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Vol. 71, No. 2, 2011
Issue release date: July 2011
Hum Hered 2011;71:97–105
(DOI:10.1159/000319536)

Attempted Replication of 50 Reported Asthma Risk Genes Identifies a SNP in RAD50 as Associated with Childhood Atopic Asthma

Murk W.a · Walsh K.a · Hsu L.-Ia · Zhao L.a · Bracken M.B.b · DeWan A.T.a
aDepartment of Epidemiology and Public Health, Yale University, and bCenter for Perinatal, Pediatric and Environmental Epidemiology, Yale University School of Public Health, New Haven, Conn., USA
email Corresponding Author

Abstract

Objectives: Asthma is a childhood disease that is strongly influenced by genetic factors. We sought to replicate an association between single nucleotide polymorphisms (SNPs) of the top-ranked candidate genes and childhood atopic asthma in Perinatal Risk of Asthma in Infants of Asthmatic Mothers (PRAM) study subjects. Methods: Using data from a systematic literature search and an exploratory genome-wide association study conducted in a subset of the PRAM cohort, we followed a strict procedure to generate a ranked list of candidate genes. SNPs in the top 50 genes were genotyped in the full PRAM cohort (n = 103 cases with doc- tor-diagnosed atopic asthma at age 6, and n = 499 controls). Results: The literature search identified 251 prior risk genes from 469 publications. RAD50 (rs2706347) and PTPRE (rs10830196) revealed crude associations with asthma at a Bonferroni-corrected level of significance (p < 0.0011). IL4R (rs1801275), CCL5 (rs2280788), and TBXA2R (rs4523) revealed nominal significance (p < 0.05). When adjusted for race and gender, only rs2706347 in RAD50 remained significantly associated with asthma. SNPs in frequently replicated asthma risk genes, including TNF, IL13, ADAM33, TGFB1, and MS4A2, revealed no association. Conclusion:RAD50 may be a promising candidate asthma risk gene. Lack of evidence of highly reported polymorphisms in the present study highlights the genetic heterogeneity of asthma and emphasizes the need for robust replication of candidate genes.


 goto top of outline Key Words

  • Association analysis
  • Asthma
  • Atopy
  • Candidate gene analysis

 goto top of outline Abstract

Objectives: Asthma is a childhood disease that is strongly influenced by genetic factors. We sought to replicate an association between single nucleotide polymorphisms (SNPs) of the top-ranked candidate genes and childhood atopic asthma in Perinatal Risk of Asthma in Infants of Asthmatic Mothers (PRAM) study subjects. Methods: Using data from a systematic literature search and an exploratory genome-wide association study conducted in a subset of the PRAM cohort, we followed a strict procedure to generate a ranked list of candidate genes. SNPs in the top 50 genes were genotyped in the full PRAM cohort (n = 103 cases with doc- tor-diagnosed atopic asthma at age 6, and n = 499 controls). Results: The literature search identified 251 prior risk genes from 469 publications. RAD50 (rs2706347) and PTPRE (rs10830196) revealed crude associations with asthma at a Bonferroni-corrected level of significance (p < 0.0011). IL4R (rs1801275), CCL5 (rs2280788), and TBXA2R (rs4523) revealed nominal significance (p < 0.05). When adjusted for race and gender, only rs2706347 in RAD50 remained significantly associated with asthma. SNPs in frequently replicated asthma risk genes, including TNF, IL13, ADAM33, TGFB1, and MS4A2, revealed no association. Conclusion:RAD50 may be a promising candidate asthma risk gene. Lack of evidence of highly reported polymorphisms in the present study highlights the genetic heterogeneity of asthma and emphasizes the need for robust replication of candidate genes.

Copyright © 2011 S. Karger AG, Basel


 goto top of outline References
  1. Worldwide variations in the prevalence of asthma symptoms: the international study of asthma and allergies in childhood (ISAAC). Eur Respir J 1998;12:315–335.
  2. Salter H: On Asthma: Its Pathology and Treatment. London, John Churchil & Sons, 1860.
  3. Los H, Postmus PE, Boomsma DI: Asthma genetics and intermediate phenotypes: a review from twin studies. Twin Res 2001;4:81–93.
  4. Ober C, Hoffjan S: Asthma genetics 2006: the long and winding road to gene discovery. Genes Immun 2006;7:95–100.
  5. Wu H, Romieu I, Shi M, Hancock DB, Li H, Sienra-Monge JJ, Chiu GY, Xu H, del Rio-Navarro BE, London SJ: Evaluation of candidate genes in a genome-wide association study of childhood asthma in Mexicans. J Allergy Clin Immunol 2010;125:321–327 e313.
  6. Bosse Y, Hudson TJ: Toward a comprehensive set of asthma susceptibility genes. Annu Rev Med 2007;58:171–184.
  7. DeWan A, Triche E, Xu X, Hsu L-I, Zhao C, Belanger K, Hellenbrand K, Willis-Owen SA, Moffatt M, Cookson WO, Weiss ST, Gauderman WJ, Baurley JW, Gilliland F, Wilk JB, O’Connor GT, Strachan DP, Hoh J, Bracken MB: Pde11a associations with asthma: results of a genome-wide association scan. J Allergy Clin Immunol 2010;126:871–873.
  8. Kang EM, Lundsberg L, Illuzzi J, Bracken MB: Prenatal exposure to acetaminophen and asthma in children: a prospective study. Obstet Gynecol 2009;114:1295–1306.
  9. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D: Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006;38:904–909.
  10. The international hapmap project. Nature 2003;426:789–796.
  11. Li X, Howard TD, Zheng SL, Haselkorn T, Peters SP, Meyers DA, Bleecker ER: Genome-wide association study of asthma identifies rad50-il13 and hla-dr/dq regions. J Allergy Clin Immunol 2010;125:328–335 e311.
  12. Weidinger S, Gieger C, Rodriguez E, Baurecht H, Mempel M, Klopp N, Gohlke H, Wagenpfeil S, Ollert M, Ring J, Behrendt H, Heinrich J, Novak N, Bieber T, Kramer U, Berdel D, von Berg A, Bauer CP, Herbarth O, Koletzko S, Prokisch H, Mehta D, Meitinger T, Depner M, von Mutius E, Liang L, Moffatt M, Cookson W, Kabesch M, Wichmann HE, Illig T: Genome-wide scan on total serum IgE levels identifies fcer1a as novel susceptibility locus. PLoS Genet 2008;4:e1000166.
  13. Marsh DG, Neely JD, Breazeale DR, Ghosh B, Freidhoff LR, Ehrlich-Kautzky E, Schou C, Krishnaswamy G, Beaty TH: Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science 1994;264:1152–1156.
  14. Postma DS, Bleecker ER, Amelung PJ, Holroyd KJ, Xu J, Panhuysen CI, Meyers DA, Levitt RC: Genetic susceptibility to asth- ma – bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med 1995;333:894–900.
  15. Lee GR, Fields PE, Griffin TJ, Flavell RA: Regulation of the Th2 cytokine locus by a locus control region. Immunity 2003;19:145–153.
  16. Fields PE, Lee GR, Kim ST, Bartsevich VV, Flavell RA: Th2-specific chromatin remodeling and enhancer activity in the Th2 cytokine locus control region. Immunity 2004;21:865–876.
  17. Lee GR, Spilianakis CG, Flavell RA: Hypersensitive site 7 of the Th2 locus control region is essential for expressing Th2 cytokine genes and for long-range intrachromosomal interactions. Nat Immunol 2005;6:42–48.
  18. Ngoc PL, Gold DR, Tzianabos AO, Weiss ST, Celedon JC: Cytokines, allergy, and asthma. Curr Opin Allergy Clin Immunol 2005;5:161–166.
  19. Tremblay K, Lemire M, Potvin C, Tremblay A, Hunninghake GM, Raby BA, Hudson TJ, Perez-Iratxeta C, Andrade-Navarro MA, Laprise C: Genes to diseases (g2d) computational method to identify asthma candidate genes. PLoS One 2008;3:e2907.

    External Resources

  20. Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, Mustelin T: Protein tyrosine phosphatases in the human genome. Cell 2004;117:699–711.
  21. Akimoto M, Mishra K, Lim KT, Tani N, Hisanaga SI, Katagiri T, Elson A, Mizuno K, Yakura H: Protein tyrosine phosphatase epsilon is a negative regulator of fcepsilonri-mediated mast cell responses. Scand J Immunol 2009;69:401–411.
  22. Chatila TA: Interleukin-4 receptor signaling pathways in asthma pathogenesis. Trends Mol Med 2004;10:493–499.
  23. Al-Abdulhadi SA, Helms PJ, Main M, Smith O, Christie G: Preferential transmission and association of the –403G–>A promoter rantes polymorphism with atopic asthma. Genes Immun 2005;6:24–30.
  24. Hizawa N, Yamaguchi E, Konno S, Tanino Y, Jinushi E, Nishimura M: A functional polymorphism in the rantes gene promoter is associated with the development of late-onset asthma. Am J Respir Crit Care Med 2002;166:686–690.
  25. Lachheb J, Chelbi H, Hamzaoui K, Hamzaoui A: Association between rantes polymorphisms and asthma severity among Tunisian children. Hum Immunol 2007;68:675–680.
  26. Wang LJ, Li YR, Chen JH, Cui TP, Wu JM: [Polymorphism of regulated upon activation, normal T cell expressed and secreted promoter region –28 position in Chinese allergic asthmatic children]. Zhonghua Jie He He Hu Xi Za Zhi 2004;27:394–397.
  27. Hoshino M, Sim J, Shimizu K, Nakayama H, Koya A: Effect of aa-2414, a thromboxane a2 receptor antagonist, on airway inflammation in subjects with asthma. J Allergy Clin Immunol 1999;103:1054–1061.
  28. Unoki M, Furuta S, Onouchi Y, Watanabe O, Doi S, Fujiwara H, Miyatake A, Fujita K, Tamari M, Nakamura Y: Association studies of 33 single nucleotide polymorphisms (SNPs) in 29 candidate genes for bronchial asthma: positive association of a t924c polymorphism in the thromboxane a2 receptor gene. Hum Genet 2000;106:440–446.
  29. Leung TF, Tang NL, Lam CW, Li AM, Chan IH, Ha G: Thromboxane a2 receptor gene polymorphism is associated with the serum concentration of cat-specific immunoglobulin E as well as the development and severity of asthma in Chinese children. Pediatr Allergy Immunol 2002;13:10–17.

    External Resources

  30. Kim SH, Choi JH, Park HS, Holloway JW, Lee SK, Park CS, Shin HD: Association of thromboxane a2 receptor gene polymorphism with the phenotype of acetyl salicylic acid-intolerant asthma. Clin Exp Allergy 2005;35:585–590.
  31. Kim SH, Kim YK, Park HW, Jee YK, Kim SH, Bahn JW, Chang YS, Kim SH, Ye YM, Shin ES, Lee JE, Park HS, Min KU: Association between polymorphisms in prostanoid receptor genes and aspirin-intolerant asthma. Pharmacogenet Genomics 2007;17:295–304.
  32. Aoki T, Hirota T, Tamari M, Ichikawa K, Takeda K, Arinami T, Shibasaki M, Noguchi E: An association between asthma and tnf-308g/a polymorphism: meta-analysis. J Hum Genet 2006;51:677–685.

 goto top of outline Author Contacts

Andrew T. DeWan, PhD, MPH
Department of Epidemiology and Public Health
Yale University, 60 College Street
New Haven, CT 06520 (USA)
Tel. +1 203 785 3528, E-Mail andrew.dewan@yale.edu


 goto top of outline Article Information

Published online: July 6, 2011
Number of Print Pages : 9
Number of Figures : 1, Number of Tables : 2, Number of References : 32
Additional supplementary material is available online - Number of Parts : 1


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 71, No. 2, Year 2011 (Cover Date: July 2011)

Journal Editor: Devoto M. (Philadelphia, Pa./Rome)
ISSN: 0001-5652 (Print), eISSN: 1423-0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Objectives: Asthma is a childhood disease that is strongly influenced by genetic factors. We sought to replicate an association between single nucleotide polymorphisms (SNPs) of the top-ranked candidate genes and childhood atopic asthma in Perinatal Risk of Asthma in Infants of Asthmatic Mothers (PRAM) study subjects. Methods: Using data from a systematic literature search and an exploratory genome-wide association study conducted in a subset of the PRAM cohort, we followed a strict procedure to generate a ranked list of candidate genes. SNPs in the top 50 genes were genotyped in the full PRAM cohort (n = 103 cases with doc- tor-diagnosed atopic asthma at age 6, and n = 499 controls). Results: The literature search identified 251 prior risk genes from 469 publications. RAD50 (rs2706347) and PTPRE (rs10830196) revealed crude associations with asthma at a Bonferroni-corrected level of significance (p < 0.0011). IL4R (rs1801275), CCL5 (rs2280788), and TBXA2R (rs4523) revealed nominal significance (p < 0.05). When adjusted for race and gender, only rs2706347 in RAD50 remained significantly associated with asthma. SNPs in frequently replicated asthma risk genes, including TNF, IL13, ADAM33, TGFB1, and MS4A2, revealed no association. Conclusion:RAD50 may be a promising candidate asthma risk gene. Lack of evidence of highly reported polymorphisms in the present study highlights the genetic heterogeneity of asthma and emphasizes the need for robust replication of candidate genes.



 goto top of outline Author Contacts

Andrew T. DeWan, PhD, MPH
Department of Epidemiology and Public Health
Yale University, 60 College Street
New Haven, CT 06520 (USA)
Tel. +1 203 785 3528, E-Mail andrew.dewan@yale.edu


 goto top of outline Article Information

Published online: July 6, 2011
Number of Print Pages : 9
Number of Figures : 1, Number of Tables : 2, Number of References : 32
Additional supplementary material is available online - Number of Parts : 1


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 71, No. 2, Year 2011 (Cover Date: July 2011)

Journal Editor: Devoto M. (Philadelphia, Pa./Rome)
ISSN: 0001-5652 (Print), eISSN: 1423-0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Worldwide variations in the prevalence of asthma symptoms: the international study of asthma and allergies in childhood (ISAAC). Eur Respir J 1998;12:315–335.
  2. Salter H: On Asthma: Its Pathology and Treatment. London, John Churchil & Sons, 1860.
  3. Los H, Postmus PE, Boomsma DI: Asthma genetics and intermediate phenotypes: a review from twin studies. Twin Res 2001;4:81–93.
  4. Ober C, Hoffjan S: Asthma genetics 2006: the long and winding road to gene discovery. Genes Immun 2006;7:95–100.
  5. Wu H, Romieu I, Shi M, Hancock DB, Li H, Sienra-Monge JJ, Chiu GY, Xu H, del Rio-Navarro BE, London SJ: Evaluation of candidate genes in a genome-wide association study of childhood asthma in Mexicans. J Allergy Clin Immunol 2010;125:321–327 e313.
  6. Bosse Y, Hudson TJ: Toward a comprehensive set of asthma susceptibility genes. Annu Rev Med 2007;58:171–184.
  7. DeWan A, Triche E, Xu X, Hsu L-I, Zhao C, Belanger K, Hellenbrand K, Willis-Owen SA, Moffatt M, Cookson WO, Weiss ST, Gauderman WJ, Baurley JW, Gilliland F, Wilk JB, O’Connor GT, Strachan DP, Hoh J, Bracken MB: Pde11a associations with asthma: results of a genome-wide association scan. J Allergy Clin Immunol 2010;126:871–873.
  8. Kang EM, Lundsberg L, Illuzzi J, Bracken MB: Prenatal exposure to acetaminophen and asthma in children: a prospective study. Obstet Gynecol 2009;114:1295–1306.
  9. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D: Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006;38:904–909.
  10. The international hapmap project. Nature 2003;426:789–796.
  11. Li X, Howard TD, Zheng SL, Haselkorn T, Peters SP, Meyers DA, Bleecker ER: Genome-wide association study of asthma identifies rad50-il13 and hla-dr/dq regions. J Allergy Clin Immunol 2010;125:328–335 e311.
  12. Weidinger S, Gieger C, Rodriguez E, Baurecht H, Mempel M, Klopp N, Gohlke H, Wagenpfeil S, Ollert M, Ring J, Behrendt H, Heinrich J, Novak N, Bieber T, Kramer U, Berdel D, von Berg A, Bauer CP, Herbarth O, Koletzko S, Prokisch H, Mehta D, Meitinger T, Depner M, von Mutius E, Liang L, Moffatt M, Cookson W, Kabesch M, Wichmann HE, Illig T: Genome-wide scan on total serum IgE levels identifies fcer1a as novel susceptibility locus. PLoS Genet 2008;4:e1000166.
  13. Marsh DG, Neely JD, Breazeale DR, Ghosh B, Freidhoff LR, Ehrlich-Kautzky E, Schou C, Krishnaswamy G, Beaty TH: Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science 1994;264:1152–1156.
  14. Postma DS, Bleecker ER, Amelung PJ, Holroyd KJ, Xu J, Panhuysen CI, Meyers DA, Levitt RC: Genetic susceptibility to asth- ma – bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med 1995;333:894–900.
  15. Lee GR, Fields PE, Griffin TJ, Flavell RA: Regulation of the Th2 cytokine locus by a locus control region. Immunity 2003;19:145–153.
  16. Fields PE, Lee GR, Kim ST, Bartsevich VV, Flavell RA: Th2-specific chromatin remodeling and enhancer activity in the Th2 cytokine locus control region. Immunity 2004;21:865–876.
  17. Lee GR, Spilianakis CG, Flavell RA: Hypersensitive site 7 of the Th2 locus control region is essential for expressing Th2 cytokine genes and for long-range intrachromosomal interactions. Nat Immunol 2005;6:42–48.
  18. Ngoc PL, Gold DR, Tzianabos AO, Weiss ST, Celedon JC: Cytokines, allergy, and asthma. Curr Opin Allergy Clin Immunol 2005;5:161–166.
  19. Tremblay K, Lemire M, Potvin C, Tremblay A, Hunninghake GM, Raby BA, Hudson TJ, Perez-Iratxeta C, Andrade-Navarro MA, Laprise C: Genes to diseases (g2d) computational method to identify asthma candidate genes. PLoS One 2008;3:e2907.

    External Resources

  20. Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, Mustelin T: Protein tyrosine phosphatases in the human genome. Cell 2004;117:699–711.
  21. Akimoto M, Mishra K, Lim KT, Tani N, Hisanaga SI, Katagiri T, Elson A, Mizuno K, Yakura H: Protein tyrosine phosphatase epsilon is a negative regulator of fcepsilonri-mediated mast cell responses. Scand J Immunol 2009;69:401–411.
  22. Chatila TA: Interleukin-4 receptor signaling pathways in asthma pathogenesis. Trends Mol Med 2004;10:493–499.
  23. Al-Abdulhadi SA, Helms PJ, Main M, Smith O, Christie G: Preferential transmission and association of the –403G–>A promoter rantes polymorphism with atopic asthma. Genes Immun 2005;6:24–30.
  24. Hizawa N, Yamaguchi E, Konno S, Tanino Y, Jinushi E, Nishimura M: A functional polymorphism in the rantes gene promoter is associated with the development of late-onset asthma. Am J Respir Crit Care Med 2002;166:686–690.
  25. Lachheb J, Chelbi H, Hamzaoui K, Hamzaoui A: Association between rantes polymorphisms and asthma severity among Tunisian children. Hum Immunol 2007;68:675–680.
  26. Wang LJ, Li YR, Chen JH, Cui TP, Wu JM: [Polymorphism of regulated upon activation, normal T cell expressed and secreted promoter region –28 position in Chinese allergic asthmatic children]. Zhonghua Jie He He Hu Xi Za Zhi 2004;27:394–397.
  27. Hoshino M, Sim J, Shimizu K, Nakayama H, Koya A: Effect of aa-2414, a thromboxane a2 receptor antagonist, on airway inflammation in subjects with asthma. J Allergy Clin Immunol 1999;103:1054–1061.
  28. Unoki M, Furuta S, Onouchi Y, Watanabe O, Doi S, Fujiwara H, Miyatake A, Fujita K, Tamari M, Nakamura Y: Association studies of 33 single nucleotide polymorphisms (SNPs) in 29 candidate genes for bronchial asthma: positive association of a t924c polymorphism in the thromboxane a2 receptor gene. Hum Genet 2000;106:440–446.
  29. Leung TF, Tang NL, Lam CW, Li AM, Chan IH, Ha G: Thromboxane a2 receptor gene polymorphism is associated with the serum concentration of cat-specific immunoglobulin E as well as the development and severity of asthma in Chinese children. Pediatr Allergy Immunol 2002;13:10–17.

    External Resources

  30. Kim SH, Choi JH, Park HS, Holloway JW, Lee SK, Park CS, Shin HD: Association of thromboxane a2 receptor gene polymorphism with the phenotype of acetyl salicylic acid-intolerant asthma. Clin Exp Allergy 2005;35:585–590.
  31. Kim SH, Kim YK, Park HW, Jee YK, Kim SH, Bahn JW, Chang YS, Kim SH, Ye YM, Shin ES, Lee JE, Park HS, Min KU: Association between polymorphisms in prostanoid receptor genes and aspirin-intolerant asthma. Pharmacogenet Genomics 2007;17:295–304.
  32. Aoki T, Hirota T, Tamari M, Ichikawa K, Takeda K, Arinami T, Shibasaki M, Noguchi E: An association between asthma and tnf-308g/a polymorphism: meta-analysis. J Hum Genet 2006;51:677–685.