions in subjects participating in the Evaluating the Effectiveness of Prednisone, Azathioprine, and N-Acetylcysteine in Patients with Idiopathic Pulmonary Fibrosis (PANTHER-IPF) clinical trial.
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>).
Moreover, patients with the MUC5B polymorphism show more severe coughing as MUC5B encodes for the dominant mucin in the honeycomb cysts of IPF patients.
Furthermore, genetic variants of TOLLIP, MUC-5B, and other genes associated with a differential response to treatment and with the development and/or the prognosis of IPF are reported.
Secreted mucins (MUC2, MUC5AC, MUC5B, MUC6-8 and MUC19) are released to the extracellular medium and recent evidence has shown that a promoter polymorphism in the secreted mucin MUC5B is associated with IPF risk.
A common variant in mucin 5B predisposes to both familial and sporadic IPF and is present in the majority of cases, indicating sporadic IPF occurs in those with genetic predisposition.
Associations between 2 polymorphisms in TERT (rs2736100) and MUC5B (rs35705950) and IPF or non-IPF sporadic ILD were tested using 227 patients with ILD and 689 control subjects.
A promoter variant in MUC5B, rs35705950, was previously found to be strongly associated with the incidence of idiopathic pulmonary fibrosis (IPF) and also the overall survival (OS) of such patients.
Baseline bacterial burden predicted the rate of decline in lung volume and risk of death and associated independently with the rs35705950 polymorphism of the MUC5B mucin gene, a proven host susceptibility factor for IPF.