Abstract
Bronchial asthma (BA) is a common chronic inflammatory disease characterized by hyperresponsive airways, excess mucus production, eosinophil activation, and the production of IgE. The complement system plays an immunoregulatory role at the interface of innate and acquired immunities. Recent studies have provided evidence that C3, C3a receptor, and C5 are linked to airway hyperresponsiveness. To determine whether genetic variations in the genes of the complement system affect susceptibility to BA, we screened single nucleotide polymorphisms (SNPs) in C3, C5, the C3a receptor gene (C3AR1), and the C5a receptor gene (C5R1) and performed association studies in the Japanese population. The results of this SNP case-control study suggested an association between 4896C/T in the C3 gene and atopic childhood BA (P=0.0078) as well as adult BA (P=0.010). When patient data were stratified according to elevated total IgE levels, 4896C/T was more closely associated with adult BA (P=0.0016). A patient-only association study suggested that severity of childhood BA was associated with 1526G/A of the C3AR1 gene (P=0.0057). We identified a high-risk haplotype of the C3 gene for childhood (P=0.0021) and adult BA (P=0.0058) and a low-risk haplotype for adult BA (P=0.00011). We also identified a haplotype of the C5 gene that was protective against childhood BA (P=1.4×10−6) and adult BA (P=0.00063). These results suggest that the C3 and C5 pathways of the complement system play important roles in the pathogenesis of BA and that polymorphisms of these genes affect susceptibility to BA.
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References
Barnes KC, Marsh DG (1998) The genetics and complexity of allergy and asthma. Immunol Today 19:325–332
Barrington R, Zhang M, Fischer M, Carroll MC (2001) The role of complement in inflammation and adaptive immunity. Immunol Rev 180:5–15
Bautsch W, Hoymann HG, Zhang Q, Meier-Wiedenbach I, Raschke U, Ames RS, Sohns B, Flemme N, Meyer zu Vilsendorf A, Grove M, Klos A, Kohl J (2000) 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 165:5401–5405
Brown CC (1981) The validity of approximation methods for interval estimation of the odds ratio. Am J Epidemiol 113:474–480
Burgi B, Brunner T, Dahinden CA (1994) The degradation product of the C5a anaphylatoxin C5adesarg retains basophil-activating properties. Eur J Immunol 24:1583–1589
CSGA (1997) A genome-wide search for asthma susceptibility loci in ethnically diverse populations. The collaborative study on the genetics of asthma (CSGA). Nat Genet 15:389–392
Daser A, Daheshia M, De Sanctis GT (2001) Genetics of allergen-induced asthma. J Allergy Clin Immunol 108:167–174
Drouin SM, Corry DB, Hollman TJ, Kildsgaard J, Wetsel RA (2002) Absence of the complement anaphylatoxin C3a receptor suppresses Th2 effector functions in a murine model of pulmonary allergy. J Immunol 169:5926–5933
Drouin SM, Corry DB, Kildsgaard J, Wetsel RA (2001a) Cutting edge: the absence of C3 demonstrates a role for complement in Th2 effector functions in a murine model of pulmonary allergy. J Immunol 167:4141–4145
Drouin SM, Kildsgaard J, Haviland J, Zabner J, Jia HP, McCray PB Jr, Tack BF, Wetsel RA (2001b) Expression of the complement anaphylatoxin C3a and C5a receptors on bronchial epithelial and smooth muscle cells in models of sepsis and asthma. J Immunol 166:2025–2032
el-Lati SG, Dahinden CA, Church MK (1994) Complement peptides C3a- and C5a-induced mediator release from dissociated human skin mast cells. J Invest Dermatol 102:803–806
Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12:921–927
Fujii K, Matsubara Y, Akanuma J, Takahashi K, Kure S, Suzuki Y, Imaizumi M, Iinuma K, Sakatsume O, Rinaldo P, Narisawa K (2000) Mutation detection by TaqMan-allele specific amplification: application to molecular diagnosis of glycogen storage disease type Ia and medium- chain acyl-CoA dehydrogenase deficiency. Hum Mutat 15:189–196
Gavett SH, O’Hearn DJ, Li X, Huang SK, Finkelman FD, Wills-Karp M (1995) Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice. J Exp Med 182:1527–1536
Gerard NP, Gerard C (2002) Complement in allergy and asthma. Curr Opin Immunol 14:705–708
Henson P (2000) Complementing asthma. Nat Immunol 1:190–192
Humbles AA, Lu B, Nilsson CA, Lilly C, Israel E, Fujiwara Y, Gerard NP, Gerard C (2000) A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature 406:998–1001
Karp CL, Grupe A, Schadt E, Ewart SL, Keane-Moore M, Cuomo PJ, Kohl J, Wahl L, Kuperman D, Germer S, Aud D, Peltz G, Wills-Karp M (2000) Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Nat Immunol 1:221–226
Khoury MJ (1998) Genetic epidemiology. In: Rothman KJ, Greenland S (eds) Modern epidemiology. Lippincott-Raven, Philadelphia, pp 609–622
Kohl J (2001) Anaphylatoxins and infectious and non-infectious inflammatory diseases. Mol Immunol 38:175–187
Krug N, Tschernig T, Erpenbeck VJ, Hohlfeld JM, Kohl J (2001) Complement factors C3a and C5a are increased in bronchoalveolar lavage fluid after segmental allergen provocation in subjects with asthma. Am J Respir Crit Care Med 164:1841–1843
Muller-Eberhard HJ (1988) Molecular organization and function of the complement system. Annu Rev Biochem 57:321–347
National Heart, Lung, and Blood Institute (1991) Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute. National Asthma Education Program. Expert panel report. J Allergy Clin Immunol 88:425–534
National Heart, Lung, and Blood Institute (1997) Guidelines for the diagnosis and management of ashtma. Second expert panel on the management of asthma. Publication 97-4051A
Niimi T, Munakata M, Keck-Waggoner CL, Popescu NC, Levitt RC, Hisada M, Kimura S (2002) A polymorphism in the human UGRP1 gene promoter that regulates transcription is associated with an increased risk of asthma. Am J Hum Genet 70:718–725
Niu T, Qin ZS, Xu X, Liu JS (2002) Bayesian haplotype inference for multiple linked single-nucleotide polymorphisms. Am J Hum Genet 70:157–169
Ober C, Cox NJ, Abney M, Di Rienzo A, Lander ES, Changyaleket B, Gidley H, Kurtz B, Lee J, Nance M, Pettersson A, Prescott J, Richardson A, Schlenker E, Summerhill E, Willadsen S, Parry R (1998) Genome-wide search for asthma susceptibility loci in a founder population. The collaborative study on the genetics of asthma. Hum Mol Genet 7:1393–1398
Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg L, Magnusson V, Brookes AJ, Tentler D, Kristjansdottir H, Grondal G, Bolstad AI, Svenungsson E, Lundberg I, Sturfelt G, Jonssen A, Truedsson L, Lima G, Alcocer-Varela J, Jonsson R, Gyllensten UB, Harley JB, Alarcon-Segovia D, Steinsson K, Alarcon-Riquelme ME (2002) A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 32:666–669
Reich DE, Goldstein DB (2001) Detecting association in a case-control study while correcting for population stratification. Genet Epidemiol 20:4–16
van de Graaf EA, Jansen HM, Bakker MM, Alberts C, Eeftinck Schattenkerk JK, Out TA (1992) ELISA of complement C3a in bronchoalveolar lavage fluid. J Immunol Methods 147:241–250
Wjst M, Fischer G, Immervoll T, Jung M, Saar K, Rueschendorf F, Reis A, Ulbrecht M, Gomolka M, Weiss EH, Jaeger L, Nickel R, Richter K, Kjellman NI, Griese M, von Berg A, Gappa M, Riedel F, Boehle M, van Koningsbruggen S, Schoberth P, Szczepanski R, Dorsch W, Silbermann M, Wichmann HE et al (1999) A genome-wide search for linkage to asthma. German asthma genetics group. Genomics 58:1–8
Acknowledgements
We thank all patients and their families, the volunteers who served as controls, and all staff members at the Osaka Prefectural Habikino Hospital, Miyatake Asthma Clinic, and Japanese Red Cross Society Wakayama Medical Center who participated in this study. This investigation was supported in part by grants-in-aid from The Ministry of Health, Labor and Welfare, Japan Science and Technology Corporation, and the Japanese Millennium project.
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Hasegawa, K., Tamari, M., Shao, C. et al. Variations in the C3, C3a receptor, and C5 genes affect susceptibility to bronchial asthma. Hum Genet 115, 295–301 (2004). https://doi.org/10.1007/s00439-004-1157-z
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DOI: https://doi.org/10.1007/s00439-004-1157-z