Familial pulmonary fibrosis is the strongest risk
factor for idiopathic pulmonary fibrosis
Cecilia Garcı ´a-Sanchoa, Ivette Buendı ´a-Rolda ´na,
Ma. Rosario Ferna ´ndez-Plataa, Carmen Navarroa,
Rogelio Pe ´rez-Padillaa, Mario H. Vargasa,
James E. Loydb, Moise ´s Selmana,*
aInstituto Nacional de Enfermedades Respiratorias “Ismael Cosı ´ o Villegas”, Tlalpan 4502, 14080 Me ´xico DF, Mexico
bDepartment of Medicine, Vanderbilt University, Medical Center, Nashville, TN, USA
Received 1 March 2011; accepted 25 August 2011
Available online 13 September 2011
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 dia-
betes 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 per-
formed a caseecontrol analysis including 100 patients with IPF and 263 controls matched
for age sex and place of residence. We used a structured questionnaire to identify poten-
tial 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 Z 6.1, CI95% 2.3e15.9; 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 Z 2.9, CI: 1.3e6.6;
p Z 0.007], former cigarette smoking [OR Z 2.5, CI: 1.4e4.6, p Z 0.003], and past or
current occupational exposure to dusts, smokes, gases or chemicals [OR Z 2.8, CI: 1.5
e5.5; p Z 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
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.
* Corresponding author. Tel.: þ55 5487 1771; fax: þ55 5665 4623.
E-mail addresses: email@example.com, firstname.lastname@example.org (M. Selman).
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/rmed
Respiratory Medicine (2011) 105, 1902e1907
0954-6111/$ - see front matter ª 2011 Elsevier Ltd. All rights reserved.
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.
ª 2011 Elsevier Ltd. All rights reserved.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive
and lethal lung disorder of unknown etiology. The disease
occurs predominantly in older adults, although the mech-
anisms for the association of aging with IPF have not been
elucidated.1IPF 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 caseecontrol studies evaluating sporadic
IPF and in one study of familial pulmonary fibrosis.2,3Also,
several occupational factors, adjusted for age and smoking
have been found significantly associated with IPF, including
metal and wood dust exposure.4,5A meta-analysis sup-
ported 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.2Likewise, some studies provide evidence of an
association between IPF and type 2 diabetes mellitus (DM2)
and gastroesophageal reflux.6e10
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
0.5e3.7% of IPF is familial.11,12However, a remarkably
higher frequency was reported in a small cohort of IPF
patients from a lung transplant program where 19% had
a positive family history13; 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 identi-
fied as familial within a single-center cohort of 229 patients
with idiopathic interstitial pneumonias.14
In this context, we designed a questionnaire-based,
caseecontrol 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
A caseecontrol study was carried out at the National
Institute of Respiratory Diseases during 2007e2009. The
research protocol was approved by the institutional
Scientific and Bioethics Committee (Comite ´ de Ciencia y
Bioe ´tica en Investigacio ´n; 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.15In 35% of the patients the diagnosis was
confirmed by surgical biopsy showing changes of usual
interstitial pneumonia.16Healthy controls were randomly
selected from the same patients’ neighborhoods, at
a ratio of 1e3 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.
Evaluation of exposures was performed with the same
questionnaire used in the PLATINO study,17,18which 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 respira-
tory conditions in interviewed subjects’ relatives. This
questionnaire was applied to all cases and controls by
two trained interviewers. Among other variables, char-
acteristics 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
medicalconditions such as
gastritis, hepatitis, heart
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 dia-
betes 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.
Familial pulmonary fibrosis is the strongest risk factor1903
Statistical analysis included Student’s t-test and chi square
test to evaluate differences between interval and cate-
gorical 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 caseecontrol groups and included the vari-
ables 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.
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 Z 0.9). Male predominance
was comparable among cases and controls (71.0% versus
69.9%, respectively, p Z 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 Z 1.6
(95% CI, 1.02e2.6), p Z 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 Z 2.4 (95% CI, 1.4e4.0), p Z 0.001].
Regarding tobacco smoke exposure, former cigarette
smokers also showed significant excess risk for IPF [58.0% vs
33.5%, OR Z 2.7 (95% CI, 1.7e4.4), p < 0.0001].
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 Z 9.1 (95% CI
3.7e22.4), 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 1.01e7.9), 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
1.04e3.6), p Z 0.04.
As previously suggested in several studies on familial
IPF,11,12,14our 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 differ-
ence 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 Z 3.1
(95% CI, 1.7e5.9) p < 0.0001], and gastritis [OR Z 1.9 (95%
CI 1.2e3.2) p Z 0.006]. Type 2 diabetes mellitus was also
more frequent among cases than controls [30.0 vs 19.0%,
OR Z 1.8 (95% CI, 1.1e3.1), p Z 0.02]. Past or current
cardiac disease was marginally associated with IPF (Table
Concerning household characteristics, the only feature
that was more frequently seen among cases was the pres-
ence of earthen floor [9.0 vs 3.4%, respectively, OR Z 2.8
(95% CI, 1.1e7.2), p Z 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
In the multivariate analysis, having a parent or sibling
with pulmonary fibrosiswas thestrongestvariable
Education and exposures of cases and controls.
(n Z 100)
(n Z 263)
Formal education ? 6 years
Occupational exposure to dusts,
smokes, gases or chemicals
Former cigarette smoker
1.6 (1.02e2.6) p Z 0.039
2.4 (1.4e4.0) p Z 0.001
58 (58) 88 (33.5) 2.7 (1.7e4.4) p < 0.0001
aData correspond to n(%).
1904C. Garcı ´a-Sancho et al.
associated with the disease [OR Z 6.1 (95% CI, 2.3e15.9)
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.
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.2
a family-based caseecontrol study of familial interstitial
pneumonia, Steele et al3evaluated 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 indi-
cates 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,19,20
a process recently reported in most sporadic IPF patients
and in a few families.21,22Telomeres are DNA-protein
structures that protect chromosome ends from erosion
and end-to-end fusion and that shorten successively with
each cell division.23Importantly, a link between telomere
length and aging-associated diseases and mortality has
been suggested.24,25In 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.26Using a caseecontrol 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.6e8In this study,
a tendency was also noted. However, given the high prev-
alence 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.2,4,5,27Recently, the accu-
mulation of inorganic dusts in lung tissues of patients with
IPF, chronic hypersensitivity pneumonitis, and collagen
vascular diseases was analyzed by polarizing light micros-
copy, scanning electron microscopy and energy dispersive
X-ray spectroscopy.28IPF lung tissues showed greater
numbers of birefringent particles, even in patients without
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 alve-
olar/bronchiolar epithelial cells may play a role in geneti-
cally susceptible individuals.
The multivariate analysis also confirmed that gastro-
esophageal reflux is associated with a risk for IPF.
Family history of pulmonary fibrosis and comorbidities of cases and controls.
IPF casesa(n Z 100)
Control subjectsa(n Z 263)OR (CI95%)
Familial IPF (parent and/or sibling)
Past gastroesophageal reflux
Type 2 diabetes mellitus
Past or current cardiac disease
9.1(3.7e22.4) p < 0.0001
3.1 (1.7e5.9) p < 0.0001
1.9 (1.2e3.2) p Z 0.006
1.8 (1.1e3.1) p Z 0.02
2.2 (1e4.6) p Z 0.05
aData correspond to n (%).
Crude and adjusted odds ratios for IPF.
Variable Crude OR (95% CI) Adjusted OR (95% CI)
Parent or sibling with IPF
Past or current occupational exposure to dusts,
smokes, gases or chemicals
Past or current gastroesophageal reflux
Type 2 diabetes
9.1 (3.7e22.4) p < 0.0001
2.7 (1.7e4.4) p < 0.0001
2.4 (1.4e4.0) p Z 0.001
6.1 (2.3e15.9) p < 0.0001
2.5 (1.4e4.6) p Z 0.003
2.8 (1.5e5.5) p Z 0.002
3.1 (1.7e5.9) p < 0.0001
1.8 (1.1e3.1) p Z 0.02
2.9 (1.3e6.6) p Z 0.007
1.6 (0.9e3.0) p Z 0.1
Familial pulmonary fibrosis is the strongest risk factor 1905
Gastroesophageal reflux and silent microaspiration have
been related with several lung diseases and is common
among those who have had lung transplantation.29Also,
a higher incidence of gastroesophageal reflux has been re-
ported in patients with IPF compared with normal individ-
uals suggesting that microaspiration may be a factor for
IPF.7e10Interestingly, it has been suggested that acute
exacerbation of IPF, a devastating diffuse alveolar damage
manifested by some patients may be also related to
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%.11,12However, 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.13Likewise,
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.14The
majority of pedigrees indicate an autosomal dominant
vertical transmission pattern of inheritance with reduced
penetrance.31In the largest collection of familial intersti-
tial pneumonias, 20 multigenerational pedigrees were
consistent with autosomal dominant inheritance.3
Clinical features of familial IPF are indistinguishable
from those of the sporadic form, except for an earlier age
of onset.11,12,14This observation was confirmed in our
study, with the cases with familial history presenting on
average 7 years earlier than sporadic patients. Neverthe-
less, 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
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 under-
reporting among controls.
In summary, we found that the presence of a familial
history of pulmonary fibrosis showed the strongest associ-
ation 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.
This study was supported by CONACYT Grant 69871.
Conflict of interest
Cecilia Garcı ´a-Sancho, Ivette Buendı ´a-Rolda ´n, Mario H. Var-
gas, and Marı ´a del Rosario Ferne ´ndez Plata contributed to
study design and statistical analyses. Carmen Navarro and
Rogelio Pe ´rez-Padilla contributed to study design and inter-
pretation of the results; Jim E Loyd contributes to the inter-
pretation of the familial findings and in the writing of the
manuscript; Moise ´s Selman contributed to study design,
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Familial pulmonary fibrosis is the strongest risk factor1907