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Familial pulmonary fibrosis is the strongest risk factor for idiopathic pulmonary fibrosis

Open ArchivePublished:September 14, 2011DOI:https://doi.org/10.1016/j.rmed.2011.08.022

      Summary

      Idiopathic pulmonary fibrosis (IPF) is a lethal lung disorder of unknown etiology. The disease is likely the result of complex interactions between genetic and environmental factors. Evidence suggests that certain environmental factors, such as cigarette smoking and metal dust exposures, or comorbidities like gastroesophageal reflux, and type 2 diabetes mellitus (DM2) may increase risk to develop IPF. Substantial uncertainty remains, however, regarding these and other putative risk factors for IPF. In this study we performed a case–control analysis including 100 patients with IPF and 263 controls matched for age sex and place of residence. We used a structured questionnaire to identify potential risk factors for IPF, including environmental and occupational exposures as well as the relevance of family history of pulmonary fibrosis. The multivariate analysis revealed that family history of pulmonary fibrosis [OR = 6.1, CI95% 2.3–15.9; p < 0.0001] was strongly associated with increased risk of IPF. Actually, 20% of the cases reported a parent or sibling with pulmonary fibrosis. Gastroesophageal reflux [OR = 2.9, CI: 1.3–6.6; p = 0.007], former cigarette smoking [OR = 2.5, CI: 1.4–4.6, p = 0.003], and past or current occupational exposure to dusts, smokes, gases or chemicals [OR = 2.8, CI: 1.5–5.5; p = 0.002] were also associated with the disease. Despite being a significant risk factor on univariate analysis DM2 was not significant in multivariate analysis. These findings indicate that family history of pulmonary fibrosis is a strong risk factor for IPF. Also, we confirmed that occupational exposures, gastroesophageal reflux and former smoking increase the risk for this disease.

      Keywords

      Abbreviation:

      ATS (American Thoracic Society), 95% CI (95% confidence intervals), DLD (Division of Lung Diseases), DM2 (Type 2 diabetes mellitus), ECRHS (European Community Respiratory SurveyII), ERS (European Respiratory Society), IIP (Idiopathic interstitial pneumonia), IPF (Idiopathic pulmonary fibrosis), LHSQ (Lung Health Study Questionnaire), OR (Odds ratio), SD (Standard deviation), SF-12 (Short Form survey-12), TSR (telomere repeat copy number to single gene copy number)

      Introduction

      Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and lethal lung disorder of unknown etiology. The disease occurs predominantly in older adults, although the mechanisms for the association of aging with IPF have not been elucidated.
      • Selman M.
      • Rojas M.
      • Mora A.L.
      • Pardo A.
      Aging and interstitial lung diseases: unraveling an old forgotten player in the pathogenesis of lung fibrosis.
      IPF is considered a complex disease where both genetic and environmental factors are believed to contribute to disease susceptibility. In the last decade a number of studies have tried to understand the genetic bases of this disease and to identify risk factors, but there are few large studies with conclusive results.
      To date, smoking has consistently been associated with IPF in a number of case–control studies evaluating sporadic IPF and in one study of familial pulmonary fibrosis.
      • Taskar V.S.
      • Coultas D.B.
      Is idiopathic pulmonary fibrosis an environmental disease?.
      • Steele M.P.
      • Speer M.C.
      • Loyd J.E.
      • et al.
      Clinical and pathologic features of familial interstitial pneumonia.
      Also, several occupational factors, adjusted for age and smoking have been found significantly associated with IPF, including metal and wood dust exposure.
      • Hubbard R.
      • Lewis S.
      • Richards K.
      • Johnston I.
      • Britton J.
      Occupational exposure to metal or wood dust and aetiology of cryptogenic fibroising alveolitis.
      • Baumgartner K.B.
      • Samet J.M.
      • Coultas D.B.
      • et al.
      Occupational and environmental risk factors for idiopathic pulmonary fibrosis: a multicenter case-control study.
      A meta-analysis supported that significant increased risk for IPF is associated with cigarette smoking and exposures to agriculture and farming, livestock, wood and metal dust, and stone and silica.
      • Taskar V.S.
      • Coultas D.B.
      Is idiopathic pulmonary fibrosis an environmental disease?.
      Likewise, some studies provide evidence of an association between IPF and type 2 diabetes mellitus (DM2) and gastroesophageal reflux.
      • Enomoto T.
      • Usuki J.
      • Azuma A.
      • Nakagawa T.
      • Kudoh S.
      Diabetes mellitus may increase risk for idiopathic pulmonary fibrosis.
      • Gribbin J.
      • Hubbard R.
      • Smith C.
      Role of diabetes mellitus and gastro-oesophageal reflux in the aetiology of idiopathic pulmonary fibrosis.
      • García-Sancho Figueroa M.C.
      • Carrillo G.
      • Pérez-Padilla R.
      • et al.
      Risk factors for idiopathic pulmonary fibrosis in a Mexican population. A case-control study.
      • Tobin R.W.
      • Pope C.E.
      • Pellegrini C.A.
      Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis.
      • Raghu G.
      • Freudenberger T.D.
      • Yang S.
      • et al.
      High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis.
      Familial IPF, which is virtually indistinguishable from sporadic IPF, is identified when two or more members of a family have the disease. Some studies suggest that 0.5–3.7% of IPF is familial.
      • Marshall R.P.
      • Puddicombe A.
      • Cookson W.O.
      • Laurent G.J.
      Adult familial cryptogenic fibrosing alveolitis in the United Kingdom.
      • Hodgson U.
      • Laitinen T.
      • Tukiainen P.
      Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland.
      However, a remarkably higher frequency was reported in a small cohort of IPF patients from a lung transplant program where 19% had a positive family history
      • Lawson W.E.
      • Loyd J.E.
      The genetic approach in pulmonary fibrosis: can it provide clues to this complex disease?.
      ; this retrospective decade-long analysis probably had higher detection due to subsequent cases occurring in the family of patients who reported a negative family history. More recently, 10% were identified as familial within a single-center cohort of 229 patients with idiopathic interstitial pneumonias.
      • van Moorsel C.H.
      • van Oosterhout M.F.
      • Barlo N.P.
      • et al.
      Surfactant protein c mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a Dutch cohort.
      In this context, we designed a questionnaire-based, case–control study to identify potential environmental risk factors in our population as well as the relevance of family history of pulmonary fibrosis in a cohort of IPF patients.

      Methods

      Study design

      A case–control study was carried out at the National Institute of Respiratory Diseases during 2007–2009. The research protocol was approved by the institutional Scientific and Bioethics Committee (Comité de Ciencia y Bioética en Investigación; Protocol #E05-07). Population studied was comprised of newly-diagnosed IPF patients (cases) consecutively seen at our institution, and healthy subjects (controls) paired by age, gender and residential area. Diagnosis of IPF was established according to ATS/ERS criteria.
      American Thoracic Society
      Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European respiratory Society (ERS).
      In 35% of the patients the diagnosis was confirmed by surgical biopsy showing changes of usual interstitial pneumonia.
      • Katzenstein A.L.
      • Mukhopadhyay S.
      • Myers J.L.
      Diagnosis of usual interstitial pneumonia and distinction from other fibrosing interstitial lung diseases.
      Healthy controls were randomly selected from the same patients’ neighborhoods, at a ratio of 1–3 controls per IPF patient. In general, matching controls were living in houses located in the same block than the patients. A trained interviewer visited every household and asked if some person living there had the same age and gender than the case patient. After explaining the purpose of the study, potential control subjects were asked to participate and, if agreed, the questionnaire was applied. Control subjects were included in the study if they were no relatives of the patients and if they denied chronic pulmonary diseases or acute respiratory symptoms in the last three weeks prior to the interview. Patients and controls were individuals with the same ethnic origin and with at least two generations born in Mexico. Patients and controls have similar access and utilization to the same quality health care. A signed consent letter was obtained from all patients and controls.

      Exposure assessment

      Evaluation of exposures was performed with the same questionnaire used in the PLATINO study,
      • Menezes A.M.
      • Victora C.G.
      • Perez-Padilla R.
      PLATINO Team. The Platino project: methodology of a multicenter prevalence survey of chronic obstructive pulmonary disease in major Latin American cities.
      • Menezes A.M.
      • Perez-Padilla R.
      • Jardim J.R.
      PLATINO Team. Chronic obstructive pulmonary disease in five Latin American cities (the PLATINO study): a prevalence study.
      which in turn derives from an already validated questionnaire (ATS-DLD-78, ECRHS, LHSQ, SF-12). The PLATINO survey was enlarged by adding questions about chronic respiratory conditions in interviewed subjects’ relatives. This questionnaire was applied to all cases and controls by two trained interviewers. Among other variables, characteristics of personal (tobacco, alcohol), occupational (dusts, smokes, gases, chemicals, dairy and poultry farms), and household (ventilation, wood smoke, tobacco smoke) exposures were investigated. The questionnaire also explores the presence of current or past presence of medical conditions such as gastroesophageal reflux, gastritis, hepatitis, heart diseases, and depression. Finally, chronic pulmonary diseases in parents and siblings were also assessed. This last question included the following specific diagnoses: chronic obstructive pulmonary disease, emphysema, asthma, lung cancer, tuberculosis and pulmonary fibrosis. A diagnosis of diabetes mellitus type 2 (DM2) was established through the questionnaire, evaluating whether it was diagnosed by a physician, type of medication (oral hypoglycemic agents or insulin), and duration. Additionally, in IPF patients, diagnosis of DM2 was confirmed by pre-prandial glucose >126 mg/dl without previous corticosteroid use.

      Statistical analysis

      Statistical analysis included Student’s t-test and chi square test to evaluate differences between interval and categorical variables, respectively. Association between two variables was assessed through odds ratio (OR) and 95% confidence intervals (95%CI). Finally, multivariate models were generated by means of conditional logistic regression for matched case–control groups and included the variables that were confounders as those that were considered to be indispensable in explaining the study event. In this analysis, the following predictive variables were included: having a parent/sibling with pulmonary fibrosis, being a former cigarette smoker, past or current occupational exposure to dusts, smokes, gases or chemicals, past gastroesophageal reflux history, and DM2. Probability criteria for a variable entering to or removing from the model were 0.05 and 0.10, respectively. The analysis was performed using Stata software, Release 9.0.

      Results

      From January 2007 through December 2009 a total of 100 IPF patients and 263 healthy controls paired by age, gender and geographical region were studied. Average age was 67.8 ± 9.5 years (mean ± SD) in IPF patients and 67.9 ± 9.1 years in the control subjects (p = 0.9). Male predominance was comparable among cases and controls (71.0% versus 69.9%, respectively, p = 0.8). The similar age and gender between the cases and controls indicate that matching was successful. The majority of the study population (75.2%) lived in the residential areas of the two nearest political demarcations, Distrito Federal and Estado de Mexico.
      Educational characteristics and tobacco smoke and other exposures of the study subjects are shown in Table 1. In the bivariate analysis, the IPF group had a marginal but significantly higher proportion of individuals with 6 or more education years [44.0 vs 32.3% from controls, OR = 1.6 (95% CI, 1.02–2.6), p = 0.039]. Occupational exposure to dusts, smokes, gases or chemicals was more frequently found among cases than in controls [77.0 vs 58.6%, respectively, OR = 2.4 (95% CI, 1.4–4.0), p = 0.001]. Regarding tobacco smoke exposure, former cigarette smokers also showed significant excess risk for IPF [58.0% vs 33.5%, OR = 2.7 (95% CI, 1.7–4.4), p < 0.0001].
      Table 1Education and exposures of cases and controls.
      CharacteristicIPF cases
      Data correspond to n(%).
      (n = 100)
      Control subjects
      Data correspond to n(%).
      (n = 263)
      OR (CI95%)
      Formal education ≥ 6 years44 (44)85 (32.3)1.6 (1.02–2.6) p = 0.039
      Occupational exposure to dusts, smokes, gases or chemicals77 (77)154 (58.6)2.4 (1.4–4.0) p = 0.001
      Former cigarette smoker58 (58)88 (33.5)2.7 (1.7–4.4) p < 0.0001
      a Data correspond to n(%).
      As shown in Table 2, significantly more IPF patients answered affirmatively to the question about the presence of pulmonary fibrosis in a parent (father or mother) or sibling (brother or sister) [20.0% vs 2.7%, OR = 9.1 (95% CI 3.7–22.4), p < 0.0001]. Three of the 20 patients reported two relatives with the disease. We were able to corroborate the diagnosis of pulmonary fibrosis in the relatives of 8 of these 20 patients because the remaining 12 parents or siblings had died several years ago when we contacted the families. Diagnosis of pulmonary fibrosis in the 7 of the 8 familial cases was corroborated in our Institute using HRCT and pulmonary function tests. The last familial case was evaluated in another Hospital and diagnosis included HRCT and lung biopsy. However, even if we consider only these 8 patients, the odds ratio continued to be significantly increased [OR: 2.8 (95% CI 1.01–7.9), p < 0.05]. On the other hand, due to the potential existence of a recall bias (with IPF cases more prone to recall pulmonary disease in their relatives), we estimated the impact of a misdiagnosis among control group’s relatives. Thus, cases and control subjects declared that 6 and 29 relatives, respectively, had chronic bronchitis, pulmonary emphysema, or chronic obstructive pulmonary disease. In this context, even if we consider that the 23 exceeding relatives of control subjects were in fact IPF patients, familial pulmonary fibrosis would remain significantly associated to IPF (20/100 and 30/263 in cases and controls, respectively) with OR: 1.9 (95% CI 1.04–3.6), p = 0.04.
      Table 2Family history of pulmonary fibrosis and comorbidities of cases and controls.
      CharacteristicIPF cases
      Data correspond to n (%).
      (n = 100)
      Control subjects
      Data correspond to n (%).
      (n = 263)
      OR (CI95%)
      Familial IPF (parent and/or sibling)20 (20.0)7 (2.7)9.1(3.7–22.4) p < 0.0001
      Past gastroesophageal reflux23 (23.0)23 (8.7)3.1 (1.7–5.9) p < 0.0001
      Past gastritis40 (40.0)66 (25.1)1.9 (1.2–3.2) p = 0.006
      Type 2 diabetes mellitus30 (30.0)50 (19.0)1.8 (1.1–3.1) p = 0.02
      Past or current cardiac disease13 (13.0)17 (6.5)2.2 (1–4.6) p = 0.05
      a Data correspond to n (%).
      As previously suggested in several studies on familial IPF,
      • Marshall R.P.
      • Puddicombe A.
      • Cookson W.O.
      • Laurent G.J.
      Adult familial cryptogenic fibrosing alveolitis in the United Kingdom.
      • Hodgson U.
      • Laitinen T.
      • Tukiainen P.
      Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland.
      • van Moorsel C.H.
      • van Oosterhout M.F.
      • Barlo N.P.
      • et al.
      Surfactant protein c mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a Dutch cohort.
      our IPF patients with family history of pulmonary fibrosis were significantly younger than those with negative family history (61.8 ± 7.1 versus 69.3 ± 9.4 years old, p < 0.001). No other variable reached a significant difference between these two subgroups of IPF patients.
      Some diseases were more often observed in IPF patients, as compared with controls. Significant increased risk for IPF was associated with past gastroesophageal reflux [OR = 3.1 (95% CI, 1.7–5.9) p < 0.0001], and gastritis [OR = 1.9 (95% CI 1.2–3.2) p = 0.006]. Type 2 diabetes mellitus was also more frequent among cases than controls [30.0 vs 19.0%, OR = 1.8 (95% CI, 1.1–3.1), p = 0.02]. Past or current cardiac disease was marginally associated with IPF (Table 2).
      Concerning household characteristics, the only feature that was more frequently seen among cases was the presence of earthen floor [9.0 vs 3.4%, respectively, OR = 2.8 (95% CI, 1.1–7.2), p = 0.035]. Some other variables such as working in crop cultivation or as a stockbreeder, carpenter or hairdresser, household nearness to a dairy farm, birds at home, dampness at home, and indoor use of insecticides were not different between cases and controls (data not shown).
      In the multivariate analysis, having a parent or sibling with pulmonary fibrosis was the strongest variable associated with the disease [OR = 6.1 (95% CI, 2.3–15.9) p < 0.0001] (Table 3). Being a former cigarette smoker, having past or current occupational exposure to dusts, smokes, gases or chemicals, and past gastroesophageal reflux were also associated with increased risk of IPF. By contrast, in this multivariate analysis, DM2, showed a tendency but it was not an independent predictor of IPF.
      Table 3Crude and adjusted odds ratios for IPF.
      VariableCrude OR (95% CI)Adjusted OR (95% CI)
      Parent or sibling with IPF9.1 (3.7–22.4) p < 0.00016.1 (2.3–15.9) p < 0.0001
      Former smoker2.7 (1.7–4.4) p < 0.00012.5 (1.4–4.6) p = 0.003
      Past or current occupational exposure to dusts, smokes, gases or chemicals2.4 (1.4–4.0) p = 0.0012.8 (1.5–5.5) p = 0.002
      Past or current gastroesophageal reflux3.1 (1.7–5.9) p < 0.00012.9 (1.3–6.6) p = 0.007
      Type 2 diabetes1.8 (1.1–3.1) p = 0.021.6 (0.9–3.0) p = 0.1

      Discussion

      Idiopathic pulmonary fibrosis is a progressive, life-threatening, lung disorder that likely arises from the interplay between genetic and environmental factors. In this context, individualization of host and environmental factors responsible for IPF predisposition and onset could play an important role for disease prevention and for devising novel therapies.
      Regarding exposures, cigarette smoking has formerly been associated with sporadic IPF.
      • Taskar V.S.
      • Coultas D.B.
      Is idiopathic pulmonary fibrosis an environmental disease?.
      Furthermore, in a family-based case–control study of familial interstitial pneumonia, Steele et al
      • Steele M.P.
      • Speer M.C.
      • Loyd J.E.
      • et al.
      Clinical and pathologic features of familial interstitial pneumonia.
      evaluated 111 families, with 309 affected and 360 unaffected individuals. After adjusting for age and sex, smoking was strongly related with pulmonary fibrosis. The results of the present study corroborate this association since 58% of the IPF patients were former smokers. Taken together, the evidence increasingly indicates that cigarette smoking, which among other effects generates a cumulative oxidative stress, may contribute to the pathogenesis of IPF. Interestingly, it has been shown that tobacco smoking enhances telomere shortening,
      • Morlá M.
      • Busquets X.
      • Pons J.
      • Sauleda J.
      • MacNee W.
      • Agustí A.G.
      Telomere shortening in smokers with and without COPD.
      • Babizhayev M.A.
      • Savel’yeva E.L.
      • Moskvina S.N.
      • Yegorov Y.E.
      Telomere length is a biomarker of cumulative oxidative stress, biologic age, and an independent predictor of survival and therapeutic treatment requirement associated with smoking behavior.
      a process recently reported in most sporadic IPF patients and in a few families.
      • Alder J.K.
      • Chen J.J.
      • Lancaster L.
      • et al.
      Short telomeres are a risk factor for idiopathic pulmonary fibrosis.
      • Cronkhite J.T.
      • Xing C.
      • Raghu G.
      • Chin K.M.
      • Torres F.
      • Rosenblatt R.L.
      • Garcia C.K.
      Telomere shortening in familial and sporadic pulmonary fibrosis.
      Telomeres are DNA-protein structures that protect chromosome ends from erosion and end-to-end fusion and that shorten successively with each cell division.
      • Armanios M.
      Syndromes of telomere shortening.
      Importantly, a link between telomere length and aging-associated diseases and mortality has been suggested.
      • Oeseburg H.
      • de Boer R.A.
      • van Gilst W.H.
      • van der Harst P.
      Telomere biology in healthy aging and disease.
      • Cawthon R.M.
      • Smith K.R.
      • O’Brien E.
      • Sivatchenko A.
      • Kerber R.A.
      Association between telomere length in blood and mortality in people aged 60 years or older.
      In addition, numerous associations between chronic degenerative diseases and telomere length have been reported.
      Intriguingly, a putative relationship between telomere length shortening and type 2 diabetes mellitus has been recently reported.
      • Zee R.Y.
      • Castonguay A.J.
      • Barton N.S.
      • Germer S.
      • Martin M.
      Mean leukocyte telomere length shortening and type 2 diabetes mellitus: a case-control study.
      Using a case–control study from a community-based population sample the association of leukocyte telomere repeat mean copy number to single gene copy number (TSR) and DM2 was examined. In a multivariable logistic regression analysis, it was found that decreased TSR [log(e)-transformed] was significantly associated with the disease. Shortened telomeres have been associated with DM2 in previous but generally small studies. DM2 has been associated with IPF in several studies involving different ethnic populations.
      • Enomoto T.
      • Usuki J.
      • Azuma A.
      • Nakagawa T.
      • Kudoh S.
      Diabetes mellitus may increase risk for idiopathic pulmonary fibrosis.
      • Gribbin J.
      • Hubbard R.
      • Smith C.
      Role of diabetes mellitus and gastro-oesophageal reflux in the aetiology of idiopathic pulmonary fibrosis.
      • García-Sancho Figueroa M.C.
      • Carrillo G.
      • Pérez-Padilla R.
      • et al.
      Risk factors for idiopathic pulmonary fibrosis in a Mexican population. A case-control study.
      In this study, a tendency was also noted. However, given the high prevalence of DM2 in our adult population, a much larger study population would be necessary to provide definitive results.
      As previously described, several exposures (dusts, smokes, gases or chemicals) were also associated with IPF supporting that the disease is more frequent in individuals exposed to dusty environments.
      • Taskar V.S.
      • Coultas D.B.
      Is idiopathic pulmonary fibrosis an environmental disease?.
      • Hubbard R.
      • Lewis S.
      • Richards K.
      • Johnston I.
      • Britton J.
      Occupational exposure to metal or wood dust and aetiology of cryptogenic fibroising alveolitis.
      • Baumgartner K.B.
      • Samet J.M.
      • Coultas D.B.
      • et al.
      Occupational and environmental risk factors for idiopathic pulmonary fibrosis: a multicenter case-control study.
      • Miyake Y.
      • Sasaki S.
      • Yokoyama T.
      • et al.
      Occupational and environmental factors and idiopathic pulmonary fibrosis in Japan.
      Recently, the accumulation of inorganic dusts in lung tissues of patients with IPF, chronic hypersensitivity pneumonitis, and collagen vascular diseases was analyzed by polarizing light microscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy.
      • Tsuchiya K.
      • Inase N.
      • Ichinose S.
      • et al.
      Elemental analysis of inorganic dusts in lung tissues of interstitial pneumonias.
      IPF lung tissues showed greater numbers of birefringent particles, even in patients without occupational exposure. The silicon/sulfur ratio and aluminium/sulfur ratio were increased in IPF independent of occupational exposure. A point elemental analysis showed that the major compound of the particles was aluminium-silicate. How tissue exposure to environmental toxicants predisposes or participates in the pathogenesis of IPF is largely unknown. However, chronic damage to alveolar/bronchiolar epithelial cells may play a role in genetically susceptible individuals.
      The multivariate analysis also confirmed that gastroesophageal reflux is associated with a risk for IPF. Gastroesophageal reflux and silent microaspiration have been related with several lung diseases and is common among those who have had lung transplantation.
      • Lee J.S.
      • Collard H.R.
      • Raghu G.
      • et al.
      Does chronic microaspiration cause idiopathic pulmonary fibrosis?.
      Also, a higher incidence of gastroesophageal reflux has been reported in patients with IPF compared with normal individuals suggesting that microaspiration may be a factor for IPF.
      • Gribbin J.
      • Hubbard R.
      • Smith C.
      Role of diabetes mellitus and gastro-oesophageal reflux in the aetiology of idiopathic pulmonary fibrosis.
      • García-Sancho Figueroa M.C.
      • Carrillo G.
      • Pérez-Padilla R.
      • et al.
      Risk factors for idiopathic pulmonary fibrosis in a Mexican population. A case-control study.
      • Tobin R.W.
      • Pope C.E.
      • Pellegrini C.A.
      Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis.
      • Raghu G.
      • Freudenberger T.D.
      • Yang S.
      • et al.
      High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis.
      Interestingly, it has been suggested that acute exacerbation of IPF, a devastating diffuse alveolar damage manifested by some patients may be also related to microaspiration.
      • Collard H.R.
      • Moore B.B.
      • Flaherty K.R.
      • et al.
      Acute exacerbations of idiopathic pulmonary fibrosis.
      The most remarkable finding in our study was the high prevalence of close relatives of our patients affected by pulmonary fibrosis. Thus, 20 percent of the patients had a parent and/or a sibling previously diagnosed with pulmonary fibrosis. In eight of these cases we were able to confirm the presence of pulmonary fibrosis in the family. Previous studies had estimated a significantly lower frequency of positive family history, e.g., between 0.5 and 3.7%.
      • Marshall R.P.
      • Puddicombe A.
      • Cookson W.O.
      • Laurent G.J.
      Adult familial cryptogenic fibrosing alveolitis in the United Kingdom.
      • Hodgson U.
      • Laitinen T.
      • Tukiainen P.
      Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland.
      However, this percentage may represent an underestimation, as evidenced by a 13 year retrospective review of the Vanderbilt Lung Transplant Program, in which 9 of 47 patients (19%) transplanted for IPF had a family history significant for interstitial lung disease.
      • Lawson W.E.
      • Loyd J.E.
      The genetic approach in pulmonary fibrosis: can it provide clues to this complex disease?.
      Likewise, around 10% of familial IPF were recently identified within a single-center cohort of 229 patients with idiopathic interstitial pneumonias indicating that the percent of familial disease is higher than we formerly believed.
      • van Moorsel C.H.
      • van Oosterhout M.F.
      • Barlo N.P.
      • et al.
      Surfactant protein c mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a Dutch cohort.
      The majority of pedigrees indicate an autosomal dominant vertical transmission pattern of inheritance with reduced penetrance.
      • Steele M.P.
      • Brown K.K.
      Genetic predisposition to respiratory diseases: infiltrative lung diseases.
      In the largest collection of familial interstitial pneumonias, 20 multigenerational pedigrees were consistent with autosomal dominant inheritance.
      • Steele M.P.
      • Speer M.C.
      • Loyd J.E.
      • et al.
      Clinical and pathologic features of familial interstitial pneumonia.
      Clinical features of familial IPF are indistinguishable from those of the sporadic form, except for an earlier age of onset.
      • Marshall R.P.
      • Puddicombe A.
      • Cookson W.O.
      • Laurent G.J.
      Adult familial cryptogenic fibrosing alveolitis in the United Kingdom.
      • Hodgson U.
      • Laitinen T.
      • Tukiainen P.
      Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland.
      • van Moorsel C.H.
      • van Oosterhout M.F.
      • Barlo N.P.
      • et al.
      Surfactant protein c mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a Dutch cohort.
      This observation was confirmed in our study, with the cases with familial history presenting on average 7 years earlier than sporadic patients. Nevertheless, a potential lead time bias (in which subjects with a parent or sibling with IPF are more prone to be submitted to earlier screening and hence to have an earlier diagnosis of IPF than subjects without IPF in the family) can not be ruled-out.
      Certainly, an important limitation of this study was the fact that familial history of pulmonary fibrosis was self-reported. We were able to confirm the diagnosis of IPF/IIP in only 8 of 20 patient’s relatives, because the remaining parents and siblings had died when we contacted the families. However, we have no reason to suspect that the accuracy of self report of disease would be different for the other 12 patients. Also, the magnitude of the odds ratio when compared to healthy controls may be subject to some bias through over-reporting among the cases and underreporting among controls.
      In summary, we found that the presence of a familial history of pulmonary fibrosis showed the strongest association with IPF. This finding supports the notion that it is crucial to carefully evaluate and if possible corroborate the presence of family history in these patients. Exposure to tobacco smoke and other environmental smokes and dusts as well as the presence of gastroesophageal reflux also were risks to develop IPF. Although the environmental associations are not a proof of causation, our findings provide evidence that gene-environment associations are likely playing a role to trigger IPF.

      Funding

      This study was supported by CONACYT Grant 69871.

      Conflict of interest

      None.

      Acknowledgments

      Cecilia García-Sancho, Ivette Buendía-Roldán, Mario H. Vargas, and María del Rosario Fernéndez Plata contributed to study design and statistical analyses. Carmen Navarro and Rogelio Pérez-Padilla contributed to study design and interpretation of the results; Jim E Loyd contributes to the interpretation of the familial findings and in the writing of the manuscript; Moisés Selman contributed to study design, writing the manuscript and takes responsibility for the report.

      References

        • Selman M.
        • Rojas M.
        • Mora A.L.
        • Pardo A.
        Aging and interstitial lung diseases: unraveling an old forgotten player in the pathogenesis of lung fibrosis.
        Semin Respir Crit Care Med. 2010; 31: 607-617
        • Taskar V.S.
        • Coultas D.B.
        Is idiopathic pulmonary fibrosis an environmental disease?.
        Proc Am Thorac Soc. 2006; 3: 293-298
        • Steele M.P.
        • Speer M.C.
        • Loyd J.E.
        • et al.
        Clinical and pathologic features of familial interstitial pneumonia.
        Am J Respir Crit Care Med. 2005; 172: 1146-1152
        • Hubbard R.
        • Lewis S.
        • Richards K.
        • Johnston I.
        • Britton J.
        Occupational exposure to metal or wood dust and aetiology of cryptogenic fibroising alveolitis.
        Lancet. 1996; 347: 284-289
        • Baumgartner K.B.
        • Samet J.M.
        • Coultas D.B.
        • et al.
        Occupational and environmental risk factors for idiopathic pulmonary fibrosis: a multicenter case-control study.
        Am J Epidemiol. 2000; 152: 307-315
        • Enomoto T.
        • Usuki J.
        • Azuma A.
        • Nakagawa T.
        • Kudoh S.
        Diabetes mellitus may increase risk for idiopathic pulmonary fibrosis.
        Chest. 2003; 123: 2007-2011
        • Gribbin J.
        • Hubbard R.
        • Smith C.
        Role of diabetes mellitus and gastro-oesophageal reflux in the aetiology of idiopathic pulmonary fibrosis.
        Respir Med. 2009; 103: 927-931
        • García-Sancho Figueroa M.C.
        • Carrillo G.
        • Pérez-Padilla R.
        • et al.
        Risk factors for idiopathic pulmonary fibrosis in a Mexican population. A case-control study.
        Respir Med. 2010; 104: 305-309
        • Tobin R.W.
        • Pope C.E.
        • Pellegrini C.A.
        Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis.
        Am J Respir Crit Care Med. 1998; 158: 1804-1808
        • Raghu G.
        • Freudenberger T.D.
        • Yang S.
        • et al.
        High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis.
        Eur Respir J. 2006; 27: 136-142
        • Marshall R.P.
        • Puddicombe A.
        • Cookson W.O.
        • Laurent G.J.
        Adult familial cryptogenic fibrosing alveolitis in the United Kingdom.
        Thorax. 2000; 55: 143-146
        • Hodgson U.
        • Laitinen T.
        • Tukiainen P.
        Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland.
        Thorax. 2002; 57: 338-342
        • Lawson W.E.
        • Loyd J.E.
        The genetic approach in pulmonary fibrosis: can it provide clues to this complex disease?.
        Proc Am Thorac Soc. 2006; 3: 345-349
        • van Moorsel C.H.
        • van Oosterhout M.F.
        • Barlo N.P.
        • et al.
        Surfactant protein c mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a Dutch cohort.
        Am J Respir Crit Care Med. 2010; 182: 1419-1425
        • American Thoracic Society
        Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European respiratory Society (ERS).
        Am J Respir Crit Care Med. 2000; 161: 646-664
        • Katzenstein A.L.
        • Mukhopadhyay S.
        • Myers J.L.
        Diagnosis of usual interstitial pneumonia and distinction from other fibrosing interstitial lung diseases.
        Hum Pathol. 2008; 39: 1275-1294
        • Menezes A.M.
        • Victora C.G.
        • Perez-Padilla R.
        PLATINO Team. The Platino project: methodology of a multicenter prevalence survey of chronic obstructive pulmonary disease in major Latin American cities.
        BMC Med Res Methodol. 2004; 4: 15
        • Menezes A.M.
        • Perez-Padilla R.
        • Jardim J.R.
        PLATINO Team. Chronic obstructive pulmonary disease in five Latin American cities (the PLATINO study): a prevalence study.
        Lancet. 2005; 366: 1875-1881
        • Morlá M.
        • Busquets X.
        • Pons J.
        • Sauleda J.
        • MacNee W.
        • Agustí A.G.
        Telomere shortening in smokers with and without COPD.
        Eur Respir J. 2006; 27: 525-528
        • Babizhayev M.A.
        • Savel’yeva E.L.
        • Moskvina S.N.
        • Yegorov Y.E.
        Telomere length is a biomarker of cumulative oxidative stress, biologic age, and an independent predictor of survival and therapeutic treatment requirement associated with smoking behavior.
        Am J Ther. 2010 Mar 29; ([Epub ahead of print])
        • Alder J.K.
        • Chen J.J.
        • Lancaster L.
        • et al.
        Short telomeres are a risk factor for idiopathic pulmonary fibrosis.
        Proc Natl Acad Sci U S A. 2008; 105: 13051-13056
        • Cronkhite J.T.
        • Xing C.
        • Raghu G.
        • Chin K.M.
        • Torres F.
        • Rosenblatt R.L.
        • Garcia C.K.
        Telomere shortening in familial and sporadic pulmonary fibrosis.
        Am J Respir Crit Care Med. 2008; 178: 729-737
        • Armanios M.
        Syndromes of telomere shortening.
        Annu Rev Genomics Hum Genet. 2009; 10: 45-61
        • Oeseburg H.
        • de Boer R.A.
        • van Gilst W.H.
        • van der Harst P.
        Telomere biology in healthy aging and disease.
        Pflugers Arch. 2010; 459: 259-268
        • Cawthon R.M.
        • Smith K.R.
        • O’Brien E.
        • Sivatchenko A.
        • Kerber R.A.
        Association between telomere length in blood and mortality in people aged 60 years or older.
        Lancet. 2003; 361: 393-395
        • Zee R.Y.
        • Castonguay A.J.
        • Barton N.S.
        • Germer S.
        • Martin M.
        Mean leukocyte telomere length shortening and type 2 diabetes mellitus: a case-control study.
        Transl Res. 2010; 155: 166-169
        • Miyake Y.
        • Sasaki S.
        • Yokoyama T.
        • et al.
        Occupational and environmental factors and idiopathic pulmonary fibrosis in Japan.
        Ann Occup Hyg. 2005; 49: 259-265
        • Tsuchiya K.
        • Inase N.
        • Ichinose S.
        • et al.
        Elemental analysis of inorganic dusts in lung tissues of interstitial pneumonias.
        J Med Dent Sci. 2007; 54: 9-16
        • Lee J.S.
        • Collard H.R.
        • Raghu G.
        • et al.
        Does chronic microaspiration cause idiopathic pulmonary fibrosis?.
        Am J Med. 2010; 123: 304-311
        • Collard H.R.
        • Moore B.B.
        • Flaherty K.R.
        • et al.
        Acute exacerbations of idiopathic pulmonary fibrosis.
        Am J Respir Crit Care Med. 2007; 176: 636-643
        • Steele M.P.
        • Brown K.K.
        Genetic predisposition to respiratory diseases: infiltrative lung diseases.
        Respiration. 2007; 74: 601-608