TABLE 2.
Genetic mutations associated with IPF.
| Targets | Physiological function of the target site | Potential pathogenic mechanisms of gene mutations | Clinical significance | Ref |
|---|---|---|---|---|
| TERT and TERC | TERT and TERC are important components of the telomerase complex | Telomere shortening may affect the turnover and healing of AEC. | TERT (rs2736100) and TERC (6793295) mutations are associated with IPF susceptibility | Armanios et al. (2007); Borie et al. (2016) |
| DKC1 | DKC1, a pseudouridine synthase, is involved in the synthesis of non-coding ribonucleic acids | Mutations in DKC1 can shorten telomeres in alveolar epithelial cells and affect the stability of telomerase RNA. | DKC1 mutations cause dyskeratosis congenita and pulmonary fibrosis | Kropski et al. (2017); Gaysinskaya et al. (2020) |
| TIN2 | TIN2 is an important component of the shelterin complex | Mutations in TIN2 can shorten telomeres | Heterozygous mutations in TINF2 causes IPF | Fukuhara et al. (2013) |
| PARN | PARN, a 3′exoribonuclease, is responsible for telomere maturation | PARN mutations lead to shortened telomeres | PARN mutations and telomere shortening are associated with leukopenia | Stuart et al. (2015) |
| RTEL | RTEL is a DNA helicase crucial for unwinding the T-loop structure | Loss of functional RTEL1 leads to cleavage of the telomeric end proximal to the T-loop by endonuclease SLX4, leading to release of T-loops and shortened telomere | RTEL and telomere shortening are associated with leukopenia | Cogan et al. (2015); Stuart et al. (2015) |
| NAF1 | NAF1, a box H/ACA RNA biogenesis factor, is required for stability and assembly into a mature telomerase holoenzyme complex | NAF1 mutations can reduce telomerase RNA levels, resulting in shorter telomeres | Pulmonary fibrosis-emphysema in NAF1 mutation patients is telomere-mediated | Stanley et al. (2016a) |
| OBFC1 | OBFC1 associates with TPP1 and is implicated in telomere length regulation | N.A. | rs11191865 was associated with a lower risk of IPF. | Fingerlin et al. (2013) |
| MUC5B | Mucin 5B is involved in mucosal clearance along with surfactant protein C and ciliates | Excess Mucin may increase the retention of harmful particles in the lung and interfere with the normal developmental pathway and alveolar epithelial repair | rs35705950 was the strongest genetic risk factor for IPF, but was associated with lower mortality. MUC5B and MUC5AC expression was increased in patients with IPF. | Peljto et al. (2013); Conti et al. (2016); Evans et al. (2016) |
| SFTPC | SFTPC regulates alveolar surface tension | SFTPC mutations may promote lung fibrosis by inducing endoplasmic reticulum stress and apoptotic cell death in AEC II. | SFPTC mutations are associated with familial and sporadic IPF onsets | Ono et al. (2011); Venosa et al. (2017) |
| SFTPA2 | SFTPA is involved in the intrinsic immunity of the lung | SFTPA mutant mouse models exhibit intracellular retention of SFTPA and enhanced ER stress | Mutations in SFTPA2 leads to the trafficking of several proteins and causes the development of IPF. | Yongyu Wang et al. (2009); Maitra et al. (2010); Guenther et al. (2019) |
| ABCA3 | A type of phospholipid carrier, involved in the secretion and transport of surface-active substances in AEC II. | ABCA3 mutations may induce ER stress and proteostasis failure through misfolded alveolar surface-active substances | Heterozygous variants of the ABCA3 gene are associated with IPF susceptibility. pG1205R, an ABCA3 gene allele, is more frequently expressed in patients with IPF and ILDs | Zhou et al. (2017); Manali et al. (2019) |
| ATP11A | ATP11A encodes ABCA1, a transmembrane protein with general transport function | N.A. | rs1278769 was associated with a lower risk of IPF. | Fingerlin et al. (2013) |
| IL1RN | IL-1RN is a competitive antagonist of IL-1R receptor | MSC exerts anti-inflammatory and anti-fibrotic effects via IL-1RN. | The proportion of IL-1RN gene polymorphisms in patients with fibrosing alveolitis was more | Whyte et al. (2000); Ortiz et al. (2007) |
| IL-4 | IL-4 is associated with type 2 immunity | IL-4 gene polymorphisms may promote a Th2 cytokine environment with exaggerated fibroproliferative healing | Higher percentage of IL-4 gene polymorphisms in IPF patients | Vasakova et al. (2013) |
| IL-8 | IL-8 is a chemokine secreted by macrophages and is involved in the recruitment of neutrophils | IL-8 increases the fibrogenicity of mesenchymal progenitor cells and is involved in the proliferation, activation, and recruitment of mesenchymal cells | IL-8 gene diversity is associated with lung alveolitis and lung function decline | Ziegenhagen et al. (1998); Yang et al. (2018) |
| TLR3 | TLR3 is known as one of the innate immunity receptors, which mediate inflammation, tissue injury and viral infection | Defective TLR3 L412F gene activates abnormal inflammation and promotes fibroplasia in IPF, which may be associated with dysregulation of fibroblast proliferation mediated by a sluggish IFN-β response | rs3775291 increase the risk for IPF patients and also reduces forced volume capacity (FVC) | O'Dwyer et al. (2013); O'Dwyer et al. (2015); Evans et al. (2016) |
| TOOLIP | TOLLIP is involved in the signaling pathway of TGF-β, TLR and ILs | rs3750920 may lead to unregulated TLR signaling pathway | rs5743890 was associated with a lower susceptibility to IPF, whereas rs5743894 was associated with a higher susceptibility to IPF. The rs3750920 polymorphism was associated with the efficacy of NAC. rs5743890 was associated with increased IPF morbidity and mortality | Noth et al. (2013); Oldham et al. (2015) |
| HLA-DRB1 | HLA gene encodes major histocompatibility complex (MHC) | N.A. | HLA-DRB1*1501 is related to greater differences in gas exchanges and immunogenic process | Xue et al. (2011); Zhang et al. (2015) |
| MDGA2 | MDGA2 encodes a paralogue for ICAM, which has been shown to be a potential biomarker of IPF disease activity | N.A. | rs7144383 was associated with a higher risk of IPF. | Noth et al. (2013) |
| DSP | DSP, a desmosomal protein, is mainly expressed in the airway epithelium and is involved in cell adhesion | rs2076304 might influence the binding of RHOXF1 | rs2076304 and rs2076295 increased the IPF risk and rs2744371 decreased the IPF sub-risk | Mathai et al. (2016); Wang et al. (2018) |
| DPP9 | DPP9 is a serine protease that belongs to a member of the S9B family. DPP9 is expressed in epithelial cells and is involved in cell adhesion, cell migration and apoptosis | N.A. | rs12610495 is associated with IPF susceptibility | Fingerlin et al. (2013); Zhou and Wang, (2016) |
| SPPL2C | SPPL2C is a transmembrane GxGD type of cleavage proteases | N.A. | rs17690703 was also known to reduce FVC in IPF. A low survival rate and mortality were reported in people with greater gene SPPL2C expression | Wu et al. (2016); Lorenzo-Salazar et al. (2019) |
| AKAP13 | AKAP13 is a Rho guanine nucleotide exchange factor regulating activation of RhoA | AKAP13 mutations may affect the RhoA/ROCK signaling pathway | rs62025270 was associated with increased production of AKAP13, but no correlation with survival was observed | Allen et al. (2017) |
| FAM13A | FAM13A contains a protein domain called Rho GTPase activating protein (Rho GAP) | FAM13A mutation may affect the RhoA/ROCK signaling pathway | The rs2609255 was associated with higher mortality rate. The FAM13A allele was associated with worse disease and lower DLCO. | Hirano et al. (2017); van Moorsel, (2018); Ruffin et al. (2020) |
| MAPT | MAPT encodes Tau protein, a microtubule-associated protein | N.A. | rs1981997 is associated with a lower risk of IPF. | Fingerlin et al. (2013); van Moorsel, (2018) |