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Variants in the gene encoding C3 are associated with asthma and related phenotypes among African Caribbean families

Genes & Immunity volume 7, pages 27–35 (2006)Cite this article

Abstract

Proinflammatory and immunoregulatory products from C3 play a major role in phagocytosis, respiratory burst, and airways inflammation. C3 is critical in adaptive immunity; studies in mice deficient in C3 demonstrate that features of asthma are significantly attenuated in the absence of C3. To test the hypothesis that the C3 gene on chromosome 19p13.3–p13.2 contains variants associated with asthma and related phenotypes, we genotyped 25 single nucleotide polymorphism (SNP) markers distributed at intervals of ∼1.9 kb within the C3 gene in 852 African Caribbean subjects from 125 nuclear and extended pedigrees. We used the multiallelic test in the family-based association test program to examine sliding windows comprised of 2–6 SNPs. A five-SNP window between markers rs10402876 and rs366510 provided strongest evidence for linkage in the presence of linkage disequilibrium for asthma, high log[total IgE], and high log[IL-13]/[log[IFN-γ] in terms of global P-values (P=0.00027, 0.00013, and 0.003, respectively). A three-SNP haplotype GGC for the first three of these markers showed best overall significance for the three phenotypes (P=0.003, 0.007, 0.018, respectively) considering haplotype-specific tests. Taken together, these results implicate the C3 gene as a priority candidate controlling risk for asthma and allergic disease in this population of African descent.

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References

  1. Fearon DT, Locksley RM . The instructive role of innate immunity in the acquired immune response. Science 1996; 272: 50–54.

    Article  CAS  Google Scholar 

  2. Medzhitov R, Janeway CAJ . Innate immunity: the virtues of a nonclonal system of recognition. Cell 1997; 9: 295–298.

    Article  Google Scholar 

  3. Kobayashi K, Inohara N, Hernandez LD, Galan JE, Nunez G, Janeway CA et al. RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 2002; 416: 194–199.

    Article  CAS  Google Scholar 

  4. Medzhitov R, Janeway CAJ . Decoding the patterns of self and nonself by the innate immune system. Science 2002; 296: 298–300.

    Article  CAS  Google Scholar 

  5. Dempsey PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT . C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 1996; 271: 348–350.

    Article  CAS  Google Scholar 

  6. Sunyer JO, Boshra H, Lorenzo G, Parra D, Freedman B, Bosch N . Evolution of complement as an effector system in innate and adaptive immunity. Immunol Res 2003; 27: 549–564.

    Article  CAS  Google Scholar 

  7. Jacquier-Sarlin MR, Gabert FM, Villiers MB, Colomb MG . Modulation of antigen processing and presentation by covalently linked complement C3b fragment. Immunology 1995; 84: 164–170.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Villiers MB, Villiers CL, Jacquier-Sarlin MR, Gabert FM, Journet AM, Colomb MG . Covalent binding of C3b to tetanus toxin: influence on uptake/internalization of antigen by antigen-specific and non-specific B cells. Immunology 1996; 89: 348–355.

    Article  CAS  Google Scholar 

  9. Carroll MC . The role of complement and complement receptors in induction and regulation of immunity. Ann Rev Immunol 1998; 16: 545–568.

    Article  CAS  Google Scholar 

  10. Burrows B, Martinez FD, Haonen M, Barbee RA, Cline MG . Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med 1989; 320: 271–277.

    Article  CAS  Google Scholar 

  11. Wills-Karp M . Immunologic basis of antigen-induced airway hyperresponsiveness. Ann Rev Immunol 1999; 17: 255–281.

    Article  CAS  Google Scholar 

  12. Karp CL, Grupe A, Schadt E, Ewart SL, Keane-Moore M, Cuomo PJ et al. Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Nat Immunol 2000; 1: 221–226.

    Article  CAS  Google Scholar 

  13. Drouin SM, Corry DB, Kildsgaard J, Wetsel RA . Cutting edge: the absence of C3 demonstrates a role for complement in Th2 effector functions in a murine model of pulmonary allergy. J Immunol 2001; 167: 4141–4145.

    Article  CAS  Google Scholar 

  14. Polack FP, Teng MN, Collins PL, Prince GA, Exner M, Regele H et al. A role for immune complexes in enhanced respiratory syncytial virus disease. J Exp Med 2002; 196: 859–865.

    Article  CAS  Google Scholar 

  15. Walters DM, Breysse PN, Schofield B, Wills-Karp M . Complement factor 3 mediates particulate matter-induced airway hyperresponsiveness. Am J Respir,Cell Mol Biol 2002; 27: 413–418.

    Article  CAS  Google Scholar 

  16. Blumenthal MN, Ober C, Beaty TH, Bleecker ER, Langefeld CD, King RA et al. Genome scan for loci linked to mite sensitivity: the Collaborative Study on the Genetics of Asthma (CSGA). Genes Immunity 2004; 5: 226–231.

    Article  CAS  Google Scholar 

  17. Lee YA, Wahn U, Kehrt R, Tarani L, Businco L, Gustafsson D et al. A major susceptibility locus for atopic dermatitis maps to chromosome 3q21. Nat Genet 2000; 26: 470–473.

    Article  CAS  Google Scholar 

  18. Venanzi S, Malerba G, Galavotti R, Lauciello MC, Trabetti E, Zanoni G et al. Linkage to atopy on chromosome 19 in north-eastern Italian families with allergic asthma. Clin Exp Allergy 2001; 31: 1220–1224.

    Article  CAS  Google Scholar 

  19. Hasegawa K, Tamari M, Shao C, Shimizu M, Takahashi N, Mao XQ et al. Variations in the C3, C3a receptor, and C5 genes affect susceptibility to bronchial asthma. Hum Genet 2004; 115: 295–301.

    Article  CAS  Google Scholar 

  20. Fong KY, Botto M, Walport MJ, So AK . Genomic organization of human complement component C3. Genomics 1990; 7: 579–586.

    Article  CAS  Google Scholar 

  21. Barnes K, Hizawa N, Neely J, Duffy D, Freidhoff L, Ehrlich E et al. Linkage analysis of atopy to chromosome 12q markers in an Afro-Caribbean population. J Allergy Clin Immunol 1997; 99: S476.

    Google Scholar 

  22. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B et al. The structure of haplotype blocks in the human genome. Science 2002; 296: 2225–2229.

    Article  CAS  Google Scholar 

  23. Kew RR, Ghebrehiwet B, Janoff A . Characterization of the third component of complement (C3) after activation by cigarette smoke. Clin Immunol Immunopathol 1987; 44: 248–258.

    Article  CAS  Google Scholar 

  24. Maruo K, Akaike T, Ono T, Okamoto T, Maeda H . Generation of anaphylatoxins through proteolytic processing of C3 and C5 by house dust mite protease. J Allergy Clin Immunol 1997; 100: 253–260.

    Article  CAS  Google Scholar 

  25. Humbles AA, Lu B, Nilsson CA, Lilly C, Israel E, Fujiwara Y et al. A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature 2000; 406: 998–1001.

    Article  CAS  Google Scholar 

  26. Bautsch W, Hoymann HG, Zhang Q, Meier-Wiedenbach I, Raschke U, Ames RS et al. Cutting edge: guinea pigs with a natural C3a-receptor defect exhibit decreased bronchoconstriction in allergic airway disease: evidence for an involvement of the C3a anaphylatoxin in the pathogenesis of asthma. J Immunol 2000; 165: 5401–5405.

    Article  CAS  Google Scholar 

  27. Barnes KC, Neely JD, Duffy DL, Freidhoff LR, Breazeale DR, Schou C et al. Linkage of asthma and total serum IgE concentration to markers on chromosome 12q: evidence from Afro-Caribbean and Caucasian populations. Genomics 1996; 37: 41–50.

    Article  CAS  Google Scholar 

  28. Barnes KC, Freidhoff LR, Nickel R, Chiu Y-F, Juo S-H, Hizawa N et al. Dense mapping of chromosome 12q13.12–q23.3 and linkage to asthma and atopy. J Allergy Clin Immunol 1999; 104: 485–491.

    Article  CAS  Google Scholar 

  29. Barnes KC, Freidhoff LR, Horowitz EM, Mathias RA, Mulkern DM, Bonacum J et al. Physician-derived asthma diagnoses made on the basis of questionnaire data are in good agreement with interview-based diagnoses and are not affected by objective tests. J Allergy Clin Immunol 1999; 104: 791–796.

    Article  CAS  Google Scholar 

  30. Taylor JD, Briley D, Nguyen Q, Long K, Iannone MA, Li MS et al. Flow cytometric platform for high-throughput single nucleotide polymorphism analysis. Biotechniques 2001; 30: 661–666; 668–669.

    Article  CAS  Google Scholar 

  31. Horvath S, Wei E, Xu X, Palmer LJ, Bauer M . Family-based association test method: age of onset traits and covariates. Genet Epidemiol 2001; 21: S403–S408.

    Article  Google Scholar 

  32. Rabinowitz D, Laird N . A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 2000; 50: 211–223.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank all the families and volunteers who graciously participated in this study. We are especially grateful to Dr Kathryn Held, Ms Sharon Patterson, Caitlin Dorer, and Kimberly Donnelly for fieldwork, and to Drs Paul Levett, Raana Naidu, and Harold Watson for facilitating the Barbados study. We thank Robert Munford for helpful discussions and Bo Zhang, Melba Muñoz, and Pat Oldewurtel for technical assistance. This work was supported by National Institutes of Health (NIH) Grants U01 HL66583 and HL67736, and an Allergy and Asthma Foundation of America Young Investigator Award. KCB was supported in part by the Mary Beryl Patch Turnbull Scholar Program.

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Authors and Affiliations

  1. Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA

    K C Barnes, D Baltadzhieva, S Zhang, T Berg, L Shao & A Zambelli-Weiner

  2. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA

    A V Grant, M D Fallin & T H Beaty

  3. Glaxo-SmithKline, Research Triangle Park, NC, USA

    W Anderson, A Nelsen, S Pillai & D P Yarnall

  4. Division of Immunobiology, Children's Hospital Research Foundation, Children's Hospital Medical Center, Cincinnati, OH, USA

    K Dienger & M Wills-Karp

  5. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    R G Ingersoll & A F Scott

  6. Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA

    R A Mathias

  7. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA

    J G N Garcia

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  1. K C Barnes
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  9. A Nelsen
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Correspondence to K C Barnes.

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Barnes, K., Grant, A., Baltadzhieva, D. et al. Variants in the gene encoding C3 are associated with asthma and related phenotypes among African Caribbean families. Genes Immun 7, 27–35 (2006). https://doi.org/10.1038/sj.gene.6364267

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  • DOI: https://doi.org/10.1038/sj.gene.6364267

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