Genetic variants, both rare and common, are associated with sporadic and familial forms of pulmonary fibrosis. Numerous rare variants (those with minor allele frequency of <0.1%) play a role in FIP (≥2 members of the same family with interstitial pneumonia; FIP) (Table 1). Familial studies have identified FIP-associated variants related to alveolar stability [SFTPC (12, 13), SFTPA1 (14), SFTPA2 (15), ATP-binding cassette-type 3 (ABCA3) (16), and NAF1 (17)] as well as five genes linked to telomere biology [TERT (18), TERC (18), DKC1 (19), TINF2 (7, 20), RTEL1 (21–23), and PARN] (24).

Common variants (defined as minor allele frequency of >5%) also appear to play a role in FIP risk (1). The most widely replicated risk variant (rs35705950), located in the promoter region of MUC5B, was initially identified in a combined linkage and association study (41) and has been strongly associated with IPF and FIP. Two large GWAS of IPF subjects (both familial and sporadic) with controls have been conducted in pulmonary fibrosis (10, 11). In addition to confirming the role of TERT at 5p15, MUC5B at 11p15, and the 3q26 region near TERC, the GWAS identified seven newly associated loci, including FAM13A (4q22), DSP (6q24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19q13), and chromosomal regions 7q22 and 15q14-15 among others that have been nominally associated (Table 2).

Rare variants are thought to be highly penetrant and to have a greater effect size, but given their low frequency, they account for a smaller proportion of overall disease risk in the general population (51). Alternatively, in general, common variants have a smaller effect size but are present at higher frequency and, in aggregate, may contribute to a larger proportion of disease risk (Figure 1). However, the MUC5B promoter variant rs35705950 is a common variant with a large effect size and therefore accounts for a substantial risk in IPF. In fact, it has been estimated the MUC5B promoter variant accounts for 30% of the risk of developing IPF (41, 51).

Surfactant proteins are synthesized in the endoplasmic reticulum (ER) of alveolar type II cells (AECII) and transported to and stored in the lamellar bodies until secretion into the alveolar space (25, 26). Rare variants identified in the genes encoding surfactant protein C and A (SFTPC, SFTPA1, and SFTPA2) have been associated with pulmonary fibrosis (53). SP-C is a small hydrophobic protein produced by AECIIs that requires the C-terminus for initial folding steps in the ER before secretion into the alveolar space (26). SFTPC rare variants are mutations that lie in the BRICHOS domain within the C-terminus of SP-C. The BRICHOS domain is critical for proper folding and trafficking (5, 26). Coding mutations in this region lead to accumulation of misfolded protein resulting in increased ER stress and activation of the unfolded protein response (26, 54). Mutations in the gene that encodes surfactant protein A (SFTPA2) have also been linked to FIP (15) and have been associated with increased ER stress as well (28, 55). Rare variants have also been identified in another gene involved with surfactant processing, ABCA3, in FIP families (16, 56). ABCA3 is a transporter protein mainly expressed in AECIIs and is involved in the transport of lipids across plasma membranes (29, 57). In AECIIs, ABCA3 mutations cause abnormal processing, trafficking, and functionality of the ABCA protein, leading to retention of lipids in the ER, ER stress, and apoptotic signaling (30). These mutations are expressed in a recessive manner, where as mutations in SFTPA2 and SFTPC are dominantly expressed (56).

In 2011, Lawson et al. (58) demonstrated that fibrotic remodeling in response to low-dose bleomycin was more severe in mice in which ER stress was induced, either through mutant SFTPC in AECIIs or by administration of tunicamycin, a chemical known to induce ER stress. In addition to effects on apoptosis, ER stress may induce biological pathways involved in cell differentiation (59, 60) through which epithelial cells acquire phenotypic characteristics of mesenchymal cells, a process known as epithelial-to-mesenchymal transition (EMT), in IPF lungs (61). EMT is hypothesized to increase the number of cells responsible for collagen production and matrix deposition thereby leading to fibrosis (13, 59, 60). To date, published data suggest that ER stress predisposes to AECII apoptosis and subsequent lung fibrosis. Surfactant proteins have been recognized as crucial in maintaining lung alveolar structure and function. However, the precise role of alveolar stability, ER stress, and EMT in IPF pathogenesis remains an area of active investigation.

Telomeres are repetitive nucleotide sequences at the ends of chromosomes that protect them from progressive shortening during the normal cell replication process (62). Telomerases restore telomere length and consist of two major components: telomerase reverse transcriptase (encoded by TERT) and telomerase RNA (encoded by TERC) (18, 37). Mutations in telomerase components were initially identified in the setting of dyskeratosis congenita (DKC), a rare inherited syndrome of telomere shortening characterized by oral leukoplakia, abnormal skin hyperpigmentation, and dystrophic nails, with pulmonary fibrosis present in about 20% of patients; bone marrow failure can also be a complication of DKC (32). More recent studies have found an association between numerous genes in the telomerase maintenance pathway and FIP, including those related to catalytic activity (TERT and TERC) (7, 32) and telomere stabilization (DKC1, PARN, and RTELI) (19, 21). These pathogenic variants cause dysfunction of telomerase activity leading to accelerated telomere shortening (32, 63) in peripheral blood and the lung (32–34). Thus far, TERT variants are the most frequently identified rare variants associated with pulmonary fibrosis; they are found in ~15% of FIP (7, 32) and in 1–3% of sporadic cases (34). A recent whole-exome sequencing study identified TERT, RTEL1, and PARN variants previously associated with FIP to be associated with sporadic IPF, further supporting the role of telomere dysfunction in IPF pathogenesis and highlighting the genetic commonalities between FIP and sporadic IPF (64).

Telomere dysfunction has further been implicated in IPF as evidence has suggested that short telomeres are not exclusively related to telomerase rare variant mutations. One study found that 25% of sporadic IPF subjects and 24% of familial IPF subjects, without identified mutations for TERT or TERC, had short telomeres. In addition, all subjects within this specific study who had a mutation in TERT or TERC and pulmonary fibrosis also had short telomeres (33).

The mechanisms by which telomere defects provoke lung disease are not fully understood. Defects in telomere maintenance have been linked to epithelial cell senescence and an impaired response to epithelial injury (65). During successive cycles of cell division, telomere shortening occurs and eventually leads to activation of the DNA-damage pathways, which result in apoptosis or senescence (32). In certain situations, cellular senescence is appropriate, but premature senescence can impair lung epithelial homeostasis and lead to stimulation of a lung remodeling response (66), resulting in fibrotic lesions (63). One study demonstrated increased epithelial cell senescence in IPF lung tissue by measuring B-galactosidase staining (a marker of senescence) and found that B-galactosidase staining was positive in all IPF cases but was not present in normal lung (67) supporting a role for senescent epithelial cells in IPF pathogenesis. Future studies are necessary to clarify the precise role of cellular senescence in lung injury response and fibrotic remodeling in IPF.

In 2011, genome-wide linkage analysis and targeted genetic sequencing identified a single nucleotide polymorphism (SNP) on chromosome 11 that was associated with both FIP and IPF (41). The SNP, rs35705950, was found to be a gain-of-function variant associated with increased expression of MUC5B. Heterozygous (GT) and homozygous (TT) individuals had an odds ratio for developing disease of 6.8 and 20.8 for FIP, and 9.0 and 21.8 for IPF, respectively, supporting the strength of the SNP’s association with development of both IPF and FIP (41). MUC5B encodes Mucin 5B, which is a major gel-forming mucin in mucus and expressed by airway epithelial cells (68, 69). The association of the MUC5B promoter polymorphism with IPF has been replicated and confirmed in nine independent cohorts (10, 11, 49, 50, 70–74), including in a 2013 GWAS (OR for T minor allele = 4.51; 95% CI = 3.91–5.21; P = 7.21 × 10⁻⁹⁵) (10). Additional genotyping studies have noted that the MUC5B variant is associated with disease in a Mexican cohort of IPF patients, but not in Asian cohorts (75). Most recently, a study of select loci in various European cohorts, including Czech and Greek IPF patients, also confirmed the association between rs35705950 and IPF (76).

MUC5B expression in IPF is localized in the distal airway, respiratory bronchiole, honeycomb cyst (77), and the bronchiolar epithelium (78). Overexpression of MUC5B in these areas of the lung and especially in the honeycomb cysts, which are a histopathological finding in IPF (77), further supports the notion that MUC5B is important in the pathogenesis of IPF. Evans and colleagues (51) hypothesize that IPF is caused by recurrent injury/repair/regeneration at the bronchoalveolar junction secondary to overexpression of MUC5B, mucociliary dysfunction, retention of particles, ER stress, and disruption of normal reparative and regenerative mechanisms in the distal lung (51).

Interestingly, the MUC5B promoter polymorphism may be specific to IIP, since studies have illustrated that rs35705950 is not associated with increased risk of sarcoidosis and scleroderma-related ILD, two other fibrotic lung diseases (10, 50, 70). However, recent data have shown that MUC5B rs357057950 variant is associated with radiographic evidence of interstitial lung abnormalities (ILA) studied in the Framingham cohort (79–81). Increasing age and number of copies of MUC5B promoter polymorphism were associated with ILA progression, which has been linked to increased mortality (80, 81). In addition, there are some data to suggest that rs357057950 genotype may be associated with higher likelihood of radiographic UIP pattern in the setting of fibrotic IIP (82).

The mechanism by which variants in MUC5B confers risk of lung fibrosis is an active area of investigation. Given that mucins play a role in innate immunity (68, 83), immune dysregulation could be a possible mechanism by which increased mucin expression contributes to the pathophysiology of IPF (84). Alternatively, IPF may be a disease of mucociliary clearance in which overexpression of MUC5B leads to impaired ciliary function, thereby allowing retention of particles and, subsequently, recurrent lung injury (51).

Several studies have also implicated the human leukocyte antigen (HLA) region in IPF (85–89). The HLA region is located on chromosome 6p21.31 (90), and its main function is regulation of immune response. The DRB1*15:01 allele has been shown to be more prevalent among IPF patients and associated with greater impairment of gas exchange (89). Recently, a genome-wide imputation-based association analysis identified two risk alleles, DRB1*15:01 and DQB1*06:02, found to be associated with fibrotic idiopathic interstitial pneumonias (48). Although not definitive, HLA association with IPF may suggest that autoimmunity may play a role in pulmonary fibrosis; further characterizing the pathophysiologic connection between this genetic variation and disease this remains an area of active investigation.

The 2013 GWAS by Fingerlin et al. (10) identified multiple susceptibility loci for fibrotic IIP, including two cell–cell adhesion molecules, DSP and DPP9. DSP gene expression was increased in lung tissue of individuals with IIP and varied by genotype for a variant in intron 5 (10, 91). DSP encodes for desmoplakin, a critical component of desmosome structure important in cell–cell adhesion. Desmosomes mechanically link cells and stabilize tissue architecture. In addition, they are involved in the regulation of cell proliferation, differentiation, migration, and apoptosis (92). The association between DSP variants and IPF, as well as the relationship between DSP variants and lung expression of this gene, was confirmed more recently by Mathai et al. (91) IPF lung has higher gene expression of DSP. However, IPF subjects with the rs2076295 variant were found to have lower DSP expression, suggesting that differential DSP expression may play a role in a subset or sub-phenotype of IPF (91). This association further implicates the airway epithelium in the pathogenesis of IPF, as DSP appears to be localized primarily to the airway epithelia and not to alveolar epithelial cells. The role of DSP in IPF pathogenesis remains an area of active investigation.