Genetic Determinants of Interstitial Lung Diseases∗

15 Genetic Determinants of Interstitial Lung Diseases* Susan K. Mathai,1,2 David A. Schwartz,1 Raphael Borie3,4 1Division

of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of ­Colorado School of Medicine, Aurora, CO, United States, 2Center for Advanced Heart & Lung Diseases, Baylor University Medical Center at Dallas, Dallas, TX, United States, 3Service de Pneumologie A Hopital Bichat, APHP, Paris, France, 4INSERM U1152, Paris, France

Interstitial lung disease (ILD) describes a set of heterogeneous lung diseases characterized by inflammation and, in some cases, fibrosis of the space between alveoli. These parenchymal lung abnormalities lead to abnormalities in gas exchange, restrictive physiology (i.e., restriction of lung expansion measured by low lung volumes), hypoxemia, dyspnea, and, if progressive, respiratory failure. In some cases, ILD can be caused by systemic disease or environmental exposures, but there is growing evidence that common and rare genetic variants are important to the development of some ILDs. Those ILDs that do not have readily identifiable causes are known as idiopathic interstitial pneumonias (IIPs). In cases where two or more members of the same family have an IIP, the disease is known as familial interstitial pneumonia (FIP). Study of FIP, and now also sporadic IIP, has led to a deeper understanding of the inherited risk of these disorders, but also suggests heterogeneity in terms of the manner of how genetic risk manifests clinically. This chapter will review the current understanding of how genetic risk factors influence the pathogenesis of ILD.

* This article is a revision of the previous edition article by William E. Lawson and James E. Loyd, “Interstitial and Restrictive Pulmonary Disorders” in Emery and Rimoin’s Principles and Practice of Medical Genetics 6th Edition, © 2013, Elsevier Ltd.

15.1 INTRODUCTION ILD describes a diverse category of lung diseases characterized by inflammation and at times fibrosis of the space between alveoli. These parenchymal lung conditions lead to dyspnea and abnormalities in gas exchange, restrictive physiology (i.e., restriction of lung expansion measured by low lung volumes), hypoxemia, and, if progressive, respiratory failure. Restrictive physiology can be measured by pulmonary function testing, specifically lung volume measurement most commonly performed through plethysmography. Over 150 diseases have been associated with ILD, and can be caused by environmental exposures (e.g., asbestos, silica), autoimmune diseases (e.g., rheumatoid arthritis and systemic sclerosis [SSc]), and underlying genetic syndromes that affect numerous organs including the lung. However, when ILD is diagnosed in patients without such identifiable causes, they are known as “idiopathic interstitial pneumonias” (IIPs; Table 15.1). Over the last 3 decades, through the careful study of FIP cohorts and of sporadic IIP cohorts, evidence has been mounting that a large proportion of IIPs may have a genetic basis, leading to the identification of potential therapeutic targets and a nascent understanding of subphenotypes of this disease. Other ILDs with identified causes have also been studied showing that in non-IIP disease, genetic factors appear to play an important role in conferring risk of disease.

Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics. https://doi.org/10.1016/B978-0-12-812532-8.00015-X Copyright © 2020 Elsevier Inc. All rights reserved.

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TABLE 15.1  American Thoracic Society/

European Respiratory Society Classification of Idiopathic Interstitial Pneumonias Based on Multidisciplinary Diagnoses Major idiopathic interstitial pneumonia Idiopathic pulmonary fibrosis (IPF) Idiopathic nonspecific interstitial pneumonia (NSIP) Respiratory bronchiolitis-interstitial lung disease (RB-ILD) Desquamative interstitial pneumonia (DIP) Cryptogenic organizing pneumonia (COP) Acute interstitial pneumonia (AIP) Rare idiopathic interstitial pneumonias Idiopathic lymphoid interstitial pneumonia (LIP) Idiopathic pleuroparenchymal fibroelastosis Unclassifiable idiopathic interstitial pneumonia Table adapted from: Travis, WD, Costabel, U, Hansell, DM, King, TE, Lynch, DA, Nicholson, AG, Ryerson, CJ, Ryu, JH, Selman, M, Wells, AU, Behr, J, Bouros, D, Brown, KK, Colby, TV, Collard, HR, Cordeiro, CR, Cottin, V, Crestani, B, Drent, M, Dudden, RF, Egan, J, Flaherty, K, Hogaboam, C, Inoue, Y, Johkoh, T, Kim, DS, Kitaichi, M, Loyd, J, Martinez, FJ, Myers, J, Protzko, S, Raghu, G, Richeldi, L, Sverzellati, N, Swigris, J, Valeyre, D. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013;188:733 -48. Reprinted with permission of the American Thoracic Society. Copyright (c) 2018 American Thoracic Society. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

This chapter is divided into three main categories: (1) the role of genetic risk factors in IIP; (2) the role of genetics in systemic diseases that can manifest clinically as ILD; and (3) defined genetic syndromes that can include ILD. 

15.2 IDIOPATHIC INTERSTITIAL PNEUMONIAS 15.2.1 Clinical Characteristics of IIPs 15.2.1.1 Idiopathic Interstitial Pneumonias Clinically, patients with ILDs of all sorts generally present with complaints of dyspnea, decreased exercise tolerance, and persistent cough. Often, they are referred to subspecialty evaluation when treatments for more common respiratory disorders such as pneumonia or emphysema are ineffective. Chest imaging (Fig. 15.1) can show bilateral parenchymal opacities with or without evidence of fibrosis, and pulmonary function testing, depending on disease severity, often illustrates restrictive physiology

and, in some cases, decreased diffusing capacity of carbon monoxide (reflecting gas exchange impairment). The initial evaluation and history-taking often focuses on identification of potential underlying disease processes (i.e., systemic diseases like autoimmune disease that often have extrapulmonary signs or symptoms) or environmental or occupational exposures (e.g., avian antigens, asbestos, silica) that could be responsible of the patient’s findings. Subsequent testing can include serologic testing for autoimmune processes if clinically indicated. In many cases, history and serologic screening will not yield an identifiable cause for ILD, in which case the patient’s diagnosis falls into a group of disorders known as the IIPs. By the latest American Thoracic Society Consensus Statements [1] the IIPs break down into the following categories: idiopathic pulmonary fibrosis (IPF) and its pathologic correlate usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP), lymphoid interstitial pneumonia (LIP), desquamative interstitial pneumonia (DIP), and respiratory bronchiolitis interstitial lung disease (RB-ILD) (Table 15.1; Figs. 15.1 and 15.2). The IIPs can present in either childhood or adulthood but are much more common in the adult population. Of these IIPs, IPF is the most common and most severe and has thus received the most attention in pulmonary research. High-resolution computed tomography (HRCT) of the chest in IPF patients shows interstitial fibrosis and will generally be described as having a UIP pattern (Fig. 15.1A), characterized by subpleural and basilar predominant reticular abnormality, honeycombing, and traction bronchiectasis with a relative paucity of ground glass opacity [2,3]. Patients typically progress to hypoxemia and respiratory failure, with most patients dying from the disease within 5 years of diagnosis [4,5]. There are no curative therapies at this time for IPF other than lung transplantation, a therapy with its own complications and feasible only for a small percentage of IPF patients. Recently, two drugs have been approved by the Federal Drug Administration after being shown to slow disease progression [6,7]. The incidence of IPF is approximately 20 per 100,000 males and 13 per 100,000 females [8], but rising. Most individuals present between ages 50 and 75 years, but patients can present outside this interval in either direction. Many individuals can be diagnosed with disease based on clinical presentation and classic findings on HRCT of the

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(A)

(B)

(C)

(D)

(E)

(F)

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Figure 15.1  High-Resolution Computed Tomography (CT) Imaging of Interstitial Lung Diseases.  (A) Example of CT image showing the usual interstitial pneumonia pattern characteristic of idiopathic pulmonary fibrosis, including basilar predominant reticular abnormalities and peripheral honeycomb cysts (arrow) with a paucity of ground glass abnormality. (B) Image from a patient with sarcoidosis demonstrating peribronchovascular thickening (curved arrow), micronodularity (thin arrow), and larger nodules (arrowhead). (C) Image showing nonspecific interstitial pneumonia radiographic changes, including fine reticular abnormalities (thin arrow) with characteristic subpleural sparing (curved arrow). (D) Example of interstitial lung disease in a patient with systemic sclerosis; note diffuse ground glass opacities and extrapulmonary manifestations of disease, in this case esophageal thickening and dilatation (arrow). (E) Image from a patient with hypersensitivity pneumonitis, illustrating ground glass opacities, reticular abnormalities (thin arrow), and mosaic attenuation consistent with lobular air trapping (curved arrow). (F) Characteristic image from a patient with pulmonary alveolar proteinosis, illustrating the “crazy-paving” pattern that results from ground glass (white arrow) with superimposed interlobular septal thickening (curved black arrow). (Images courtesy of Drs. J. Caleb Richards and Christopher J.G. Sigakis, National Jewish Health, Department of Radiology.)

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Figure 15.2  Examples of Lung Pathology Observed in Interstitial Lung Diseases.  (A) Hematoxylin and eosin (H&E) staining of lung tissue from a patient with idiopathic pulmonary fibrosis showing changes consistent with the usual interstitial pneumonia pattern, specifically honeycomb cysts (arrow). (B) H&E staining of lung tissue from a patient with systemic sclerosis-related interstitial lung disease illustrating the nonspecific interstitial pneumonia pattern, with thickening of the alveolar septae (arrow). (C) Image of lung tissue sample from a patient with pulmonary sarcoid, showing characteristic granulomatous inflammation in a subpleural area (arrow). (D) Lung tissue from a patient with hypersensitivity pneumonitis, illustrating interstitial cellular inflammation, poorly formed granulomas (arrow), and organizing pneumonia (arrowhead). (Images courtesy of Dr. Carlyne Cool, National Jewish Health and University of Colorado, Department of Pathology.)

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chest (Fig. 15.1A), but when expert HRCT review is not definitive, patients are referred to lung biopsy for diagnosis. IPF patients have lung pathology consistent with a UIP pattern, characterized by interstitial fibrosis, honeycomb change, fibroblastic foci, and a paucity of inflammation [2,3] (Fig. 15.2). While the cause of IPF remains unknown, over the past 3 decades, genetic discoveries in familial forms of disease have led to significant insights into the role of inherited risk in disease pathogenesis. 

15.2.1.2 Familial Interstitial Pneumonia Although there is no consensus definition, in the research setting FIP is usually defined as a case of IIP in which the patient also has a family history of two or more relatives with IIP [9–11]. These cases of pulmonary fibrosis have been critical to understanding inherited risk and this disease and continue to play a role in ongoing investigation into the genetics of this complicated disease. Early studies from Europe suggested that familial forms of the disease accounted for 2%–4% of IPF [12,13], though later evidence suggests that this percentage may be higher [14,15]. Studies performed in the United Kingdom and at the Mayo Clinic suggested that adults with FIP were essentially indistinguishable from sporadic IPF patients in terms of clinical presentation, radiographic findings, histopathology, except that those with FIP tended to present at earlier ages [13,16]. Indeed, one of the strongest risk factors for the development of IPF is a family history of pulmonary fibrosis [17]. A multicenter study of 111 families with FIP containing 309 subjects with disease and 360 unaffected relatives revealed that male gender (55.7% vs. 37.2%, P < .0001), age (68.3 vs. 53.1 years, P < .0001), and cigarette smoking history (67.3% vs. 34.1%, P < .0001) were risk factors for developing disease within these families. Eight-five percent of those in this study who had underwent lung biopsy had evidence of UIP; however, pathologic heterogeneity was observed within individual families—45% of these families had two or more pathologic patterns noted within the affected individuals, with numerous families having evidence of UIP and NSIP histopathology [18]. This was not the first time that different histopathologic findings within FIP families had been observed [19]; Alan Q. [20], and so is consistent with other smaller studies of FIP. These observations suggest that though pathologic evaluation may suggest distinct IIP categorizations, they may actually have similar pathogenesis. In addition, the finding that cigarette

409

smoking was a risk factor for FIP development within these families also suggested that interplay between genetic predisposition and environmental exposures is central to familial disease [18]. As specific gene mutations have been discovered in these families, it has been observed that those with mutations in telomere-related genes may have phenotypic characteristics, in particular earlier age of onset as well as extrapulmonary manifestations of disease (see section below for further information; [9,10]). Many analyses of FIP families have suggested autosomal dominant patterns of inheritance with incomplete penetrance [13,16,18], though continued study suggests a great deal of locus heterogeneity in FIP, such that many different individual genes across different families likely contribute to the observed disease phenotypes. Indeed, the study of FIP and sporadic IPF suggests that unlike classic Mendelian disorders, in many cases the relationship between genetic factors and disease development is complex and may involve numerous genetic risk factors and also gene by environment interactions. 

15.3 GENETIC BASIS OF IIP 15.3.1 Familial Studies 15.3.1.1 Surfactant Proteins Early studies of genetic risk in the development of IPF used FIP subjects. Twin and family aggregation studies were utilized, since it had been observed that a reported family history of pulmonary fibrosis itself was a clinical risk factor for IPF [17,21,22]. The first disease-associated genetic variants were identified in surfactant protein genes among FIP patients [19,23–25]. These studies identified heterozygous coding mutations in SFTPC coding for the surfactant protein C (SPC) [19], numerous coding and noncoding variants in SFTPC [24], and rare coding mutations in surfactant protein A [25,26] that segregated with diseased subjects and not found to be present in controls. SPC is one of four surfactant proteins expressed in the alveoli and functions to alter surface tension to prevent alveolar collapse. This protein is expressed throughout the lung epithelium during lung development, but in the mature lung it is localized to type II alveolar epithelial cells (AECs) [27]. Both pediatric and adult ILD has been linked to SFTPC mutations. The initial report linking SFTPC mutations to ILD was made by Nogee and colleagues when they reported an infant with NSIP whose

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mother had been diagnosed with DIP in the first year of life [19]. Genetic sequencing revealed a heterozygous G→A transition in intron 4 (IVS4+ G→A) on a single allele in both the mother and child, consistent with an autosomal dominant mode of inheritance. This particular mutation caused deletion of exon 4 and is referred to in the literature as the SFTPC Δexon4 mutation; mature SPC was not detected in the lung of either the mother or the child, but an inappropriately processed form of the pro-protein (pro-SPC) was noted in the type II AECs. Subsequent to this study, SFTPC mutations have been described in numerous cases of pediatric ILD with many pathologic mutations found in the carboxy-terminal region of pro-SPC [27–31]. Various reports suggest that impairment or absence of SPC in the alveolar space, with or without actual mutations in SFTPC, itself can cause fibrosis, perhaps through the mechanism of impaired regenerative capacity in the lung [32]. After the initial report by Nogee and colleagues, Amin et al. reported a mother and her children with chronic ILD and SPC deficiency (i.e., lack of mature protein in the alveolar space), but no mutations in SFTPC or SFTPB [33]. In vivo experiments with murine models also suggest that mice deficient in SPC have a tendency to develop fibrosis in experimental models [34,35]. Therefore, defective surfactant protein itself may play a role in the lung’s susceptibility to fibroproliferation in response to injury. Indeed, aberrant intracellular processing of pro-SPC and associated type II AEC dysfunction may be important in terms of the mechanism by which implicated mutations cause disease [32,36]. SFTPC transcription and translation creates a 197 amino acid precursor protein (pro-SPC), which then requires processing through the endoplasmic reticulum (ER), Golgi body, and distal secretory pathway before the secretion of a mature 35 amino acid SPC protein into the alveolar space. SPFTC mutations in the carboxy-terminal region lead to the production of pro-SPC that cannot be normally folded and processed by the ER, leading to protein accumulation, ER stress, activation of the unfolded protein response, and subsequent type II AEC injury [37–39]. Though SFTPC mutations were first linked to pediatric cases of ILD, adult FIP is also definitively associated with mutations in this gene. In 2002, Thomas and colleagues described a family in which 11 adults had ILD, 6 with biopsy-confirmed UIP/IPF and 5 with clinical diagnoses of IPF, as well as 3 pediatric cases of NSIP

[20]. In this family, a heterozygous T to A transversion in exon 5 led to the substitution of glutamine for leucine at amino acid position 188 (L188Q) in pro-SPC. Examination of tissue from these lungs showed abnormal SPC staining with accumulation of intracytoplasmic vesicles in Type II AECs on electron microscopy. Similar intracytoplasmic vesicles were noted in mouse lung epithelial cells that expressed the L118Q mutation, pointing to aberrant pro-SPC processing as the underlying cause [20]. In vitro studies also revealed that the L188Q SFTPC mutation results in a pro-SPC molecule that cannot be folded properly, prompting ER stress and caspase pathway activation [38,40]. Subsequently, additional mutations in SPFTC have been found in other FIP cohorts [41,42]—indeed, Van Moorsel and colleagues have published evidence arguing that in a Dutch cohort, SFTPC mutation cause approximately 25% of FIP cases, higher than what has been observed elsewhere. Despite its prevalence in FIP cases, SFTPC mutations are not commonly found in sporadic IPF cases. However, in 2004, Lawson and colleagues studied 89 patients with UIP, 46 with NSIP, and 104 normal subjects and found only 1 coding mutation in SFTPC [24]. This one case led to an exon 3 substitution of threonine to isoleucine at amino acid 73 (I73T). This mutation is one of the most common SFTPC mutations reported, observed in both pediatric and adult FIP cases [27–31,42]. Interestingly de novo mutations are frequent in children and may explain as much as 50% of cases [43]. Though rarely found in sporadic IPF, the prevalence of SFTPC mutations in FIP including biopsy-proven UIP cases suggests that type II AECs may be critical in the pathogenesis of this disease, at least in a subset of patients. Study of genetic pathways important in SFTPC mutation-mediated disease could therefore be relevant more generally to IPF or other forms of pulmonary fibrosis. In 2008, two separate groups reported studies suggesting a role for ER stress in Type II AECs in ILD without evidence of SFTPC mutations [40,44]. Specifically, ER stress markers were prominent in the AECs lining fibrotic areas of human lung, even in cases where no SFPTC mutations were found, in FIP and IPF cases [40]. Thereafter, Korfei and colleagues also reported a cohort of IPF/UIP lung biopsies with AEC ER stress evidence, but also showed that caspase pathways were activated in those same epithelial cells [44]. These studies suggest that ER stress pathways may be important in human pulmonary fibrosis.

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Given the numerous findings of SFTPC mutations in FIP cases, investigators soon examined other surfactant proteins in terms of their role in FIP. In 2009, Wang and colleagues analyzed a large family with 15 affected subjects with FIP and/or lung adenocarcinoma with bronchoalveolar cell carcinoma features [25]. Genetic sequencing of surfactant proteins found a heterozygous mutation in SFTPA2 (G→T transversion in codon 231) which predicted a valine for glycine substitution at a highly conserved amino acid position (G231V). An additional 58 families were studied, and a different SFTPA2 mutation was found (F198S). Both of these mutations are found in the carbohydrate recognition domain—in vitro study of these mutations suggest that the resultant protein becomes retained in the ER and causes ER stress [25,26]. More recently Nathan and colleagues analyzed 12 families affected by IPF and lung cancer. They identified, in one family, nine members carrying heterozygous missense mutation (p.Trp211Arg), of SFTPA1 located in the carbohydrate recognition domain that impairs SP-A1 secretion [45]. These again implicate protein processing and ER stress in Type II AECs as a potential driver of pulmonary fibrosis. Though not a mutation in SFTPC, ATP-binding cassette transporter A3 (ABCA3) is expressed in Type II AEC lamellar bodies, suggesting that it may be important in surfactant processing. In 2004, Shulenin and colleagues reported a study of 21 infants with severe neonatal surfactant deficiency of unknown etiology. Of the 21, 16 (76%) had ABCA3 mutations and were either homozygous for the same mutation or heterozygous for different mutations [46]. Lung tissue revealed grossly abnormal lamellar bodies, suggesting that this gene is critical for surfactant processing and lamellar body formation. Subsequent examination of pediatric ILD cases for ABCA3 mutations revealed that in those without SFTPC or SFTPCB mutations, three of four subjects contained compound heterozygous mutations in ABCA3 [47]. Later, Young and colleagues reported a teenage ILD patient with UIP pattern and an ABCA3 mutation [48]. However, studies have not definitively linked ABCA3 mutations to adult cases of FIP [42]. Other studies have suggested that in infant ILD those with heterozygous SFTPC mutations and concomitant heterozygous mutations in ABCA3 may be more likely to develop clinical ILD [49]. Therefore, ABCA3 mutations may modify the effects of SFTPC mutations [50].

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NKX2-1 encodes a transcription factor closely related to surfactant protein transcription [51]. Heterozygous mutations are classically associated with the triad of ILD, hypothyroidism, and neurologic anomalies (hypotonia, delayed development, chorea) [52]. These mutations may be associated with ILD without hypothyroidism and neurologic anomalies in up to 1/3 of cases, including adult cases in which the most common HRCT pattern is UIP [52] (Fig. 15.3). 

15.3.1.2 Telomere Pathway Genes and Telomere Length in FIP Telomeres are regions of noncoding repetitive nucleotide repeats (TTAGGG) at the ends of chromosomes that protect them from deterioration during mitosis or fusion with neighboring chromosomes. The telomerase complex is the group of proteins and RNA that catalyzes the addition of these nucleotide repeats to the ends of chromosomes. There are numerous components to the telomere complex, including telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC), which are essential for normal operation and telomere integrity. Shortening of telomeres has been associated with numerous disease manifestations, as have mutations in telomere-related genes [53], including ILD and pulmonary fibrosis. Indeed, numerous studies of FIP cases and their kindred have identified mutations in various telomere pathway genes (TERT, TERC, RTEL1, PARN, NAF1, DKC1, TINF2). For instance, TERT and TERC mutations have been identified in up to one-sixth of pulmonary fibrosis families [54,55]. Dyskeratosis congenita (DKC) is a diagnosis made based on a triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia, but can affect numerous organ systems [56], including the bone marrow. Pulmonary fibrosis is found in 20% of cases, and behind aplastic anemia respiratory failure is the most common proximal cause of death in these patients [57]. In X-linked DKC, mutations in DKC1 are causative [58–60], but some autosomal dominant forms of DKC are linked to mutations in TERT and TERC [61–63]. In 2005, Armanios and colleagues reported a TERT mutation in a family affected by DKC in which pulmonary fibrosis was the dominant clinical finding [61], prompting investigators in the field to examine telomere-related genes for associations with FIP.

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(A)

(B)

(C)

(D)

(E)

(F)

Figure 15.3  Computed Tomography (CT) of Interstitial Lung Disease (ILD) in Patients with Rare Mutations Associated with Familial Interstitial Pneumonia. Representative chest CT images of ILD in different patients with (A and B) SFTPA1, (B and C) ABCA3, and (D and E) NKX2-1 mutations. These images illustrate the variety of radiographic abnormalities seen in the spectrum of ILD associated with rare genetic variants, such as tree-in-bud nodularity (B, black arrow), traction bronchiectasis (C, black arrow), septal thickening (D, black arrow), and ground glass opacities (E, white arrow). Patients with mutations in the same gene can have different radiographic patterns of ILD (contrast panels C and D, for instance).

Subsequent to the discovery of TERT mutations in pulmonary fibrosis predominant DKC, Armanios and colleagues analyzed 73 FIP families and found that 5 carried genetic mutations in TERT and 1 had a mutation in TERC. Of six probands from these families, five

had UIP pattern on lung biopsy, while one was read as IIP [54]. Across the families of the 6 probands, 19 were affected by FIP, and classic mucocutaneous manifestations of DKC were not present. The mutation carriers in these families that did not have identifiable lung disease

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were younger than their affected relatives. Subsequent in vitro studies of the identified mutations demonstrated decreased telomerase activity, and telomere shortening in peripheral blood lymphocytes was prominent in mutation carriers when compared to those without the mutation. Indeed, when compared to age-based telomere distributions in normal subjects, all mutation carriers had average telomere lengths at or below the 10th percentile [54]. After this initial report, another group reported similar findings in a distinct FIP cohort. While the earlier study relied on a candidate gene approach, Tsakiri and colleagues utilized two highly genetically informative families to link to a region of interest on chromosome 5 [55]. Based on this location, TERT was then selected as a candidate gene, and two separate mutations (one missense and one frameshift) in the two families were discovered. To follow up this finding, the group analyzed an additional 44 FIP families and found 4 to have heterozygous TERT mutations and 1 heterozygous TERC mutation [55]. As with the Armanios study [54], in vitro examinations of the mutations demonstrated decreased telomerase activity, and peripheral blood leukocyte telomere lengths were shorter in mutation carriers when compared to age-matched noncarriers. An additional 44 cases of sporadic (nonfamilial) ILD were sequenced, identifying a single subject with a TERT mutation. In total, this study identified two frameshift deletions and five missense mutations in TERT associated with pulmonary fibrosis, and none of these mutations were found in ethnically matched local control subjects [55]. Considered together, these studies suggested that telomerase-related mutations cause disease in approximately 10% of FIP. Subsequent to these genetic studies, both groups also examined telomere length itself and its relationship to pulmonary fibrosis, independent of mutations in TERT and TERC [64,65]. Cronkhite and colleagues analyzed a cohort of pulmonary fibrosis patients without TERT and TERC, including probands from 59 families with FIP and 73 subjects with sporadic IPF. They found that 24% of FIP subjects and 23% of sporadic IPF subjects had evidence of telomere shortening, with peripheral blood leukocyte telomere lengths below the 10th percentile compared to age-matched controls [65]. Alder and colleagues analyzed 100 cases of sporadic IPF and found one subject with a TERC mutation, and no mutations in TERT. Sixty-two of these subjects had their telomere lengths measured in peripheral blood

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lymphocytes, and 97% showed telomere lengths shorter than the median in healthy controls; furthermore, 10% had telomere lengths shorter than the first percentile of healthy controls. A subset of these subjects also underwent examination of their lung tissue—using fluorescent in situ hybridization, it was found that AECs in these sporadic IPF as well as those with known telomere mutations also showed evidence of telomere shortening [64]. A few of the subjects with IPF were also examined for evidence of extrapulmonary telomeropathy, specifically bone marrow suppression and liver cirrhosis. The data presented in these studies indicate a critical role for telomere shortening in the pathogenesis of both FIP and IPF, even in the absence of defined telomerase gene mutations. Alder and colleagues found cryptogenic cirrhosis in a few of the IPF subjects, which prior to this publication had only been described in the setting of DKC. These additional findings suggested that at least in a small subset of patients, “telomeropathy,” or a syndrome in which multiple organs affected by telomere shortening [64]. A subsequent study that examined this link further sequenced numerous subjects with both aplastic anemia and pulmonary fibrosis and found that the concurrence of these two disorders (both separately associated with telomere dysfunction) was highly predictive for the presence of germline telomerase mutation [66,67], a finding that could affect the clinical evaluation and decision-making for those contemplating bone marrow or lung transplantation. More recent studies have utilized exome-sequencing techniques to discover rare variants in other telomerase pathway genes. Specifically, this technique has been utilized to find rare variants in telomere elongation helicase 1 (RTEL1) and polyadenylation-specific ribonuclease deadenylation nuclease (PARN) associated with FIP [68–70]. As in the case of other telomerase pathway genes, affected subjects with the identified genetic variants in these genes had evidence of shortened peripheral blood leukocyte telomeres [68,70], though the mechanism through which PARN mutations affect telomere length remains poorly understood [71]. Exome sequencing has identified rare TINF2 and NAF1 mutations in FIP, as well [72,73]. Additionally, a novel DKC1 mutation was also recently described in association with FIP [74]. Mechanistically, though the specific link between telomere-related gene mutations and pulmonary fibrosis remains an area of active research, in  vivo

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studies utilizing mouse models for loss of function of telomere-related genes suggest that when these genes dysfunction, the lung epithelia’s response to injury is impaired [75]. 

15.3.1.3 ELMOD2 in Finnish FIP Cases A less well-understood gene associated with FIP is ELMOD2. In 2002, Hodgson and colleagues reported familial clustering of IPF, describing the possibility of a distant shared ancestor [12]. A subsequent study of a subset of this cohort using a genome-wide approach identified five potential loci [76]. The authors found a haplotype significantly more prevalent in affected individuals; this region included a gene known as ELMOD2. Gene expression evaluation showed that ELMOD2 expression was decreased in IPF lung compared to normal, though exon sequencing of the affected individuals did not reveal a pathogenic mutation [76].

15.3.2 Idiopathic Pulmonary Fibrosis The described early studies in the realm of genetics and pulmonary fibrosis utilized the genetic power FIP families to discover rare mutations and candidate genes that could guide further analyses. However, as some of the telomerase pathway studies revealed, there were hints that the genetic findings in FIP could be relevant to sporadic cases of IPF, or cases where no family history of pulmonary fibrosis was reported (Tables 15.2 and 15.3). More recent investigations have used genome-wide approaches and discovered common genetic variants (defined as a minor allele frequency (MAF) in the relevant population as >0.05) associated with pulmonary fibrosis. In 2008, expanding on the rare variant observations by other investigators described earlier in this chapter [54,55], researchers from Japan analyzed a cohort of patients with IPF and controls with a genomewide association study (GWAS) and identified an

TABLE 15.2  Rare Variants Associated With Interstitial Lung Disease Phenotype

Gene

Key References

Idiopathic pulmonary fibrosis, dyskeratosis ­congenital

TERT-TERC-TINF2- PARN- NAF1RTEL1/DKC1

Idiopathic pulmonary fibrosis, lung cancer, combined pulmonary fibrosis and emphysema, alveolar proteinosis Interstitial lung disease Chronic beryllium disease (CBD)

SFTPA1-SFTPA2-SFTPC/ABCA3

Hermansky–Pudlak syndrome Tuberous sclerosis Alveolar proteinosis

HPS1, HPS2, HPS3, HPS4 TSC1 TSC2 CSF2RA/CSF2RB

Alveolar proteinosis Alveolar proteinosis Lysinuric protein intolerance Birt–Hogg–Dube syndrome Type 1 neurofibromatosis Pulmonary alveolar microlithiasis Lipoid proteinosis Gaucher’s disease Niemann–Pick disease Fabry disease Marfan’s syndrome

GATA2 MARS SLC7A7 FLCN NF-1 SLC34A2 ECM1  GBA SMPD1 GLA FBN1

[66] [77] [78] [70] [73] [45] [42] [47] [52] [79] [80] [81] [82] [43] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94]

NKX2.1 (TITF1) DPB1*02:01

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TABLE 15.3  Common Variants Associated

With Idiopathic Pulmonary Fibrosis Gene AKAP13 ATP11A CDKN1A

Single-Nucleotide Polymorphism Key References

MAPT MDGA2 MUC2 MUC5B

rs62025270 rs1278769 rs2395655 rs733590 rs12610495 rs2076295 Unknown rs2609255 rs2395655 rs408392 rs419598 rs2637988 rs4073 rs2227307 rs1981997 rs7144383 rs7934606 rs35705950

OBFC1 SPPL2C TERC TERT

rs11191865 rs17690703 rs6793295 rs2736100

TGFB1 TLR3 TOLLIP

rs1800470 rs3775291 rs111521887 rs5743894 rs2743890 rs12951053 rs12602273

DPP9 DSP ELMOD2 FAM13A HLA-DRB1 IL1RN

IL8

TP53

[95] [96] [97] [96] [96] [98] [96] [96] [41,97]

[99] [96] [100] [96] [96] [100] [11] [101] [102] [41] [96] [100] [96] [96] [103] [41] [100] [104] [100]

[94]

association of a common TERT variant with susceptibility to IPF [105]. This A→C single-nucleotide polymorphism (SNP) is located in intron 2 of TERT (rs2736100). Among 242 IPF cases and 1469 controls, the MAF in diseased subjects was 0.277 versus 0.409 in controls (P = 2.9 × 10−8), indicating that the more common A was the risk allele in this cohort [105]. 

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15.3.2.1 MUC5B In 2011, with the benefit of a larger study cohort, Seibold and colleagues utilized genome-wide linkage analysis followed by targeted sequencing and an association study to determine that an SNP rs35705950 on chromosome 11p15 was associated with both FIP and IPF [11]. rs35705950 is located in the promoter region of MUC5B, which encodes mucin 5B, a glycosylated macromolecular component of mucus. MUC5B is found in various mucosal surfaces in the human (e.g., saliva, cervix, and normal lung) [106]. This variant is located in a highly conserved genetic region. Using case-control analysis of non-Hispanic whites, the authors determined that subjects heterozygous (GT) and homozygous (TT) had increased odds ratios (ORs) for disease—6.8 (95% confidence interval [CI], 3.9–12.0) and 20.8 (95% CI, 3.8–113.7) for FIP and 9.0 (95% CI, 6.2–13.1) and 21.8 (95% CI, 5.1–93.5) for IPF, respectively [11]. This initial study revealed that the rs35705950 MAF was 0.338 in FIP subjects and 0.375 in sporadic IPF subjects, indicating a similar influence in disease risk in the two conditions. Study of whole lung tissue from affected subjects revealed that an IPF diagnosis was associated with a 14-fold increase in MUC5B gene expression, regardless of genotype; however, the T-allele as associated with a 37.4-fold increase in whole lung gene expression in unaffected subjects [11]. Microscopy of diseased lung also reveals that MUC5B protein is found in the honeycomb cyst, a characteristic pathologic finding of UIP, the pattern consistent with IPF [107]. Numerous groups have validated the association between rs35705950 genotype and IPF, making this variant the strongest and most well-replicated single genetic risk factor for disease [11,100,102,108–112]. However, in the non-Hispanic white population, the rs35705950 variant is common, found in 19% (MAF = 0.09) of those without disease [113]. Since IPF does not occur in 19% of this population, the presence of the variant alone is insufficient to cause disease; furthermore, approximately half of subjects with IPF do not carry this variant. Therefore, the rs35705950 variant is not necessary to cause disease, but it is also not sufficient to cause disease, suggesting interplay between rs35705950 and other genetic or environmental factors to cause disease development; this remains an area of active research [114]. The MUC5B promoter polymorphism also appears to be specific to the risk of IPF and some specific fibrotic

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IIPs. Studies of Ssc-ILD [102,108], asbestosis, sarcoidosis [102], chronic obstructive pulmonary disease, and asthma have not shown significant associations between rs35705950 and disease [115]. A subsequent GWAS that examined numerous genetic loci as well as rs35705950 in a fibrotic IIP cohort that largely contained IPF subjects but also contained other forms of fibrotic IIP confirmed the association between MUC5B genotype and the fibrotic IIP phenotype [96]. Furthermore, a recent study of two separate cohorts with chronic hypersensitivity pneumonitis (HP) showed that minor allele at rs35705950 was associated with disease and the MAFs observed were similar to those previously published in IPF cohorts [116]. Therefore, while the MUC5B promoter polymorphism is not associated with all forms of ILD, IPF and chronic HP are at least two forms of progressive fibrotic lung disease that show specific disease associations with rs35705950. The rs35705950 variant is present in 19% of NHWs with an MAF of 0.09 [11], but is not as frequent in other ethnic groups. Studies of diverse ethnic groups suggest that rs35705950 is a genetic risk factor for IPF in Mexican cohorts (OR 7.36, P = .0001), but is rare in Korean IPF cohorts [110]. The overall rs35705950 frequency is low in Asian populations, yet the variant had higher prevalence in IPF cases compared to controls in Japanese and Chinese cohorts [109,117]. Overall, the MAF for rs35705950 appears to be associated with populations in which IPF is more commonly diagnosed; NHWs appear to be at higher risk of developing IPF than Hispanics or Asians, and the disease is thought to be rare in African populations [118] where the rs35705950 MAF is extremely low (NCBI dbSNP [https://­www.ncbi.nlm.nih.gov/projects/SNP/]: rs35705950). The examination of rs35705950 in the context of other disease-associated SNPs and rare variants will be critical to understand its relative importance to disease in different populations. 

15.3.2.2 Other Common Genetic Variants and IPF Although the common MUC5B promoter polymorphism is the most widely and well-studied common genetic variant associated with IPF and FIP, other common variants have been discovered through GWAS as high-throughput variant screening methods have d ­ eveloped. In 2013, Fingerlin and colleagues performed a case-control GWAS in 1616 fibrotic IIP and 4683 control

subjects. This large GWAS confirmed several known disease-associated loci (chromosome 5p15 which contains TERT; 11p15 which contains MUC5B; 3q25 near TERC), but also identified seven new loci, including FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q4), DPP9 (19p13), and regions on chromosomes 7q22 and 15q14-15 [96]. The implicated genes span a wide variety of biological functions, but could be categorized into the following: host defense (MUC5B and ATP11A), cell–cell adhesion (DSP and DPP9), and DNA repair (TERT, TERC, and OBFC1) [96,114,119,120]. It has been estimated that these loci, excluding the MUC5B variant, may account for up to one-third of disease risk, emphasizing the importance of genetic predisposition in fibrotic ILD [96,119]. Another GWAS performed by an independent group compared IPF subjects to nondiseased controls, confirming the MUC5B promoter polymorphism association, but also noted further risk alleles, including one in Toll-interacting protein (TOLLIP) and another in signal peptidase-like 2C (SPPL2C) [100]. Importantly, this study not only identified risk variants, but also drew connections between specific variants (rs5743890) in TOLLIP and differential mortality from disease [100,121]. Interestingly, as was observed in the initial MUC5B promoter polymorphism study [11], the ORs for loci identified by the 2013 GWAS by Fingerlin and colleagues did not differ between FIP and sporadic IPF cases [96]. The same was true in a secondary analysis of the data that compared non-IPF fibrotic IIPs to the cases of diagnosed IPF, suggesting that genetic risk factors for fibrotic IIPs in general, whether recognized as familial or not, are similar. 

15.3.3 Rare Variants and Common Variants The studies described in detail above have generally taken the approach of examining either common variants or rare variants and their relationship to IIP or IPF risk [66,122]. Future studies will need to address the interactions between common variants and rare variants. Are there differences in disease phenotype dictated by the variants an individual has? Does having numerous common disease-associated variants increase disease risk or severity in a dose-dependent fashion? How do common and rare variants interact or modify one another? And critically, how does sequence variation

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directly lead to disease? Future studies will need to address these critical questions in order translate scientific discovery to bedside clinical care. 

15.3.4 Clinical Outcomes Further study of the disease-associated variants described above has also been examined for links to disease phenotype and clinical outcomes. Given the heterogeneity of clinical course for IPF patients, the ability to improve prognostication or personalize therapeutic choices would be a major advance in the clinical care of the disease.

15.3.4.1 Disease Severity 15.3.4.1.1 MUC5B. Retrospective analyses of large clinical trials data reveal that IPF patients with the minor allele (T) at rs35705950 had improved survival when compared to wild-type (GG) subjects of the safe cohort [101]. This survival difference is significant even when controlling for age, sex, lung function, and treatment status. Therefore, while the minor allele at rs35705950 increases risk of disease, IPF patients with the risk allele appear to have improved survival [101], suggesting that the MUC5B promoter variant identifies a subset of patients with IPF who have a distinct phenotype/prognosis. Similarly, genotype at the variant in TOLLIP first associated with IPF by Noth and colleagues (rs5743890) is also associated with differential survival [100]. In the case of rs5743890, the minor allele (G) is associated with decreased disease severity within diseased subjects, minor allele carriers with IPF have increased mortality [100].  15.3.4.1.2 Telomerase Pathway Mutations. The disease phenotype of patients with telomerase pathway mutations is varied. In subjects with known telomerase pathway mutations, the prevalence of ILD increases with age, as illustrated by a study of TERT mutation carriers in which none of the subjects less than age 40 years had evidence of ILD, yet its prevalence of those older than 60 years was 60% [123]. An observational study of 115 pulmonary fibrosis patients with telomerase pathway mutations (TERC, TERT, RTEL1, and PARN) was conducted and found that TERC mutation carriers were diagnosed at an earlier age (mean 51 yeas) relative to the other study subjects (58 years for TERT, 60 years for RTEL1, and 65 years for PARN) [124]. Compared with

417

the decline in lung function observed in large clinical trials for IPF [125], this study reported a larger decline in lung function (as measured by absolute FVC decline) for these telomerase mutation carriers regardless of the subtype of pulmonary fibrosis [124]. Interestingly, the clinical diagnoses of these patients varied—only 46% had a clinical diagnosis of IPF, while others’ diagnoses included HP, pleuroparenchymal fibroelastosis, and undifferentiated fibrosis, and connective tissue disease–related ILD. Though all of the studied patients had uniformly progressive, lethal disease, survival was not significantly different between these four mutation groups, though TERC mutation carriers had a higher rate of hematologic abnormalities [124].  15.3.4.1.3 Telomere Length. Given the evidence for a relationship between telomere mutations and risk of pulmonary fibrosis, a study of telomere length and its association with survival in ILD and IPF was performed [103]. Adjusting for age, sex, and severity of illness, telomere length is an independent predictor of transplant-free survival in IPF, but not in nonIPF ILD. In this study, the prevalence of rare TERT mutations was low (2%–6%) in the IPF cohorts, and only in 4 of the 40 IPF subjects with short telomeres were TERT mutations found. Therefore, authors concluded that other genetic, epigenetic, or environmental factors may be affecting telomere length in these subjects [103]. 

15.3.4.2 Response to Medical Therapy Retrospective analysis of the PANTHER-IPF clinical trial data showed that when TOLLIP (rs5743890/rs5743894/ rs5743854/rs3750920) and MUC5B (rs35705950) variants were examined, of those who received oral N-acetylcysteine (NAC), those with TT genotype at rs3750920 (TOLLIP) had decreased risk of the trial’s composite endpoint of death, transplantation, hospitalization, or greater than 10% decrease in FVC [121]. Patients with the CC genotype at rs3750920, on the other hand, had an increased risk of the composite endpoint. These findings suggest that though NAC has not been shown to be efficacious in treating IPF in general [126], it is possible that a subset of patients defined by their rs3750920 genotype could benefit from the drug. Currently approved medications for IPF (nintedanib [7] and pirfenidone [6]) have not been examined in terms of efficacy by genotype. 

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15.3.4.3 Lung Transplant Outcomes Given the extrapulmonary manifestations associated with telomeropathy, telomerase mutation carriers have been examined for differences in clinical outcome. Specifically, retrospective analyses of post–lung transplant survival in telomerase mutation carriers with pulmonary fibrosis have illustrated a greater incidence of posttransplant complications in these patients when compared to historical controls [127]. The complications observed were largely driven by hematologic abnormalities thought to be due to the bone marrow dysfunction described in telomerase mutation carriers [127,128]. Larger more recent studies of telomere length in posttransplant pulmonary fibrosis patients show that telomere length <10th percentile was associated with worse survival and also a shorter time to onset of chronic lung allograft dysfunction [129]. Comparison of the <10th percentile telomere length group compared with the >10th percentile group showed higher rate of primary graft dysfunction, but there were no differences in the incidence of acute rejection, cytopenias, infection, or renal dysfunction [129].  15.3.4.4 Utilization in Clinical Care Though these initial studies suggest that genetic variants could be useful in assisting with prognostication, the relationship between genotype at different variants and survival are still being investigated and need to be validated in prospective studies. Future therapeutic trials will need to take into account phenotypic and genotypic variation to allow for a deeper understanding of how these characteristics can and should be integrated into shared decision-making. At this time, given the limited data definitively linking genetic variants with concrete clinical outcomes or therapeutic responses, sequencing and genotyping patients are not part of routine IPF or fibrotic IIP care. 

15.3.5 Early Fibrosis An active area of research in the field of IIP is the early identification of lung fibrosis. This is particularly relevant in the case of IPF, where approved medical therapies have been shown to slow progression, but not to reverse disease [6,7]. Therefore, if it were possible to diagnose patients earlier in the course of disease, there is potential to avoid established, irreversible fibrosis. A study examining the Framingham Heart Study cohort found that the MAF for the rs35705950 variant

in the NHW was 0.105. Interstitial lung abnormalities (ILAs), defined as radiographic evidence of parenchymal lung abnormality (ground glass abnormality, centrilobular nodularity, nonemphysematous cysts, honeycombing, or traction bronchiectasis) were 2.8 times more common for each copy of the rs35705950 variant [113]. Though ILAs are by no means equivalent to lung fibrosis, studies have found that ILAs are associated with increased all-cause mortality and with respiratory disease–related mortality [130]. However, the Framingham Heart ILA study analysis also did show definite radiographic evidence of pulmonary fibrosis in those over 50 years of age was approximately 2%, higher than what was previously reported in the literature [113,119]. This association between the MUC5B promoter polymorphism, FIP, IPF, as well as early lesions like ILA are intriguing, as they suggest that genetic variants could allow for identification of those most at risk for disease or could be useful in risk stratification and shared-decision making when it comes to screening for disease [119]. 

15.4 SYSTEMIC DISEASES THAT CAN CAUSE ILD 15.4.1 Systemic Sclerosis and ILD Numerous autoimmune disorders are associated with ILD, and for many of them it is a prominent finding with significant implications for morbidity and mortality. SSc, or scleroderma, is an autoimmune disease that is not inherited in a Mendelian fashion; however, having a relative with SSc increases an individual’s risk of disease [131]. SSc has a strong association with pulmonary fibrosis, which is a frequent cause of mortality in this disease [131]. SSc is characterized by excessive deposition of connective tissue (collagen) in various tissues, prominently the skin, leading to abnormalities in the microvasculature and abnormalities in the immune system; in most cases, it is diagnosed with the aid of detectable antinuclear antibodies in the serum (anti-RNA polymerase, anticentromere, antitopoisomerase [ATA]), each of which are consistent with clinical subsets of disease. ATA, for instance, is also frequently denoted as anti-Scl-70, and this phenotype is strongly associated with lung fibrosis [132]. Various lung pathologies are observed in SSc-ILD: NSIP is commonly found on histologic pattern (77.5% in one observational study), though UIP is often observed (15%) [133]. Though

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Genetic Determinants of Interstitial Lung Diseases

treatment with immunosuppressive medications is generally pursued in these patients, clinical course is variable, and there are many patients with progressive and fatal lung disease. The pathogenesis of SSc has been thought to be T-cell-mediated, and so early genetic studies examined the major histocompatibility complex on chromosome 6. In 2001, one group reported that 72% of ATA-positive patients carried an HLA-DRB1*11 allele in comparison to 18% of controls (P = .00006). Although the relationship was not as strong, they also found an association with another allele, HLA-DPB1*1301. A separate study in Greece found similar associations with HLADRB1*11, specifically finding that the allelic subtype *1104 was associated with the presence of ATAs and lung fibrosis [134]. There have been many associations among various HAL alleles and SSc [131], with different findings among different ethnic population, specifically HLA-C and HLA-D. Numerous other genes have been analyzed as well using a candidate gene approach. In a study by Sato and colleagues, tumor necrosis factor (TNF) alleles were not associated with lung fibrosis, but the TNF-863A allele was strong associated with anticentromere antibody disease, in which pulmonary fibrosis is observed less frequently [135]. Weak associations with lung fibrosis have been found with both secreted protein acidic and rich in cysteine/osteonectin (SPARC) and fibronectin 1 (FN1) [136,137]. Two haplotypes (Hap-5 and Hap-6) in the fibrillin 1 gene (FBN1) have been associated with SSc, with Hap-5 specifically associated with pulmonary fibrosis [138]. Two separate studies detailed an association between the TGF-β L10P codon and lung fibrosis in Ssc [139,140]. In a study by Beretta and colleagues [141], 104 subjects with Ssc were followed longitudinally, with 25 (12.3%) of these individuals developing severe lung fibrosis. In this cohort, the interleukin-1β (IL-1β) C+3962T polymorphism was found to be associated with the presence of severe restrictive lung disease [141]. The connective tissue growth factor (CTGF) locus was one of many loci significantly associated with SSc in a genome-wide study of a cohort enriched for the disease [142]. CTGF is upregulated in the circulation, skin, and fibroblasts of SSc patients and plays a role in regulating fibroblast proliferation and extracellular matrix (ECM) production [143]. Subsequent study of this locus through targeted sequencing in cases and

419

follow-up larger-scale genotyping found that genotype at rs6918698, an SNP in the CTGF promoter region, was found to be significantly associated with SSc [144]. Additionally the G allele at this variant was associated with SSc-ILD [144]. The C variant is thought to reduce CTGF production through alteration of the binding of transcription factors [131,144]. Subsequent study of a Japanese cohort confirmed this association between the G allele at rs6918698 and SSc as well as SSc-ILD. Though there have been attempts to replicate these findings in diverse ethnic groups, these studies have not always validated earlier findings, suggesting that different genetic risk factors may be at play in different subgroups of ­disease.

15.4.2 Sarcoidosis Sarcoidosis is a multisystem disease characterized by granulomatous growth and inflammation in various tissues. The disease can affect any organ in the body, but observational studies have shown that over 90% of patients present with pulmonary findings, ocular involvement, and/or skin abnormalities [145]. The pulmonary phenotype of this disease can vary widely, from incidental hilar adenopathy seen on chest imaging with minimal to no symptoms to respiratory failure with severe parenchymal fibrosis. However, the granuloma is the central pathologic finding in sarcoidosis, and immune-related processes have been the focus of investigation into disease pathogenesis [145]. Genetic predisposition in combination with an as-of-yet unspecific environmental exposure acting as an antigen are thought to be the key to disease pathogenesis [146]. Various genetic epidemiologic approaches have been attempted to define genetic susceptibility to this disease, though many approaches have proven challenging, perhaps because of the variation observed in clinical phenotype [146]. Familial relative risk of disease is 2.8 in African-American patients and 18 in NHW [147]. Genome-wide linkage studies in sarcoid have been conducted in African-American families [148] and German cohorts [149,150], and these identified two loci on the HLA region of Chromosome 6p21 and a different region on Chromosome 9q33.1. Subsequent large GWAS studies (examining variants with MAP >0.01) have been performed in sarcoid cohorts. The strongest, most consistent regions associated with sarcoid risk and disease severity are those in the major histocompatibility

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complex region and HLA-DRB1 variants [146,151–155]. Given that sarcoidosis can affect numerous organs, specific examination of pulmonary manifestations in an Scandinavian cohort showed that HLA-DRB1*07,*14, and *15 were associated with progressive disease, while 01 and 03 were associated with nonprogressive disease [151,152]. In an African-American cohort, the HLADRB1*0301 allele was associated with decreased risk of persistent disease [156]. Additional studies have focused on butyrophilin-like 2 gene (BTNL2), toll-like receptors, chemokine receptors (CCR2, CCR2), cytokines (TNF-alpha, TNA-beta, TGF-beta, IL-23), signaling molecules (e.g., Annexin A111 [ANXA11]) [146], NOTCH4 [157], and X-linked inhibitor of apoptosis (XAF1) [158]. Some of these associations have been replicated in independent cohorts, but there appears to be significant variation based on the genetic backgrounds of separate cohorts [146]. In the case of ANXA11, in 2008, a GWAS in a German population found an association between that locus and disease [159]—this finding has been replicated multiple times, including a fine-mapping effort in African-American sarcoidosis patients which identified two additional disease-associated variants in this subpopulation of patients [160–164]. Given the associations observed between sarcoidosis and various occupational/environmental exposures, it is likely that interplay between genetic risk factors and environmental antigens plays an important role in disease development. In particular, Mycobacteria are emerging as potential etiologic antigens, as proteins from and antibodies to mycobacteria have been noted in biological samples from sarcoidosis patients [165–171]. Further study is needed to clarify the relationship between different genetic risk variants, disease phenotype, environmental exposures, and an individual patient’s risk for disease [146,162]. 

15.4.3 Hypersensitivity Pneumonitis HP, described in part in the sections above, describes parenchymal lung disease characterized by inflammation and, in certain forms, fibrosis resulting from environmental exposures. Acute and chronic forms of HP exist, and once lung fibrosis develops it has potential to progress to end-stage lung disease, especially with prolonged exposure to the inciting antigen. Different histopathologic patterns can be seen on lung biopsy,

including UIP; poorly formed granulomas are a hallmark of this disease. As is the case with sarcoidosis, another disease marked by dysregulated immune responses and granulomatous inflammation, HLA associations have reported, particularly in the case of “pigeon breeder’s lung,” a commonly encountered form of HP triggered by exposure to avian antigens. This association has been noted in HLA-DR7 [172], HLA DRB1-1305, and HLADQB1*0501 [173]. As described in detail above, a recent study of two distinct cohorts with HP showed that minor allele at rs35705950 in the MUC5B promoter polymorphism strongly associated with IPF and FIP was associated with chronic HP. The reported MAFs were similar to those previously published in IPF cohorts [116]. The same study also examined telomere length in these chronic HP patients and revealed that shortened peripheral blood leukocyte telomeres are also associated with fibrosis, poorer survival, and radiographic/histopathologic findings characteristic of IPF (e.g., honeycombing, traction bronchiectasis) [116]. These results suggest that in terms of MUC5B and telomere length, the genetic predisposition to chronic forms of HP may be similar to that of IPF and FIP.  

15.4.4 Chronic Beryllium Disease Exposure to beryllium (Be), a rare alkaline earth metal utilized in high technologies industries like aerospace, ceramics, electronics, and nuclear defense, can lead to prominent ILD in susceptible individuals known as chronic beryllium disease (CBD). Depending on the type of exposure and individual genetic susceptibility, CBD develops in 1%–16% of exposure individuals [79]. CBD is characterized by noncaseating granulomatous inflammation—though it primarily affects the lungs, it can also be found in other organs. Based on histopathology alone, CBD is indistinguishable from sarcoidosis, so exposure history and testing for sensitization is how clinicians distinguish between the diseases; a third of untreated patients will progress to end-stage respiratory failure [174]. Though Be exposure is required for development of CBD, genetic susceptibility is central to this disease development. HLA-DPB1 alleles with a glutamic acid (E) at position 69 on the beta-chain (Beta-Glu69) were strongly linked to disease; the most common such allele is HLA-DPB1*02:01 [79,80].

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Genetic Determinants of Interstitial Lung Diseases

Since the initial report of this association, numerous studies have corroborating these findings—BetaGlu68 containing DPB1 alleles are present in 73%–95% of Be sensitized subjects and CBD patients compared with 30%–48% of controls; of those with Be exposure, BetaGlu69 polymorphism carriers have a tenfold increased risk of developing disease [79,175]. In those CBD patients without a BetaGlu69-containing HLA-DP allele, different alleles that lead to amino acid substitutions have been found [79].

15.5 OTHER GENETIC DISEASES THAT CAN CAUSE ILD Numerous Mendelian disorders can involve pulmonary manifestations including ILD—these will be discussed briefly, as they are referenced elsewhere in this text.

15.5.1 Dyskeratosis Congenita DKC, discussed earlier in this chapter as it relates to telomerase mutations in FIP, is a rare disorder diagnosed based on a triad of mucocutaneous manifestations: oral leukoplakia, nail dystrophy, and abnormal skin pigmentation. This disorder affects numerous tissues and can involve bone marrow failure, which is the major cause of death in this disorder. As described above, pulmonary fibrosis, presenting similarly to IPPs, occurs in about one-fifth of DKC patients and following bone marrow failure is the leading cause of death. UIP pattern is commonly observed on lung pathology [56,176]. In some DKC registries, about half of subjects do not have a clearly defined causative gene mutation [56,176]. However, as described above, telomere-related gene mutation have been linked to DKC. The X-linked form of the disease has been mapped to chromosome Xq28 [59,60,177]. Other mutations in DKC1, the gene that encodes the protein dyskerin, a component of the telomerase complex, have also been linked to disease and are found in 33% of DKC registry cases [56,58,176]. Autosomal dominant forms of the disease can also be caused by mutations in TERT [61] and TERC [62,63], and heterozygous mutations in TINF2, a gene encoding proteins in the shelterin complex, which protects telomeres [178,179]. Autosomal recessive cases of DKC can arise from mutations in TERT and two other genes encoding telomerase complex proteins (NOP10, NHP2) [180–182]. Telomere shortening can be caused

421

by mutations in these genes, and in vivo murine experiments suggest that clinical manifestations of DKC may be the result of progressive telomere shortening caused by decreased telomerase activity [183–185]. However, though pulmonary fibrosis has been observed in DKC cases caused by DKC, TERT, and TERC, the importance of pulmonary disease in DKC caused by NOP10, NHP2, or C16orf57 is not known. 

15.5.2 Hermansky–Pudlak Syndrome Hermansky–Pudlak syndrome (HPS) refers to a group of heterogeneous autosomal recessive disorders. To date, eight different subtypes have been described associated with different genetic abnormalities. HPS is diagnosed clinically in patients with oculocutaneous albinism, clotting dysfunction secondary to defective platelets, and, in some subtypes that affect Type II AECs, ILD. It is thought that genetic mutations in HPS lead to abnormal protein trafficking with associated lysosome-related organelles [186]. HPS is the most commonly encountered genetic disease in Puerto Rico, with 1/1800 individuals in regions of Puerto Rico affected [187]. HPS-1 is the most common subtype of this disease, accounting for approximately 50% of HPS cases outside the Puerto Rican population. Over 20 disease-causing mutations have been reported in HPS1 [186], located on chromosome 10q23.1–23.3 [188]. HPS-2 is caused by mutations in AP3B [189]. HPS3 is on chromosome 3q24 [190], HPS4 on chromosome 22q11.2-q12.2 [191], HPS5 on chromosome 11p14 [192], HPS6 on chromosome 10q24.32 [192], DTNBP1, the gene for HPS-7 on chromosome 6p22.3 [193], and BLOC1S3, the gene for HPS-8, on chromosome 19q13 [194]. Among these subtypes, ILD and pulmonary fibrosis occur in HPS-1 and HPS-4. In most individuals with HPS-1 and HPS-4 who survive to adulthood, ILD can be found, with many patients having severe progressive pulmonary fibrosis resulting in respiratory failure [195,196]. Patients who present with lung fibrosis have a mean age of onset of symptoms of 35 years and an average age of death related to respiratory failure of 37years—therefore, these patients experience rapidly progressive disease [195]. Clinical presentations for HPS-1- and HPS-4-related pulmonary fibrosis have much in common with what can been seen with some IIPs. Lung biopsy in HPS can reveal a pathologic pattern similar to UIP, but can also

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show hyperplastic AECs filled with phospholipid-rich droplets and enlarged lamellar bodies, pointing to possible defects in the secretory pathway [197]. Compared to HPS-1, HPS-4 is much less common, but lung manifestations occur in the same pattern as noted in HPS-1 [191].  

15.6 OTHER RESTRICTIVE LUNG DISEASES 15.6.1 Lymphangioleiomyomatosis and Tuberous Sclerosis Lymphangioleiomyomatosis (LAM) is a systemic disease characterized by the presence of multiple pulmonary cysts, abnormal lymphatic vessels, and chylous serous effusions [198]. The prevalence of LAM is estimated of 2.6–7.8 cases/million of women (either sporadic or associated with tuberous sclerosis) [82]. The prevalence of tuberous sclerosis is estimated to be between 1/25,000 and 1/11,300 in Europe [82]. Tuberous sclerosis is linked to mutations or deletions genes, TSC1 or TSC2, whereas sporadic LAM is usually not associated with germline mutation [82]. The genes TSC1 and TSC2 code for the hamartine and tuberin proteins, respectively, which act on the m-TOR (mammalian target of rapamycin) pathway. M-TOR inhibitors, sirolimus and everolimus, have proven their clinical benefit in treating the disease [199].  15.6.2 Pulmonary Langerhans Cell

Histiocytosis

Langerhans cell histiocytosis (LCH) is a systemic disease, predominant between 20 and 40 years, which may include, in addition to lung involvement, bone, skin, endocrine manifestations (hypothalamic–pituitary disease with diabetes insipidus) [200]. Pulmonary involvement, correlated with smoking in more than 90% of cases, is most often isolated in adults (PLCH) [201]. PLCH has been shown to be associated with somatic mutation of BRAF, or less frequently NRAS or MAP3K1 [202]. However, there is no evidence for familial predisposition of PLCH in adults, and PLCH has not been associated with rare or frequent germline mutation. 

15.6.3 Pulmonary Alveolar Proteinosis Pulmonary alveolar proteinosis (PAP) is characterized by alveolar accumulation of surfactant. Autoimmune alveolar proteinosis is the most frequent form of PAP,

representing 90% of cases. PAP may also result from several mutations. PAP may be observed in patients with surfactant gene mutations [43,83]. GM-CSF receptor is composed of an α chain, coded by CSF2RA, and a β chain, coded by CSF2RB. Homozygous mutations of CSF2RA and heterozygous mutations of CSF2RB have been associated with PAP. Except for a lower age at disease onset, PAP with mutation of CSF2RA is very similar to autoimmune PAP [203]. Indeed, unlike mutations of surfactant proteins, interstitial cell infiltration is absent; however, alveolar and serum concentration of GM-CSF is increased, and anti-GM-CSF antibodies are absent. Whole-lung lavage may be effective, whereas GM-CSF therapy does not seem to be effective [204–206]. GATA2 is a transcriptional factor required by hematopoietic stem cells. GATA2 mutations were initially associated with MonoMAC syndrome (monocytopenia, lymphopenia, mycobacterial infection) and further associated with numerous hematological disorders [207]. GATA2 mutation was initially associated with PAP, but pulmonary fibrosis has also been reported [84,208]. Hematopoietic stem cell transplantation may improve lung disease [207]. Homozygous mutations of methionyl-tRNA synthetase (MARS), an enzyme that catalyzes the binding of methionine to tRNA and plays a critical role in protein synthesis, has been described in a cohort of 34 children with ILD from La Réunion Island belonging to the same family [85]. Most of them presented with PAP [209], and a similar mutation was detected in two independent families [85]. The mean age at diagnosis was 8.9 months. All patients had respiratory failure and failure to thrive, half had hepatomegaly related to steatosis, and one-third had splenomegaly. CT scanning showed a crazy paving pattern and consolidations (76%). In addition to PAP pattern, pulmonary histology showed lipoid pneumonia (42%), fibrosis (42%), and interstitial inflammation (84%). Overall survival at age of 5 years was 65%. Despite temporary improvement after pulmonary lavage, survival was not different between the patient receiving therapeutic pulmonary lavage or not. The PAP did not recur after pulmonary transplantation [209] The enzyme activity of MARS in yeast was decreased in the presence of these mutations. This activity was restored in vitro by methionine supplementation, suggesting a possible therapy [85]. 

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Genetic Determinants of Interstitial Lung Diseases

15.6.4 Lysinuric Protein Intolerance Lysinuric protein intolerance (LPI) is an autosomal-recessive disease caused by mutation of SLC7A7 contributing to defective transport of cationic amino acid at the membrane of epithelial cells in the intestine and kidney [86]. The disease is usually diagnosed in children with failure to thrive and gastrointestinal symptoms. The most frequent chronic manifestations are related to renal and pancreatic insufficiency. LPI is diagnosed by the presence of excessive amounts of dibasic amino acids (arginine, lysine, ornithine) in the urine, particularly after protein ingestion and/or mutation of SLC7A7 [86]. Pulmonary manifestations are variable and range from subclinical ILD to respiratory insufficiency. PAP is frequently present and patients may develop lung fibrosis independently from the severity of PAP [86]. The treatment is based on a low protein diet and oral supplementation with citrulline. Whole-lung lavage and nebulized GM-CSF therapy seem to be effective [86]. However, PAP may lead to death and relapse after lung transplantation [86]. 

15.6.5 Birt–Hogg–Dube Birt–Hogg–Dube (BHD) syndrome is characterized by specific cutaneous lesions (fibrofolliculomas, among others) frequently associated with cystic lung disease [87]. BHD syndrome is an autosomal dominant disease with partial penetrance related to mutation within the foliculin gene. Besides the risk of pneumothorax, cysts usually do not increase. There is, however, a high risk of renal cancer, and patients with BHD require specific surveillance for kidney abnormalities [210]. 

15.6.6 Neurofibromatosis Type 1 neurofibromatosis is one of the most common genetic diseases, with an incidence of 1/3500 live births [211]. Most frequent signs are café-au-lait spots, present in over 90% of cases. Cutaneous neurofibromas manifest at a later time point, often not until adulthood, then multiplying from the age of 30 years onwards. Type 1 neurofibromatosis is an autosomal-dominant transmitted disease with complete penetrance, secondary to NF1 mutations [212]. Multiple pulmonary diseases have been reported either benign or tumoral. However, an association between lung cancer and NF1 has yet to be confirmed [212].

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However, parenchymal neurofibromas have also been reported in up to 5% of the cases. The lesions are mostly asymptomatic and CT shows centrilobular nodules and parenchymal cysts, without any clearly defined walls. The lesions may cluster, potentially leading to the misdiagnosis of centrilobular emphysema and be associated with pulmonary hypertension [88]. A specific association with noncystic ILD and NF1 mutation has yet to be determined [213]. 

15.6.7 Pulmonary Alveolar Microlithiasis Pulmonary alveolar microlithiasis is characterized by the intraalveolar accumulation of microliths, caused by biallelic mutation of SLC34A2 encoding a sodium phosphate cotransporter in AEC [89,214]. Patients can be asymptomatic or present respiratory insufficiency, but few patients remain stable. Chest radiography and CT scan are usually characteristics showing diffuse nodular calcifications, but bronchoalveolar lavage and/ or transbronchial biopsy are usually proposed to confirm the presence of alveolar calcifications [89]. No treatment but lung transplantation has shown to be effective [89]. 

15.6.8 Lipoid Proteinosis Lipoid proteinosis is an autosomal recessive genodermatosis secondary to biallelic mutation of ECM1 characterized by deposition of an amorphous hyaline material predominantly in the skin and mucosa of upper aerodigestive tract [90]. Mutation in the ECM1 results in abnormalities in the glycolipids or sphingolipids degradation pathway [90]. Any organ may virtually be involved, and ILD has been anecdotally been reported [215]. 

15.6.9 Gaucher Disease Gaucher disease is an autosomal recessive disease secondary to mutations in the glucocerebrosidase gene, resulting in deficiency of the lysosomal hydrolase acid β-glucosidase and in accumulation of its substrate, the glucosylceramide [91]. Most frequent manifestations of type 1 Gaucher disease are infiltration of bone marrow, liver, spleen, and lung by lipid-engorged macrophages (Gaucher cells). Type 2 and 3 Gaucher disease manifest with primary central nervous system involvement expressed as spasticity, oculomotor apraxia, and seizures with onset in infancy and leading to premature death [91].

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Respiratory Disorders

Very few cases of lung involvement of Gaucher disease have been specifically reported; CT shows predominant ground glass pattern with superimposed thickening of interlobular septa [216]. The natural history of Gaucher disease has been dramatically modified by the development of enzyme replacement therapy [217]. 

15.6.10 Niemann–Pick Disease Niemann–Pick disease is an autosomal recessive disease secondary to acid sphingomyelinase deficiency. The most frequent clinical presentation is a neurovisceral infantile form in type A, but a chronic visceral form presenting with hepatosplenomegaly and pulmonary involvement may also encountered in adults in type B disease [92]. The incidence of type B Niemann–Pick is estimated to be 1/230,000 in France. Type B Niemann–Pick disease is an autosomal recessive inherited disease related to mutation within SMPD1 [92]. Most frequent CT patterns are interlobular septal thickening and ground glass opacities, and bronchoalveolar lavage shows characteristic Niemann–Pick cells [218,219]. Although pulmonary manifestations eventually worsen, enzyme replacement therapy is actually evaluated. 

15.6.11 Fabry Disease Fabry disease is an X-linked lysosomal storage disorder caused by mutation of the α-galactosidase gene (GLA) causing deficiency of α-galactosidase A activity [220]. This enzymatic defect leads to the progressive accumulation of glycosphingolipids resulting in neurological, ocular, skin, renal, and cardiac manifestations in classical type of the disease [220]. Respiratory symptoms are most frequently related to cardiac involvement. Few patients have ILD and ground glass pulmonary infiltrations on CT scan [93]. Enzyme replacement therapy may improve or stabilize respiratory manifestations [93,220]. 

15.6.12 Marfan Syndrome Marfan syndrome is a phenotype caused by mutations of the gene FBN1, coding for the protein fibrillin-1 [94]. Cardiovascular, musculoskeletal, and ophthalmic manifestations are the most commonly observed, but minor diagnostic criteria also include pulmonary manifestations. Pneumothorax, frequently relapsing,

affects 5%–11% of patients. Rib cage abnormalities (pectus excavatum or pectus carinatum) and apical blebs may contribute to their occurrence [221]. Treatment does not require any specific procedure, but there is an increased risk of recurrence. Pectus excavatum affects up to 60% of the patients, without any functional impairment in most cases [221]. Surgery may be required in patients with significant cardiovascular or physiologic symptoms [222]. 

15.7 CONCLUSION Restrictive and ILDs encompass a wide variety of phenotypes. Accordingly, the genetic variants found to be associated with these diseases are in genes associated with diverse biological processes, from host defense to cell senescence. Though there has been rapid growth in the understanding of the genetic risk factors of ILD in the last decade, many of the mechanistic links between genetic variation and disease pathophysiology remain areas of active research. Further advances in clinical care will require translating our understanding of genetic risk into more effective and personalized approaches to diagnosis and treatment of respiratory diseases.

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CHAPTER 15 

Genetic Determinants of Interstitial Lung Diseases

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