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Published ahead of print on May 28, 2003, doi:10.1164/rccm.200302-221OC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 330-334, (2003)
© 2003 American Thoracic Society

Complement Receptor 1 Gene Polymorphisms Are Associated with Idiopathic Pulmonary Fibrosis

Michele Zorzetto, Ilaria Ferrarotti, Rocco Trisolini, Luigi Lazzari Agli, Roberta Scabini, Monique Novo, Annalisa De Silvestri, Marco Patelli, Miryam Martinetti, MariaClara Cuccia, Venerino Poletti, Ernesto Pozzi and Maurizio Luisetti

Laboratorio di Biochimica e Genetica, Clinica Malattie Apparato Respiratorio; Servizio di Immunoematologia e Trasfusione e Centro di Immunologia dei Trapianti; Servizio di Patologia Neonatale, Dipartimento di Genetica e Microbiologia, IRCCS Policlinico San Matteo and Università degli Studi, Pavia; Unità Operativa di Endoscopia Toracica, Dipartimento di Scienze Oncologiche, Ospedale Maggiore, Bologna; Dipartimento di Malattie dell'Apparato Respiratorio e del Torace, Ospedale G.B. Morgagni, Forlì, Italy

Correspondence and requests for reprints should be addressed to Maurizio Luisetti, M.D., Laboratorio di Biochimica e Genetica, Clinica di Malattie dell'Apparato Respiratorio, IRCCS Policlinico San Matteo, Via Taramelli 5, 27100 Pavia, Italy. E-mail: m.luisetti{at}smatteo.pv.it


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrotic disorder underlain by aberrant wound healing of repeated lung injury. Environmental triggers and genetic background are likely to act as modifiers of the fibrotic response. Erythrocyte complement receptor 1 is a membrane protein mediating the transport of immune complexes to phagocytes. Three gene polymorphisms are related to the erythrocyte surface density of complement receptor 1 molecules, which in turn are related to the rate of immune complexes' clearance. There is evidence of association between sarcoidosis and the complement receptor 1 gene. We wondered whether IPF is associated with the complement receptor 1 gene alleles coding for a reduced molecule/erythrocyte ratio. We studied 74 patients and 166 control subjects. Three polymorphic sites of the gene, A3650G exon 22, HindIII RFLP intron 27, and C5507G exon 33, were analyzed and found to be in linkage disequilibrium. The GG genotype for the C5507G exon 33 polymorphism was significantly more common in patients with IPF than in control subjects (odds ratio = 6.232, 95% confidence interval = 2.198–18.419, p = 0.00023). The significant difference was found in both sexes. These findings agree with speculations on the role of the complement receptor 1 gene in idiopathic pulmonary fibrosis.

Key Words: polymerase chain reaction • gene sequencing • candidate gene • association study • immune complexes

Idiopathic pulmonary fibrosis (IPF) is a disorder belonging to the family of idiopathic pneumonias, which are characterized by interstitial infiltrates predominantly affecting the lung bases, by progressive dyspnea, and by worsening lung function (1). A current hypothesis on the pathogenesis of IPF suggests that aberrant wound healing, in response to multiple, microscopic, repeated alveolar epithelial injury, culminates in pulmonary fibrosis. The fibrotic response is likely to be influenced by several modifiers, such as environmental triggers, pattern of inflammatory response, and genetic background (1). The most compelling evidence for a genetic component in IPF is its familial clustering (2, 3). This has led to a search for putative candidate genes in IPF (4). Although some associations with genetic polymorphisms have been reported, firm evidence for a genetic basis in unrelated cases of IPF is still lacking (1).

Erythrocyte complement receptor 1 (CR1, CD35, C3b/C4b receptor) is a transmembrane glycoprotein that mediates the transport of immune complexes (ICs) throughout the bloodstream to phagocytes in the liver and spleen. It has been suggested that the rate of IC clearance may be directly correlated with the number of CR1 molecules expressed on erythrocytes (the CR1/E ratio) (5). Several single nucleotide polymorphisms have been found on the CR1 gene, located on chromosome 1 (6). Three polymorphic sites of the CR1 gene, namely A3650G exon 22, HindIII RFLP intron 27, and C5507G exon 33 (GenBank accession number L 17390–L 17430), have been reported to be in strong linkage disequilibrium (7, 8). In addition, individuals homozygous for the common allele of each of the polymorphisms described previously have a CR1/E ratio as much as a 10 times higher than in subjects homozygous for the rare allele; heterozygous individuals have intermediate CR1 expression (6, 9, 10).

We recently reported (8) that the GG genotype for the C5507G exon 33 polymorphism was significantly associated with sarcoidosis in a group of Italian patients (odds ratio [OR] = 3.13 vs. healthy control subjects) and that the same genotype was particularly associated with the disease in females (OR = 7.05 vs. healthy control subjects). We speculated that, in sarcoidosis, polymorphisms of the CR1 gene related to a low CR1/E ratio might be responsible for impaired clearance of ICs, in turn resulting in increased tissue damage (7, 8).

Although the general concepts of the pathogenesis of sarcoidosis and IPF differ greatly, these disorders do have two features in common: the possibility that microorganisms, behaving in a noninfectious fashion, may trigger the disorder (1, 4, 11), and the presence of ICs (12, 13). As we hypothesized a possible involvement of CR1 gene polymorphisms in sarcoidosis on the basis of the aforementioned features, we decided to enlarge our investigation of CR1 gene polymorphisms to a group of patients affected by IPF.


   METHODS
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RESULTS
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Study Design
The investigation was designed as a case–control association study with a candidate gene (14).

Subjects
Whites of Italian descent were investigated. A group of consecutive, unrelated patients with IPF were recruited from January 2000 to July 2002 in three Clinical Centers (Pavia, Forlì, and Bologna). Patients already being followed (prevalent cases) and newly diagnosed patients who completed the diagnostic process (incident cases) were included. The American Thoracic Society/European Respiratory Society criteria for diagnosis of IPF (15) were strictly followed. Patients with surgical lung biopsy findings consistent with usual interstitial pneumonia were included if their clinical and radiologic signs were compatible with IPF and no other cause of interstitial lung disease could be identified. In the presence of clinical, functional, and high-resolution computed tomography patterns strongly consistent with IPF, a surgical biopsy was not considered to be necessary; in this case, the subjects were recruited based on criteria required for a clinical diagnosis of IPF (15), namely major criteria (all required): (1) exclusion of other causes of interstitial lung disease, (2) high-resolution computed tomography scans with bilateral basal reticular abnormalities and minimal ground glass opacities, (3) abnormalities in pulmonary function tests (restrictive pattern and impaired gas exchange), and (4) transbronchial lung biopsy or bronchoalveolar lavage fluid (showing no features to support an alternative diagnosis) and minor criteria (at least three present: (1) age more than 50 years, (2) insidious onset of dyspnea, (3) duration of disease more than 3 months, and (4) bilateral inspiratory crackles.

The second group comprised ethnically matched healthy control subjects, recruited from the clinical staff and blood donors. All control subjects were recruited from the Pavia area, belonging to the Po valley region, as well as Bologna and Forlì. This region is not interrupted by geologic barriers, and the inhabitants are considered genetically homogeneous (16, 17). All control subjects underwent a medical examination, completed a questionnaire, and had blood and urine analyses, chest X-ray, and pulmonary function tests that excluded any disease.

All individuals gave their consent before entering the study, which was approved by the Ethical Committees of the Institutions involved.

Analysis of Polymorphic Sites of the CR1 Gene
The three polymorphisms of the CR1 gene were studied by restriction analysis. Regions encompassing each polymorphism were amplified from genomic DNA (8). We used the same primers, polymerase chain reaction conditions, and restriction enzymes as those described in our previous work (8).

All heterozygous samples, samples homozygous for the less common alleles, and 10 random samples homozygous for the common alleles of each polymorphism were analyzed by sequencing (Big Dye terminator cycle sequencing kit; Perkin–Elmer, Norwalk, CT).

Statistical Analysis
Clinical data are presented as mean ± SD. The Hardy–Weinberg equilibrium was assessed by the goodness-of-fit test for biallelic markers. Frequencies were compared with the {chi}2 test, and differences were considered statistically significant at a p value less than 0.05. The p value was corrected for the number of the investigated alleles (pc).

Linkage disequilibrium and haplotype frequencies (18) were estimated with the ASSOCIATE software program (http://linkage.rockefeller.edu/ott/linkutil.htm) Distributions of continuous variables were analyzed by the Mann–Whitney U test or Kruskal–Wallis test.


   RESULTS
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DISCUSSION
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Subjects
Seventy-four subjects with IPF (51 males and 23 females) were recruited in our investigation. Thirty of these 74 patients (40.5%) had had a lung biopsy confirming the diagnosis of IPF, whereas the diagnosis of IPF had been made without resorting to lung biopsy in the remaining 44 patients (59.5%). Twenty-one patients (28.4%) were already known to have IPF and had had at least 1 year of follow-up (prevalent cases), whereas 53 (71.6%) were newly diagnosed patients, recruited at the end of the assessment process (incident cases). The characteristics of this group of patients with IPF are summarized in Table 1 . Prevalent and incident subjects with IPF did not differ in terms of clinical characteristics.


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  		TABLE 1. Characteristics of the patients with idiopathic pulmonary fibrosis

 
A total of 166 healthy subjects (105 males and 61 females) were also recruited. The mean age in this group was 61.7 ± 8.4 years (p > 0.05 vs. IPF group).

Genetic Analysis
Sequencing of the intron 27 of the CR1 revealed a T -> C substitution at nucleotide 520 with a 100% concordance with the gel-resolved polymerase chain reaction products (H and L alleles). Thus, the intron 27 polymorphism, previously referred to as HindIII RFLP, is henceforth referred to as T520C intron 27 (19).

Table 2 reports the genotypes of the three CR1 polymorphic sites examined. In the present groups of subjects we confirm the strong linkage disequilibrium among the three polymorphisms, taken two by two (D'22,i27 = 0.9877, D'22,33 = 0.945, D'33,i27 = 0.9746), already reported in our previous investigation (8) dealing with subjects with sarcoidosis, chronic obstructive pulmonary disease, and healthy control subjects.


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  		TABLE 2. Complement receptor 1 gene polymorphism multiple genotypes

 
The deduced haplotype frequencies in healthy control subjects and subjects with IPF were significantly different ({chi}2 = 15.446, p = 0.00085).

Table 3 reports the frequencies of the C5507G exon 33 polymorphism in the two groups of subjects. As in our previous work (8), we focused on this polymorphism because the C -> G substitution leads to a Pro -> Arg amino acid change at position 1,827 of the protein sequence in the proximal extramembrane region, thus creating a possible cleavage site for accelerated proteolysis (6). Genotypes of both control subjects and subjects with IPF agreed with the Hardy–Weinberg equilibrium (p > 0.05). The GG genotype was significantly more frequent in patients with IPF than in healthy control subjects ({chi}2 = 13.559, OR = 6.232, 95% CI = 2.109–18.419, p = 0.00023). This finding agreed with the significant difference ({chi}2 = 9.335, OR = 5.538, 95% CI 1.647–18.621, p = 0.0022) between control subjects and subjects with IPF when the GG CC GG multiple genotype was examined within a multiple genotype comparison (Table 2). Interestingly, the level of significance was similar in males and females with IPF, after stratification by sex (p = 0.0090 and 0.0065, respectively). No differences according to sex were detected among control subjects. Frequency of the GG genotype was similar between never smokers (#37) and smokers (former or current, #37) as well as between prevalent and subjects with incident IPF (p = > 0.05). As previously reported for subjects with sarcoidosis, in IPF too the presence of the two less common alleles seems to be needed for the association, in agreement with a possible recessive gene effect. Subjects with IPF homozygous for the common allele C were underrepresented with respect to healthy control subjects (OR = 0.447, p = 0.0041). Again, this observation was strengthened by the difference ({chi}2 = 6.824, OR = 0.478, 95% CI 0.274–0.835, p = 0.0089) between subjects with IPF and control subjects when the multiple genotype AA TT CC was examined (Table 2). Sex stratification showed a difference between males with IPF and control males (OR = 0.43, p = 0.0144, pc = not significant) but not between females with IPF and control females.


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  		TABLE 3. Frequencies of complement receptor 1 c5507g polymorphism in control subjects and subjects with idiopathic pulmonary fibrosis

 
Finally, we examined the relationship between the C5507G e33 genotype and some clinical characteristics of the patients with IPF, namely age at disease onset and functional parameters. We did not find any associations between the C5507G genotype and the clinical characteristics considered (data not shown).


   DISCUSSION
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REFERENCES
 
In this paper we provide evidence that the G allele and the GG genotype of the CR1 gene C5507G e33 polymorphism are significantly more frequent in a group of subjects affected by IPF than in sex-, age-, and ethnically matched healthy control subjects (Table 3). This significant deviation from the control frequency seemed to be present in both males and females, but we should take into account that only ~ one third of our series were females. The common CC genotype showed a contemporary protective effect toward IPF, being less represented in the patients than in control subjects (OR = 0.447, p = 0.0041), but this feature was limited to male patients (OR = 0.43, p = 0.0144, pc = not significant) (Table 3). We also investigated the possibility that the C5507G e33 polymorphism could be a modifier, related to different presentations of the disease, such as age at onset or severity of respiratory function impairment, but we failed to find any associations. Only 21 patients (28.4%) had had more than 1 year of follow-up, so we could not relate genotype to disease progression.

As an offshoot of our work, we also provide the first description of the molecular basis of the CR1 intron 27 polymorphism, previously referred to only as an RFLP. We now suggest the novel nomenclature, T520C i27, for this polymorphism (19).

IPF is the second respiratory disorder reported to be significantly associated with CR1 gene polymorphism, following the original description of the polymorphism's association with sarcoidosis (8). The frequency of the GG genotype of the C5507G e33 polymorphism is very similar in the overall populations (18% in sarcoidosis, 16% in IPF), but in IPF there were no differences on stratification by sex, whereas, in marked contrast, in sarcoidosis the GG genotype was particularly associated with the disease in females; the frequency of the GG genotype in males with sarcoidosis was not statistically different from that in control subjects. A possible recessive gene effect is suggested for both disorders.

An obvious question deriving from our findings is: How can we fit this information on CR1 polymorphisms into the current knowledge about the pathogenesis of IPF? CR1 is expressed in a variety of cells, including erythrocytes, phagocytes, all B cells and some T cells, and dendritic cells (20) and is involved in different activities of the complement system (21). As stated earlier, CR1 seems to mediate the transport of ICs throughout the bloodstream to phagocytes in the liver and spleen, and it has been suggested that the rate of IC clearance may be directly correlated to the number of CR1 molecules expressed on erythrocytes (the CR1/E ratio) (5).

ICs have been detected in both bronchoalveolar lavage fluid and blood of patients with IPF (22, 23). In addition, consistent with the presence of ICs, committed IgG Fc and C3b receptors have repeatedly been demonstrated on alveolar macrophage surfaces of patients with IPF (22, 24–26). Intracytoplasmic granular fluorescence for IgG within IPF alveolar macrophages suggested an IgG–ICs phagocytosis (22). In the original, "inflammatory" hypothesis of the pathogenesis of IPF, ICs seemed to play a relevant role as possible triggers for alveolar macrophages to release chemotactic factors for neutrophils that, in turn, release destructive mediators (13). In the current hypothesis of the pathogenesis of IPF, the focus has been moved to aberrant wound healing, witnessed by the presence of fibroblast foci, as the result of sequential lung injury promoted by unidentified stimuli.

Inflammatory triggering, genetic determinants, and Th1/Th2 balance are possible modifiers of the fibrotic response (1). Among possible environmental triggers, several viruses have been repeatedly associated with IPF (4). In particular, Epstein–Barr virus DNA has been detected in the lung tissue of patients with IPF (27, 28), and the expression of the Epstein–Barr virus latent membrane protein 1 was associated with rapid progression of IPF in the Japanese (29). ICs containing viral particles and complement-opsonized viruses are included among complement-opsonized substrates bound to erythrocyte CR1 and thus shuttled through the circulation to the monocyte/phagocyte system for safe clearance (30). Interestingly, a significant correlation between CR1 intron 27 polymorphism and the capacity of erythrocytes to bind to hepatitis B virus– or hepatitis C virus–containing ICs has recently been reported (31).

Thus, speculating on a possible scenario opened up by our findings, one hypothesis would be that, in a subset of subjects who eventually develop IPF, CR1 polymorphisms related to a low CR1/E ratio might contribute to an impaired clearance of ICs containing viral particles and/or complement-opsonized viruses. In conjunction with other environmental and genetically determined factors, this might result in repeated episodes of acute lung injury and the subsequent aberrant wound healing. Alternatively, we could suppose that an impaired clearance might be related to a different disease course, in analogy with a suggested role of the CR1 gene in sarcoidosis (32). Unfortunately, the essentially cross-sectional design of our investigation does not allow us to test such a hypothesis.

Another limitation of our study is the lack of investigation of a relationship between CR1 gene polymorphisms and CR1 expression on erythrocytes. However, such an approach would be limited by the fact that, in the C5507G exon 33 polymorphism, the C -> G substitution leads to a Pro -> Arg amino acid change at position 1,827 of the protein sequence in the proximal extramembrane region, thus creating a possible cleavage site for accelerated proteolysis (6, 7). As an example, in subjects with systemic lupus erythematosus, the reduced number of CR1 molecules on erythrocytes has been reported to be associated with disease activity, and is therefore more likely to be an acquired phenomenon than an inherited one (33, 34), although a genetic component cannot be ruled out (35, 36). In this case, there would be an overlap between inherited and acquired mechanisms leading to a low CR1/E ratio, which could be a transient and/or cyclic phenomenon and therefore difficult to "freeze" in an investigation with a cross-sectional design.

IPF and sarcoidosis are two markedly different disorders from the viewpoints of epidemiology, pathogenesis, and clinical features (1, 2, 15, 37, 38). Major advances have been made in the investigation of genetic determinants in sarcoidosis (39), whereas only a few genes, such as TNF-{alpha}, IL-1 receptor antagonist (40), IL-6 (41), and surfactant protein C (42) have been reported to be associated with IPF. Interestingly, despite the hugely different pathogenetic mechanisms, other reports suggest a possible genetic link between sarcoidosis and IPF: the IL-1 gene and the TNF gene clusters seem to contain candidate genes for both sarcoidosis and IPF (40, 41, 43–46). In addition, the two disorders seem to share at least two features: the presence of local and/or systemic ICs (at least in a phase of the disease life cycle), and the hypothesis that an environmental organic factor, perhaps microbial, triggers the disorder. It has been postulated that a variety of microorganisms or microbial products, acting as "superantigens," are implicated in certain infectious or autoimmune disorders (47). Superantigens bind to the T cell receptor Vß portion and to the proximal domain of human leukocyte antigen molecules, are poorly processed by macrophages, are related but not restricted by human leukocyte antigen, and are able to stimulate a high number of lymphocytes, leading them to apoptosis (48). According to this suggestion, we may hypothesize that CR1 gene polymorphisms could be related to the autoimmune component of both IPF (15) and sarcoidosis (48).

We are aware that the sample size we investigated is relatively small, even if sufficiently large for a rare disorder such as IPF. Thus, we believe that, to receive a nomination of candidate gene in IPF (49), our findings on the association of CR1 gene polymorphisms with IPF should be confirmed in different ethnic groups and by different strategies. In this case, they would open up intriguing speculations on a possible common genetic doorway for intruder(s) triggering different disorders, based on the nature of the intruder, and cooperation with different environmental factors and genetic backgrounds.


   Acknowledgments
 
The technical skill of Paola Mazzola is gratefully acknowledged. The authors are deeply indebted to Dr. Rachel Stenner for editing of the manuscript.


   FOOTNOTES
 
Supported in part by IRCCS Policlinico San Matteo Ricerca Corrente.

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Received in original form February 14, 2003; accepted in final form May 14, 2003


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