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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 43-46, (2002)
© 2002 American Thoracic Society

Original Article

Association between TNFA Polymorphism and the Development of Asthma in the Japanese Population

Emiko Noguchi, Yukako Yokouchi, Masanao Shibasaki, Michharu Inudou, Satoko Nakahara, Tetsuo Nogami, Masashi Kamioka, Kimiko Yamakawa-Kobayashi, Kunio Ichikawa, Akira Matsui and Tadao Arinami

Department of Medical Genetics, Institute of Basic Medical Sciences and Department of Pediatrics, Institute of Clinical Medicine, University of Tsukuba, Tsukuba City; Kensei General Hospital, Nishiibaraki-gun; and Nogami Children's Clinic, Ryugasaki City, Ibaraki-ken, Japan

Correspondence and requests for reprints should be addressed to Emiko Noguchi, M.D., Ph.D., Department of Medical Genetics, Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki-ken, 305-8575, Japan. E-mail: mo00f210{at}md.tsukuba.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Tumor necrosis factor (TNF) is a proinflammatory cytokine that participates in the inflammatory reaction in patients with asthma. The TNFA and TNFB genes, which encode TNF-{alpha} and TNF-ß, respectively, are located within the region encoding the human major histocompatibility complex on chromosome 6p21.3, which showed linkage to atopic asthma in our genome-wide search. To determine whether polymorphisms in the 5' flanking region of the TNFA gene (-1031C/T, -863C/A, and -857C/T) and an NcoI polymorphism in the TNFB gene (LTA NcoI) are associated with the development of asthma, we performed transmission disequilibrium tests of families identified through children with atopic asthma. Genotypes of families were determined by polymerase chain reaction–based restriction fragment length polymorphism or SNaPshot analysis. Transmission disequilibrium tests of 144 asthmatic families revealed that transmission of the -857C allele and the -1031T-863C-857C haplotype in the TNFA gene to asthma-affected offspring occurred more frequently than expected (-857C allele, p = 0.0055; -1031T-863C-857C haplotype, p = 0.0002). Our results suggest that TNFA or nearby genes, including those in the major histocompatibility complex region, may contribute to the development of asthma in the Japanese population.

Key Words: genetics • haplotype • transmission disequilibrium test


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Asthma is a complex disorder in which both genetic and environmental factors are involved. Atopy, which is characterized by increased levels of immunoglobulin E (IgE) against common environmental allergens, is considered the strongest predisposing factor for asthma. More than 90% of children with asthma develop specific IgE against the house dust mite, and dust mite allergy is associated strongly with asthma (1, 2). However, only a small subset of subjects with dust mite allergy develop asthma (3), suggesting that other factors are necessary for development of asthma.

Tumor necrosis factor (TNF) is a proinflammatory cytokine that participates in the inflammatory reaction in patients with asthma (4). The TNFA and TNFB genes, which encode TNF-{alpha} and TNF-ß, respectively, are located within the human major histocompatibility complex (MHC) on chromosome 6p21.3, where we previously found evidence for linkage to atopic asthma (5). A -308G/A polymorphism in the promoter of TNFA was identified and reported to be associated with asthma (6–8) and increased bronchial hyperresponsiveness (9). The -308A allele was also shown to be associated with increased transcription of TNFA compared with that of the -308G allele in a B cell line (10). Also, the level of TNF secretion seems to be associated with allele 1 of an NcoI polymorphism in the first intron of the TNFB gene, which is known as the lymphotoxin {alpha} gene (LTA) (11). Therefore, TNFA and TNFB are excellent candidate genes for asthma, especially with respect to the inflammation aspect of the disease.

The frequency of the -308A allele in TNFA varies significantly between ethnic groups, and it is rare in the Japanese (less than 3%). Therefore, large sample populations are necessary to evaluate associations between the -308G/A polymorphism and diseases in the Japanese. Other more common polymorphisms in the promoter of TNFA (-1031T/C, -863C/A, and -857C/T) have been identified, and associations between these polymorphisms and immune-mediated diseases such as rheumatoid arthritis and Crohn's diseases have been reported (12, 13). In the present study, we examined associations of these polymorphisms in the 5' flanking region of the TNFA gene and the NcoI polymorphism in the TNFB gene with atopic asthma in Japanese families identified through children with asthma.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Probands were children with asthma who visited the Pediatric Allergy Clinic of the University Hospital of Tsukuba (Tsukuba City, Japan). A full verbal and written explanation of the study was given to all family members interviewed, and 144 families (476 members) gave informed consent and participated in this study. The clinical details of the asthmatic families are described in Table 1. Asthma was diagnosed in subjects according to the criteria of the National Institutes of Health (Bethesda, MD), with minor modifications (14). Patients had to satisfy the two following criteria: (1) two or more episodes of wheezing and shortness of breath during the past year and (2) reversibility of the wheezing and dyspnea, either spontaneously or by bronchodilator treatment. Methacholine challenge was not done because of the low age of the children with asthma in these families; however, the diagnoses of asthma in this population were confirmed clinically by participating physicians or pediatricians who had treated the children for more than 2 years. Because wheezing is often associated with viral respiratory infection in young children, we excluded children younger than 3 years old (15). The young adult patients included in this study had suffered from chronic asthma since childhood. Total serum IgE levels and IgE levels specific for Dermatophagoides farinae (Df) were determined with the Pharmacia (Uppsala, Sweden) CAP system. To achieve homogeneity of the patients with asthma, we selected families having at least one child with asthma with Df-RAST scores greater than 3. Probands were selected, and the parents–proband trio for each family was examined by transmission disequilibrium test (TDT). Some of the families examined in this study also participated in our genome-wide study (5). This study was approved by the Committee of Ethics of the University of Tsukuba.


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  		TABLE 1. Clinical details of asthmatic families

 
Molecular Method
DNA was extracted from peripheral blood leukocytes. Polymorphisms were analyzed by polymerase chain reaction (PCR) with primer pairs 5'-GGGGAGAACAAAAGGATAAG-3' and 5'-CCCCATACTC GACTTTCATA-3' for the -1031C/T polymorphism in the TNFA gene, and with 5'-CCGTGCTTCGTGCTTTGGACTA-3' and 5'-AGA GCTGGTGGGGACATGTCTG-3' for the LTA NcoI polymorphism in the TNFB gene. The expected product sizes for the -1031C/T and LTA NcoI polymorphisms were 270 and 741 bp, respectively. The -1031C/T alleles were differentiated by BbsI restriction digestion (C allele, 161 and 109 bp; T allele, 270 bp), and the LTA NcoI alleles were differentiated by NcoI restriction digestion (G allele, 545 and 196 bp; A allele, 741 bp). Digested PCR fragments were subjected to agarose gel electrophoresis and visualized by ethidium bromide staining and UV transillumination.

Because there are no differences in restriction enzyme sites to permit discrimination of the -863C/A and -857C/T polymorphisms, the SNaPshot protocol (PE Biosystems, Foster City, CA) was performed according to the manufacturer's instructions to determine genotypes. The region of interest, which encompassed both alleles, was amplified by PCR with primers 5'-CAATGGGTAGGAGAATGTCC-3' and 5'-ACTCTGGGGTCCCTGATTTT-3'. Primers used to determine the genotypes are 5'-TCGAGTATGGGGACCCCC-3' for the -863C/A polymorphism and 5'-CCCTCTACATGGCCCTGTCTTC-3' for the -857C/T polymorphism. Accuracy of the genotypes was confirmed by direct sequencing of PCR products from 144 subjects randomly selected from the asthmatic family members.

Serum TNF-{alpha} Assays
TNF-{alpha} levels in serum were determined by an enzyme-linked immunosorbent assay (ELISA) (Japan Immunoresearch Laboratories, Takasaki, Japan) according to the manufacturer's instructions. Serum was added to the well of an ELISA plate that had been preincubated with monoclonal antibody to recombinant human TNF-{alpha}. A standard curve was constructed for each assay plate with recombinant human TNF-{alpha} in serial dilutions. The minimal detectable level of TNF-{alpha} with this assay was 4.0 pg/ml, and the values below 4.0 pg/ml were replaced by 0 pg/ml. One extreme value (> 3 SD above the mean) was excluded from the analysis.

Statistics
Allelic and haplotypic TDTs were performed with the GeneHunter program (16). SIMWALK2 (17) was used to construct haplotypes of TNFA polymorphisms, and linkage disequilibrium between the two polymorphisms was calculated with the software GOLD (18).

There are eight possible haplotypes for TNFA polymorphisms. Among these, haplotypes with frequencies exceeding 0.1 were subjected to haplotypic TDT analysis. p Values were corrected for multiple TDT comparisons, and p < 0.0071 was considered statistically significant. The statistical power of TDT for detecting a polymorphism directly affecting risk was calculated according to the method proposed by Risch and Merikangas (19).

Associations between serum TNF-{alpha} levels and genotypes were analyzed by Wilcoxon test because TNF-{alpha} levels did not show a normal distribution. A p value < 0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Linkage Disequilibrium of the Polymorphisms
The frequencies of the LTA NcoI *G, –1031T, -863A, and -857T alleles in the parents were 0.38, 0.14, 0.15, and 0.13, respectively, and did not deviate from expected Hardy–Weinberg equilibrium (p > 0.1). Table 2 shows the results of the linkage disequilibrium between polymorphisms. There was significant linkage disequilibrium between the LTA NcoI polymorphism in TNFB and polymorphisms in TNFA and between the -1031C/T and –863C/A polymorphisms in TNFA. No statistically significant linkage disequilibrium was observed between the -857C/T and -863C/A polymorphisms or between the -857C/T and –1031C/T polymorphisms in TNFA.


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  		TABLE 2. Linkage disequilibrium between all pairs of loci

 
Transmission Disequilibrium Test
TDT analysis showed transmission of the C allele of the -857C/T polymorphism to offspring with asthma occurred more frequently than expected (p = 0.0055) (Table 3). Because TNFA haplotypes are reported to be associated with some MHC loci (20), we constructed TNFA haplotypes for the -1031C/T, -863C/A, and -857C/T polymorphisms and conducted haplotype TDTs of families with asthma. Haplotype TDTs revealed that transmission of the -1031T-863C-857C haplotype of the TNFA gene to offspring with asthma occurred more frequently than expected (p = 0.0002) and that the -1031T-863C-857T haplotype was undertransmitted to the affected children (p = 0.0027) (Table 4). The statistical power of TDT to determine for the LTA NcoI *G allele, -1031T allele, -863A allele, and -857T allele was 0.93, 0.77, 0.79, and 0.75, respectively, at the {alpha} level of 0.05 if the relative risk for asthma in those persons carrying a putative risk allele is 1.7 compared with that in persons without the allele.


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  		TABLE 3. Tdts for the polymorphisms in the tnfa gene and the ncoi polymorphism in the tnfb gene

 

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  		TABLE 4. Haplotype tdts for the polymorphisms in the tnfa gene

 
Serum TNF-{alpha} Assays
Because significant association between the -857C/T polymorphism, -1031T-863C-857C haplotype, and atopic asthma was observed, we performed serum TNF-{alpha} assays in parents with the -1031T-863C-857C/-1031T-863C-857C haplotype (27 subjects), 2-1031T-863C-857C/-1031T-863C-857T haplotype (22 subjects), and -1031T-863C-857T/-1031T-863C -857T haplotype (5 subjects). Mean ± SD serum TNF-{alpha} levels of parents with the -1031T-863C-857C/-1031T-863C -857C haplotype, with the -1031T-863C-857C/-1031T -863C-857T haplotype, and with the -1031T-863C-857T/-1031T-863C-857T haplotype were 6.5 ± 9.6, 3.5 ± 11.8, and 0.0 pg/ml, respectively. Significant association was observed between serum TNF-{alpha} levels and the haplotypes of the TNFA gene (p = 0.001, by Wilcoxon test).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our data showed that the -857C allele and the -1031T -863C-857C haplotype of the TNFA gene are associated with childhood atopic asthma.

Overproduction of TNF-{alpha} leads to autoimmune diseases such as Crohn's disease and rheumatoid arthritis, and anti-TNF reagents have shown marked clinical efficacy in the treatment of rheumatoid arthritis and Crohn's disease (21–23). In subjects with asthma, an increase in the production of TNF-{alpha} in macrophages and peripheral blood monocytes after allergen challenge has been observed, and accumulating data suggest that TNF-{alpha} is responsible for smooth muscle activation and late-phase inflammatory responses in subjects with asthma (24). Several polymorphisms have been identified in TNFA, and among them, the -308G -> A polymorphism with an allele frequency of 0.16 in white individuals has been well studied for possible association with immune-mediated diseases. There have been studies showing association between the -308A allele (TNF2) in TNFA and asthma (6–8) and between the -308A allele and increased bronchial hyperresponsiveness (9), although other studies have yielded conflicting results (25–27). The -308G/A polymorphism is not in linkage disequilibrium with -1031C/T, -863C/A, or -857C/T (28). We did not genotype the -308G/A polymorphism in our population because the allele frequency of this polymorphism in the general Japanese population is less than 3%.

A luciferase assay of the TNFA promoter revealed that transcriptional activities of the -1031C, -863A, and -857T alleles were significantly greater than the transcriptional activity of the wild-type allele (28), indicating that both the -857C allele and the -1031T-863C-857C haplotype of the TNFA gene have low promoter activity. However, a chloramphenicol acetyltransferase assay of the TNFA promoter did not reveal transcriptional activities that differed significantly between the -863A and -853T alleles and the wild-type alleles (29). Our data regarding serum TNF-{alpha} levels in subjects with the -1031T-863C-857C/-1031T-863C-857C, -1031T-863C -857C/-1031T-863C-857T, and -1031T-863C-857T/-1031T -863C-857T haplotypes in the TNFA gene suggest that the -1031T-863C-857C haplotype is more active transcriptionally than is the -1031T-863C-857C haplotype, which is in agreement with our TDT results.

The significance of genetic variants in the TNF loci with respect to asthma susceptibility is complicated because these loci are in linkage disequilibrium with some MHC alleles. The -1031T-863C-857C haplotype of TNFA, which is associated with the development of asthma by TDT, was the dominant TNFA promoter haplotype in the Japanese population, followed by the -1031T-863C-857T, -1031C-863A-857C, and -1031C-863C-857C haplotypes (20). The -1031T-863C -857C haplotype is reported to be in linkage disequilibrium with MHC A*3303, B*5201, B*4403, B*4601, B*0702, DRB1*1502, DRB1*0101, and DRB1*1302 alleles (20). Therefore, it is possible that the -1031T-863C-857C haplotype may be in linkage disequilibrium with asthma susceptibility loci within the MHC.

The LTA NcoI polymorphism has been shown to be associated with lymphotoxin {alpha} production (11). We did not find an association between the LTA NcoI polymorphism and the development of asthma. Because the detection power of the sample in the present study was 0.93 for atopic asthma, if the relative risk for asthma in persons carrying a putative risk allele is 1.7 compared with that in persons without the allele, our failure to find an association was not due to the sample size, although a minor contribution of the LTA NcoI polymorphism to asthma susceptibility cannot be excluded.

Linkage of asthma to chromosome 6p21, where the TNFA gene is located, was observed previously in our families (5). The association between the TNFA polymorphisms and asthma likely accounts, at least in part, for this linkage.


   Acknowledgments
 
Supported by scientific research grants (12204001 and 12024201) from the Ministry of Education, Science, and Culture of Japan.

Received in original form October 13, 2001; accepted in final form April 1, 2002


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Shibasaki M, Tajima K, Morikawa A, Mitsuhashi M, Sumazaki R, Tokuyama K. Relation between frequency of asthma and IgE antibody levels against Dermatophagoides farinae and total serum IgE levels in schoolchildren. J Allergy Clin Immunol 1988;82:86–94.[CrossRef][Medline]
  2. Sears MR, Herbison GP, Holdaway MD, Hewitt CJ, Flannery EM, Silva PA. The relative risks of sensitivity to grass pollen, house dust mite and cat dander in the development of childhood asthma. Clin Exp Allergy 1989;19:419–424.[CrossRef][Medline]
  3. Shibasaki M, Noguchi E, Takeda K, Takita H. Distribution of IgE and IgG antibody levels against house dust mites in schoolchildren, and their relation with asthma. J Asthma 1997;34:235–242.[Medline]
  4. Ying S, Robinson DS, Varney V, Meng Q, Tsicopoulos A, Moqbel R, Durham SR, Kay AB, Hamid Q. TNF {alpha} mRNA expression in allergic inflammation. Clin Exp Allergy 1991;21:745–750.[CrossRef][Medline]
  5. Yokouchi Y, Nukaga Y, Shibasaki M, Noguchi E, Kimura K, Ito S, Nishihara M, Yamakawa-Kobayashi K, Takeda K, Imoto N, et al. Significant evidence for linkage of mite-sensitive childhood asthma to chromosome 5q31-q33 near the interleukin 12 B locus by a genome-wide search in Japanese families. Genomics 2000;66:152–160.[CrossRef][Medline]
  6. Moffatt MF, Cookson WO. Tumour necrosis factor haplotypes and asthma. Hum Mol Genet 1997;6:551–554.[Abstract/Free Full Text]
  7. Chagani T, Pare PD, Zhu S, Weir TD, Bai TR, Behbehani NA, Fitzgerald JM, Sandford AJ. Prevalence of tumor necrosis factor-{alpha} and angiotensin converting enzyme polymorphisms in mild/moderate and fatal/near-fatal asthma. Am J Respir Crit Care Med 1999;160:278–282.[Abstract/Free Full Text]
  8. Winchester EC, Millwood IY, Rand L, Penny MA, Kessling AM. Association of the TNF-{alpha} –308 (G->A) polymorphism with self-reported history of childhood asthma. Hum Genet 2000;107:591–596.[CrossRef][Medline]
  9. Li Kam Wa TC, Mansur AH, Britton J, Williams G, Pavord I, Richards K, Campbell DA, Morton N, Holgate ST, Morrison JF. Association between -308 tumour necrosis factor promoter polymorphism and bronchial hyperreactivity in asthma. Clin Exp Allergy 1999;29:1204–1208.[CrossRef][Medline]
  10. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW. Effects of a polymorphism in the human tumor necrosis factor {alpha} promoter on transcriptional activation. Proc Natl Acad Sci USA 1997;94: 3195–3199.[Abstract/Free Full Text]
  11. Messer G, Spengler U, Jung MC, Honold G, Blomer K, Pape GR, Riethmuller G, Weiss EH. Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-ß gene correlates with a variant amino acid in position 26 and a reduced level of TNF-ß production. J Exp Med 1991;173: 209–219.[Abstract/Free Full Text]
  12. Waldron-Lynch F, Adams C, Amos C, Zhu DK, McDermott MF, Shanahan F, Molloy MG, O'Gara F. Tumour necrosis factor 5' promoter single nucleotide polymorphisms influence susceptibility to rheumatoid arthritis (RA) in immunogenetically defined multiplex RA families. Genes Immun 2001;2:82–87.[CrossRef][Medline]
  13. Negoro K, Kinouchi Y, Hiwatashi N, Takahashi S, Takagi S, Satoh J, Shimosegawa T, Toyota T. Crohn's disease is associated with novel polymorphisms in the 5'-flanking region of the tumor necrosis factor gene. Gastroenterology 1999;117:1062–1068.[CrossRef][Medline]
  14. National Heart, Lung, and Blood Institute, National Institutes of Health. Guidelines for the diagnosis and management of asthma. Washington, D.C.: U.S. Government Printing Office; 1997.
  15. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 1995;332:133–138.
  16. Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 1996;58:1347–1363.[Medline]
  17. Sobel E, Lange K. Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet 1996;58:1323–1337.[Medline]
  18. Abecasis GR, Cookson WO. GOLD–graphical overview of linkage disequilibrium. Bioinformatics 2000;16:182–183.[Abstract/Free Full Text]
  19. Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science 1996;273:1516–1517.[Medline]
  20. Matsushita M, Tsuchiya N, Nakayama T, Ohashi J, Shibue T, Shiota M, Oka T, Yamane A, Tokunaga K. Allele typing of human TNFA 5'-flanking region using polymerase chain reaction-preferential homoduplex formation assay (PCR-PHFA): linkage disequilibrium with HLA class I and class II genes in Japanese. Tissue Antigens 1999;54:478–484.[CrossRef][Medline]
  21. Davidson A, Diamond B. Autoimmune diseases. N Engl J Med 2001; 345:340–350.[Free Full Text]
  22. Bell S, Kamm MA. Antibodies to tumour necrosis factor {alpha} as treatment for Crohn's disease. Lancet 2000;355:858–860.[CrossRef][Medline]
  23. Maini RN, Taylor PC. Anti-cytokine therapy for rheumatoid arthritis. Annu Rev Med 2000;51:207–229.[CrossRef][Medline]
  24. Thomas PS. Tumour necrosis factor-{alpha}: the role of this multifunctional cytokine in asthma. Immunol Cell Biol 2001;79:132–140.[CrossRef][Medline]
  25. Zhu S, Chan-Yeung M, Becker AB, Dimich-Ward H, Ferguson AC, Manfreda J, Watson WT, Pare PD, Sandford AJ. Polymorphisms of the IL-4, TNF-{alpha}, and Fc{varepsilon} RIß genes and the risk of allergic disorders in at-risk infants. Am J Respir Crit Care Med 2000;161:1655–1659.[Abstract/Free Full Text]
  26. Albuquerque RV, Hayden CM, Palmer LJ, Laing IA, Rye PJ, Gibson NA, Burton PR, Goldblatt J, Lesouef PN. Association of polymorphisms within the tumour necrosis factor (TNF) genes and childhood asthma. Clin Exp Allergy 1998;28:578–584.[CrossRef][Medline]
  27. Louis R, Leyder E, Malaise M, Bartsch P, Louis E. Lack of association between adult asthma and the tumour necrosis factor {alpha} -308 polymorphism gene. Eur Respir J 2000;16:604–608.[Abstract]
  28. Higuchi T, Seki N, Kamizono S, Yamada A, Kimura A, Kato H, Itoh K. Polymorphism of the 5'-flanking region of the human tumor necrosis factor (TNF)-{alpha} gene in Japanese. Tissue Antigens 1998;51: 605–612.[Medline]
  29. Uglialoro AM, Turbay D, Pesavento PA, Delgado JC, McKenzie FE, Gribben JG, Hartl D, Yunis EJ, Goldfeld AE. Identification of three new single nucleotide polymorphisms in the human tumor necrosis factor-{alpha} gene promoter. Tissue Antigens 1998;52:359–367.[Medline]



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Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2002 American Thoracic Society