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* From Royal Brompton Hospital. London, UK.
Correspondence to: R. M. du Bois, MD, Consultant Physician, Royal Brompton Hospital, Sydney St, London, SW3 6NP, UK; e-mail: r.dubois{at}rbh.nthames.nhs.uk
Key Words: candidate genes • genetics • idiopathic pulmonary fibrosis • sarcoidosis • single-nucleotide polymorphisms • systemic sclerosis
The approach to the genetic predisposition to diffuse lung disease (previously known as interstitial lung disease) poses a number of unique problems. The diffuse lung diseases comprise a large number of distinct clinical diseases. Of these, the idiopathic interstitial pneumonias are of particular importance because they include idiopathic pulmonary fibrosis (IPF), the most lethal form of diffuse lung disease, together with a number of diffuse lung disorders that have been (and continue to be) misdiagnosed as IPF. Each diffuse lung disease is likely to be a genetically complex disease with several genetic loci conferring variable risk of developing disease or modifying its severity together with an equally variable contribution from environmental triggers.
There are a number of key considerations that must be addressed in the design of studies to assess genetic influence on diffuse lung disease. These considerations are not unique to diffuse lung disease but apply to them particularly in the context of phenotype. Precise clinical phenotyping is essential.
Historically, too often the diffuse lung diseases were considered as being synonymous with "pulmonary fibrosis," and inappropriate attempts were made to derive meaningful correlations of treatment response and outcome in this heterogeneous population. With the advent of high-resolution CT, it has become increasingly clear that there are a number of quite distinct, but easily mistaken, forms of diffuse lung disease. The establishment of the definitive phenotype is therefore paramount. Secondly, it also seems likely that there will be a number of genes that enhance susceptibility to disease, but arguably, and more likely, polymorphisms at one or more genetic loci will affect severity and progression of disease once this is established. In this regard, it is possible that this is due to combinations of genes, not all on the same chromosome, that may be "linked" to provide a complex genotype. Thirdly (and ideally from the purest viewpoint), specific genetic polymorphism will be identified that affect function of the gene product in a way that affects biological outcome.
In addition to these issues that are more specific to diffuse lung disease, there are a number of areas that require close scrutiny in designing genetic studies in the diffuse lung diseases (for review, see Silverman and Palmer1 ). Two broad approaches can be taken. The first is familial studies in which linkage of gene polymorphism to disease trait is established. The second is an approach that involves association of genetic polymorphism with disease by comparison with control. These two approaches are complementary in that familial studies can generate hypotheses that will be tested in case-control investigation populations, but an a priori assumption that the genetics of familial and sporadic disease are the same should not be made. It must be recognized that many genetic approaches will be no more definitive than hypothesis generators, but in a field in which the complexity of interrelationship is almost infinite, this is a crucial first phase. In the majority of the diffuse lung diseases, there are insufficient numbers of families to perform linkage studies and the majority approach at present is case-control association studies using single-nucleotide polymorphism analysis.
Ideally large numbers of patients and control subjects will be studied with the ratio of patients to control subjects being at least 2:1. Power calculations, coupled with Bonferroni corrections, usually indicate that almost infinite numbers of patients are needed, but there are strategies that can be employed to provide perfectly valid data. By exploring populations of patients from different ethnic backgrounds, it may be possible to draw reasonably firm conclusions if the data are concordant. A two-set approach may also be taken, in which hypotheses are generated from a comparison of one set of cases with control subjects and then tested on independent cohorts. Whatever approach is taken to attempt to provide meaningful data, large p values are usually reassuring as are high odds ratios. It goes without saying that associations that are sought should make biological sense and, if possible, affect the function of the protein product. However, positional cloning has become markedly easier with increased single-nucleotide polymorphism density for most areas of the genome.
With this background, we have followed a strategy of defining as perfectly as possible our clinical phenotypes, utilizing array, single-nucleotide polymorphism, and sequencing data to select single-nucleotide polymorphisms in the genes of interest, utilized robot assays for single-nucleotide polymorphism and multiple-site polymorphism (multiple polymorphisms within the same gene), and have then constructed databases of clinical and genetic data on which to undertake data mining graphical representation and multivariate analysis approaches.
The basis of all of our association studies has involved the analysis of single-nucleotide polymorphisms grouped together in a series of "phototype" polymerase chain reaction plates that allows the coanalysis of a number of genes of common interest on 96 or 192 well plates with primers constructed such that they all operate optimally under the same reaction conditions. Such phototyping approaches allow, for example, human leukocyte antigen (HLA) class I, DR, and DQ typing to be performed simultaneously with a series of positive and negative bands indicating the major histocompatibility complex (MHC) haplotype. Other phototyping plates have been constructed for functionally related genes such as a fibrosis set, an oxidant set, a granuloma set, and so on.
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Clinical Phenotypes |
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 TOP Clinical Phenotypes ConclusionReferences |
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Systemic Sclerosis
Although the defining features of systemic sclerosis in all
individuals affected are thickening of the skin together with
peripheral vascular abnormalities, the internal manifestations of
disease are hugely variable. The diffuse lung disease of systemic
sclerosis appears to be quite distinct from that of IPF, even though
many clinical, radiologic, and physiologic features are shared.
Specifically, survival from systemic sclerosis with diffuse lung
disease is better than IPF even when matched for a variety of indexes
including severity of disease at presentation and duration of disease.
We have shown (presentation to The American Thoracic Society; Toronto,
ON; 2000) that the histopathologic pattern of lung disease in
systemic sclerosis is that of nonspecific interstitial pneumonia, which
may explain the survival advantage: idiopathic nonspecific interstitial
pneumonia carries a much better prognosis than IPF. This has important
implications for issues of pathogenesis, including disease
predisposition, treatment response, and outcome.
Patients with systemic sclerosis may carry autoantibodies to specific extractable nuclear antigens. What is striking about these is that there appears to be no overlap: an individual will carry one, but virtually never more than one, of these autoantibodies that include the Scl 70 anti-DNA topoisomerase autoantibody, the anticentromere antibody, and the anti-RNA polymerase autoantibody. We and others have shown that the autoantibodies carry high predictive value for the internal manifestations of disease.2 3 4 In this regard, the antitopoisomerase autoantibody is strongly associated with diffuse lung disease, anticentromere antibody is strongly associated with limited cutaneous systemic sclerosis and appears to be a very highly negative predictor of diffuse lung disease, whereas the anti-RNA polymerase autoantibody is strongly associated with diffuse cutaneous systemic sclerosis and even more strikingly renal disease.
Candidate Genes
MHC:
As the first step in the production of an autoantibody is
presentation of antigen as a complex with HLA class II molecules to CD4
+ T cells, we have explored the relationship between class II MHC
alleles and systemic sclerosis. We have found strong associations
between HLA DR11 and have also shown more strongly than previously an
association between HLA DPB1*1301 and the presence of
antitopoisomerase. This is in contrast with some previous negative
study findings at the HLA DPB1 locus and is significantly stronger than
previous positive study findings.2
Other
studies3
4
have suggested that HLA-DR and HLA-DQR are
important alleles in the production of this autoantibody, and there is
some evidence to suggest that it is an amino-acid motif, shared by the
different class II susceptibility alleles that may be pivotal in
predisposing to autoantibody formation.2
Irrespective of
the precise functional relevance of our findings, however, there
appears to be a very strong genetic influence on the production of an
autoantibody that in turn is a specific predictor of diffuse lung
disease in systemic sclerosis. By contrast, the anticentromere antibody
appears to be "protective" and, again, the mechanism for this
requires elucidation.
Tumor Necrosis Factor-
/Lymphotoxin-:
The
proximity of the tumor necrosis factor (TNF)-/lymphotoxin (LT)-
loci to the class II genes has led to studies to define complex
haplotypes in that region. In this regard, preliminary studies
from our group have suggested by fine mapping across the TNF locus in
scleroderma subsets, that a haplotype of TNF- polymorphisms is more
prevalent in individuals with the anticentromere autoantibody by
comparison with those without it (unpublished data; Welsh K, PhD; May,
2001). A slightly weaker association is also found when patients with
diffuse lung disease are compared with those with no such disease. This
has important implications for potential intervention with specific
strategies such as TNF- blockade using either the chimeric
mouse/human monoclonal antibody (infliximab) or the anti-TNF–receptor
fusion product (etanercept).
The association between class II haplotype and antitopoisomerase may be based on differential antigen presentation. In order to mount an immune response, oligopeptides, bound to the groove on the class II MHC molecule, are presented to CD4+ T cells. Hypothesizing that oligopeptides of the topoisomerase enzyme are responsible for the immune response that results in the production of the specific autoantibody, we assessed the effects of stimulating peripheral blood T cells from patients with systemic sclerosis with a panel of oligopeptides of the topoisomerase enzyme. The panel of oligopeptides was chosen after protein modeling experiments were done with TEPITOPE software (Vaccinome; www.vaccinome. com; accessed January 22, 2002). This program allows the tightness of fit of a panel of overlapping oligopeptides of the topoisomerase enzyme with HLA-DR alleles to be predicted. Six oligopeptides that bound tightly to the DR11 allele that is closely associated with antitopoisomerase antibody production were studied. We found that in 50% of our scleroderma patient population, peripheral blood T cells proliferated with a proliferation index > 2:1 for more oligopeptides than was seen in a control population. These studies are consistent with the data reported by Kuwana et al.4
Sarcoidosis
There are a number of lines of evidence that would support
the concept that sarcoidosis develops under a strong genetic influence.
Firstly, there is wide variation in disease prevalence and incidence
across different ethnic and racial groups. Secondly, there are a number
of studies5
6
that have shown that relatives of
individuals with sarcoidosis are more likely to have the disease
develop. These studies have demonstrated that in the majority of
populations familial sarcoidosis is present and is not restricted to
individual ethnic groups, and that there is a multiple-fold increased
risk of disease in family members. This risk can be quantified as a
ratio of disease prevalence in siblings or family members of
individuals with sarcoidosis to the prevalence of the disease in the
general population. This relative risk varies from 8 to 73 across
various populations. This range is likely due to a combination of
differences in different countries and also the variable ascertainment
of disease due particularly to variable surveillance and awareness. In
further support of a genetic predisposition to disease is the finding
of high levels of genetic heterogeneity that implies varying
contributions of genetic and environmental factors to the initiation
and/or progression of disease.
Candidate Genes
Sarcoidosis is a granulomatous disease. Although the trigger is
unknown, this is a CD4 T-cell–driven process. In this regard, MHC
genes are, as in systemic sclerosis autoantibody production, prime
candidates.
MHC:
Antigen is recognized by CD4+ and CD8+ T lymphocytes only
when it is presented in the context of a self-MHC molecule. HLA class I
MHC molecules bind peptides derived from endogenous antigen (the
endogenous pathway), whereas exogenous antigen is internalized by
endocytosis, processed and bound to HLA class II molecules (the
endocytic pathway). Peptide-binding assays using natural and synthetic
peptides show that natural polymorphisms of HLA molecules can influence
the specificity and affinity of peptide binding.7
MHC Class I:
A number of studies have reported variable HLA
class I associations with sarcoidosis. HLA-B7 and HLA-B8 have been the
class I alleles most frequently linked to disease. HLA-B7 is of
interest because it has been reported to be increased significantly in
frequency in African-American patients who have a high prevalence of
sarcoidosis, but is decreased significantly in Japanese patients, in
whom sarcoidosis prevalence is much lower.8
9
The HLA-A1,
B8, DR3 haplotype association is particularly relevant with regard to
outcome, being associated with disease of acute onset and short
duration in several studies.10
11
MHC Class II:
It is likely that sarcoidosis is triggered by
exogenous antigen and HLA class II presentation to CD4+ T cells.
Studies of HLA class II allele associations with sarcoidosis have
generally studied individual population cohorts, and varying
associations have been described depending on the populations studied.
HLA-DR alleles have been the major focus of MHC class II studies. In
Japanese patients, the strongest associations are seen with the
HLA-DR5, HLA-DR8, and HLA-DR9.9
12
13
In Germans, HLA-DR5
has been found to be significantly associated with chronic disease;
HLA-DR3 is associated with acute disease.14
15
In a
Scandinavian study, a strong association between HLA-DR3 (17)
and acute onset disease with good prognosis has been described,
while the alleles HLA-DR14 and HLA-DR15 were associated with chronic
disease.11
In a study from our group, a variety of alleles
was associated with disease susceptibility in three large European
cohorts of patients (Czech, Polish, and United Kingdom), but more
striking was the negative association with two apparently
"protective" alleles, DR1 and DR4.16
Comparison was
made with three of the largest previously reported studies in the
literature.9
10
11
This confirmed that "susceptible"
alleles vary among these populations but the HLA-DR1 and HLA-DR4
alleles were consistently protective. Comparison of amino-acid motifs
for the susceptible and protective allele sequences showed position 11
of the DRB1 sequence to be most variable with five different residues
present across the different "susceptibility" and "protective"
alleles.
Comparison of the chemical properties of the position 11 amino
acids revealed that the protective alleles both contain bulky, highly
hydrophobic, aliphatic side chains but the susceptibility alleles
all contain small hydrophilic amino acids. The position 11 amino acid
is located in pocket 6 of the ß sheet that links the HLA-DR and
ß chains in the tertiary structure of the heterodimer. Alteration in
the hydrophilic/hydrophobic balance may be important in HLA-DR
heterodimer formation/conformation and antigen binding. These findings
further support the concept that HLA alleles encoding class II MHC
molecules are more likely to be pivotal to sarcoidosis than class I
alleles.
There is also some evidence that the HLA-DP locus might play a role in sarcoidosis susceptibility. A study of African-American sarcoidosis patients found an increased risk associated with alleles with a valine residue at position 36 and aspartate at position 55, suggesting that these HLA-DP residues may play a role in this cohort.17 Individuals carrying HLA-DP molecules with a glutamic-acid residue at position 69 (Glu69+) of the ß chain are found to have a much higher risk of having granulomatous disease develop when exposed to beryllium than individuals who do not carry this residue at position 69.18 19 The concept that this association might apply to sarcoidosis has not been confirmed, even though berylliosis is histologically indistinguishable from sarcoidosis, and despite the findings of a previous small UK pilot study.20 21 Recently, Schürmann et al,22 using multipoint nonparametric linkage scoring, concluded that the MHC region is linked to sarcoidosis but that the HLA-DPB1 locus does not sufficiently explain this finding. A peak score at the microsatellite marker locus D6S1666 in the class III region was demonstrated, pointing to this gene cluster as having the strongest influence for developing the disease. Further studies from the same group22 have reported linkage with a number of other loci, but the distance between the markers was great and the precise association with potential candidate genes must remain speculative until more fine mapping can be undertaken. A number of other attractive candidate options need to be considered.
Antigen Processing and Presentation:
Whole proteins require
antigen processing before they can be immunologically recognized via
the class I or class II restricted antigen presentation pathways, and
this is an important step in the initiation of a chronic antigen-driven
immunologic disease. Various proteins are involved in the
transportation and processing of antigen. These include TAP
(transporter associated with antigen
processing genes I and II, with class I molecules and the
endogenous pathway) and HLA-DM and HLA-DO (associated with class II
molecules and the endocytic pathway). Variations in these genes may
modulate the transport and presentation of antigenic peptide to CD4+ T
lymphocytes at the onset of the granulomatous response. Associations
with transporter antigen peptide 2 genes have been found in UK and
Polish cohorts but not Japanese cohorts.23
24
Subsequent
analysis has revealed that they are in linkage with the protective
HLA-DR1 allele discussed above.16
Cytokines
TNF- is the most extensively studied cytokine in many
inflammatory processes including sarcoidosis, in which its production
is increased in the lung and its role in the formation of granulomas is
established.25
26
The TNF gene complex is located in the
so-called class III MHC region of chromosome 6 between the complement
region and the HLA-B locus. It includes the TNF- and LT-
(previously known as TNF-ß) genes. Several bi-allelic TNF gene
complex polymorphisms have been described but those at TNF-308 in the
promoter region of the TNF- gene (TNFA) and the Ncol restriction
fragment length polymorphism in the first intron of the LT-
gene have received most attention because polymorphisms are associated
with differences in protein synthesis and secretion.27
28
29
30
31
In general, studies32
33
have found no significant
association of either polymorphism with sarcoidosis, although a higher
frequency of the less common TNFA2 (high TNF- production) allele was
demonstrated in the acute form of sarcoidosis-Löfgren’s
syndrome.25
One study used six markers that identified linkage to selected cytokine
candidate genes in African-Americans patients.34
The
candidates that were best associated with sarcoidosis were interleukin
(IL)-1*137 (on chromosome 2q13) and F13A*188 (on chromosome
6p23–25). If both alleles were present, there was a sixfold increased
risk of sarcoidosis and a 15-fold increase if the analysis was confined
to patients with a familial history. IL-1 is an important mediator of
inflammatory reactions, and is upregulated in sarcoidosis. The F13A
marker is close to the interferon regulatory factor-4 gene, a recently
discovered member of the interferon regulatory factor family of
transcription factors.
Chemokines:
Chemokines are small peptides produced by a
variety of cells that influence and often control the adhesion,
chemotaxis, and activation of leukocytes.35
The CC
chemokine receptor 2 and CC chemokine receptor 5 are receptors for the
CC chemokine ligands monocyte chemoattractant protein and RANTES
(regulated upon activation, normal T-cell expressed and secreted),
respectively. Studies of polymorphisms in the receptor genes in
sarcoidosis have shown that the CC chemokine receptor 2–64I allele (a
valine to isoleucine substitution) appears to have a protective effect
against developing sarcoidosis whereas the CC chemokine receptor 5
32
(32-base pair deletion), confers an increased susceptibility to
sarcoidosis.37
Vitamin D receptor:
Vitamin D, 1,25
(OH)2D3 is the active metabolite of vitamin D
and has roles in whole-body calcium homeostasis and immunoregulation.
Its effects are mediated through interaction with the nuclear vitamin D
receptor. A study38
of Japanese sarcoidosis patients
found an association with a BsmI restriction site in
intron 8, the rare B allele being associated with increased frequency
of disease.
Natural Resistance-Associated Macrophage Protein:
Human
natural resistance-associated macrophage protein (NRAMP) has been
linked with susceptibility to tuberculosis.39
NRAMP is
involved in macrophage priming and activation. An African-American
population study40
has revealed an association
between NRAMP1 polymorphisms and sarcoidosis. Several NRAMP1 gene
polymorphisms were analyzed in a case-control study of 157 patients
and, by contrast with patients with tuberculosis, it was found that at
least one NRAMP1 polymorphism, a (CA)n repeat in the immediate
5' region of the gene, might be protective against
sarcoidosis.40
Angiotensin-Converting Enzyme:
A 287-base pair
insertion/deletion polymorphism in intron 16 of the
angiotensin-converting enzyme (ACE) gene, which encodes ACE and
accounts for 30 to 40% of the phenotypic variation in serum ACE levels
(thus > 50% of ACE levels are accounted for by other polymorphisms),
has been identified with the DD genotype being associated with
increased levels in patients and control subjects. This has led to a
number of studies in patients with sarcoidosis (reviewed by McGrath et
al41
). These studies42
43
44
45
46
47
48
49
50
illustrate ethnic
heterogeneity in insertion/deletion genotype frequency. In Western
studies, the D allele is more common in disease and health, whereas in
Japan the I allele is commoner. In only one series48
has
any difference been reported. In this study, the D allele was more
frequent in African-American patients than control subjects in whom the
I allele was more prevalent. In two studies that have explored
the relationship of ACE alleles and disease progression, the study
designs and results have been inconsistent, with one
study49
reporting an association between poor prognosis
and the D allele, and the other study,48
paradoxically,
finding that prognosis related to the presence of the II genotype even
though susceptibility to disease was greater in those with the D
allele. In a more recent study41
that addressed the
relationship of ACE genotype with respiratory disease outcome
specifically, no association was found.
IPF
There have been far fewer studies of the immunogenetic
predisposition to this disease than in systemic sclerosis and
sarcoidosis. Reasons for this include the rarity of the disease, but
also difficulties in obtaining meaningful data because of the
heterogeneity of the clinical phenotypes that have been studied.
Familial Pulmonary Fibrosis:
It has long been recognized
that there is a familial form of IPF. While some units have
observed that individuals in different generations have the usual
interstitial pneumonia pattern of histopathology that, by the newly
defined IPF, is truly IPF, such phenotypic definition is not true for
all pedigrees. This will become a crucial component of any future study
designed to address the genetic predisposition in familial IPF. Despite
these caveats, a cooperative in the United States has been successful
in accruing a number of families with lung fibrosis, and it is hoped
that a combination of linkage analysis with subsequent fine mapping
will elucidate key genetic factors. At the 44th Annual Meeting of the
Aspen Lung Conference, there were studies reported of familial disease
including microsatellite instability and loss of heterozygosity using a
gene marker approach.
A mutation in the surfactant protein C gene was also reported in a mother and her infant offspring.51 This mutation produced a substitution at base 1728 at the junction of exon 4 and intron 4, and resulted in a decreased or absent protein in both individuals’ lungs. Subsequent studies have identified several mutations in this gene in sporadic interstitial lung disease in children. In adults, there have been no genetic studies in families.
Sporadic IPF:
There have been few studies that have identified
susceptibility factors for the development of sporadic IPF. In one
report of case association studies from two cohorts of patients in the
United Kingdom and Italy, differences in the IL-1–receptor antagonist
(at + 2018) and TNF- (at –308) genes were reported.52
However, the same authors were unable to confirm their findings in a
third cohort from New Mexico. Unpublished data from our group
(Pantelidis P, PhD; January, 2001) have also not found any association
between case patients and control subjects at these loci.
Our group has, however, been able to identify associations
between severity of disease and candidate cytokines. Our approach has
been to study the genes involved in the "early" cytokine pathway.
These genes include the ligands, receptors, and natural antagonists
together with genes that modulate expression in the IL-1 and TNF
clusters. For both of these, we have identified associations between
polymorphisms at different epistatic sites and severity of lung
function involvement corrected for length of disease. The severity of
gas transfer impairment appears to be associated with a combination of
an IL-6 intron-4 region polymorphism particularly when combined with
the C allele at position 1690 of the TNF-RII gene.53
In
the case of IL-1, a number of genes and their receptors together with
the natural antagonist are located on chromosome 2 at 2q12–2q14.2.
Severity of gas transfer deficit appears to be particularly linked to
the T polymorphism at - 889 of the IL-1 gene; there were lesser
degrees of involvement in polymorphisms in genes both telomeric and
centromeric to IL-1.
To date there have been no descriptions of associations between growth factor genes and either disease susceptibility or progression. Further appropriate targets would be genes that affect the balance of control within the lung, including oxidant/antioxidant; proteases/antiproteases; T-helper 1/T-helper 2; angiogenic/angiostatic pathways.
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TOPClinical PhenotypesConclusionReferences |
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Footnotes |
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References |
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TOPClinical PhenotypesConclusionReferences |
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and HLA-DR genotyping as potential prognostic markers in pulmonary sarcoidosis. Eur Cytokine Netw 10,143-146[ISI][Medline]
promoter gene polymorphism in sarcoidosis. Cytokine 9,787-790[CrossRef][ISI][Medline]
gene in Japanese. Tissue Antigens 51,605-612[ISI][Medline]
(TNF ) gene detectable by NcoI restriction of PCR product. Hum Mol Genet 1,353 promoter region polymorphism and insulin-dependent diabetes mellitus. Eur J Immunol 23,3050-3053[ISI][Medline]
and TNF-ß by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus. Eur J Immunol 23,224-231[ISI][Medline]
and lymphotoxin in relation to polymorphisms in the TNF genes and HLA-DR alleles: relevance for inflammatory bowel disease. Scand J Immunol 43,456-463[CrossRef][ISI][Medline]
promoter on transcriptional activation. Proc Natl Acad Sci U S A 94,3195-3199 and in the first intron of the TNF-ß genes and spontaneous and lipopolysaccharide-induced TNF- release in sarcoidosis. Cytokine 11,882-887[CrossRef][ISI][Medline]
expression in interstitial lung disease. J Immunol 151,2852-2863[Abstract]
gene polymorphisms. Am J Respir Crit Care Med 162,755-758, lymphotoxin-, tumor necrosis factor receptor II, and interleukin-6 polymorphisms in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 163,1432-1436This article has been cited by other articles:
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  M. R. Hill, A. Papafili, H. Booth, P. Lawson, M. Hubner, H. Beynon, C. Read, G. Lindahl, R. P. Marshall, R. J. McAnulty, et al. Functional Prostaglandin-Endoperoxide Synthase 2 Polymorphism Predicts Poor Outcome in Sarcoidosis Am. J. Respir. Crit. Care Med., October 15, 2006; 174(8): 915 - 922. [Abstract] [Full Text] [PDF]
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 J. C. Grutters and R. M. du Bois Genetics of fibrosing lung diseases Eur. Respir. J., May 1, 2005; 25(5): 915 - 927. [Abstract] [Full Text] [PDF]
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 P. Bonniaud, G. Martin, P. J. Margetts, K. Ask, J. Robertson, J. Gauldie, and M. Kolb Connective Tissue Growth Factor Is Crucial to Inducing a Profibrotic Environment in "Fibrosis-Resistant" Balb/c Mouse Lungs Am. J. Respir. Cell Mol. Biol., November 1, 2004; 31(5): 510 - 516. [Abstract] [Full Text] [PDF]
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J. A. Whitsett, C. J. Bachurski, K. C. Barnes, P. A. Bunn Jr., L. M. Case, D. N. Cook, D. Crooks, M. W. Duncan, L. Dwyer-Nield, R. C. Elston, et al. Functional Genomics of Lung Disease Am. J. Respir. Cell Mol. Biol., August 1, 2004; 31(2/S1): S1 - S81. [Full Text] [PDF]
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T. Ohchi, N. Shijubo, I. Kawabata, S. Ichimiya, S.-i. Inomata, A. Yamaguchi, Y. Umemori, Y. Itoh, S. Abe, Y. Hiraga, et al. Polymorphism of Clara Cell 10-kD Protein Gene of Sarcoidosis Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 180 - 186. [Abstract] [Full Text] [PDF]
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M. K.B. Whyte Genetic Factors in Idiopathic Pulmonary Fibrosis: Transforming Growth Factor-{beta} Implicated at Last Am. J. Respir. Crit. Care Med., August 15, 2003; 168(4): 410 - 411. [Full Text] [PDF]
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A. Xaubet, A. Marin-Arguedas, S. Lario, J. Ancochea, F. Morell, J. Ruiz-Manzano, E. Rodriguez-Becerra, J. M. Rodriguez-Arias, P. Inigo, S. Sanz, et al. Transforming Growth Factor-{beta}1 Gene Polymorphisms Are Associated with Disease Progression in Idiopathic Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., August 15, 2003; 168(4): 431 - 435. [Abstract] [Full Text] [PDF]
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