Published ahead of print on January 25, 2007, doi:10.1164/rccm.200609-1286OC
© 2007 American Thoracic Society doi: 10.1164/rccm.200609-1286OC
Association Analysis of CD40 Polymorphisms with Asthma and the Level of Serum Total IgE1 Genome Research Center for Allergy and Respiratory Diseases, Soonchunhyang University Hospital, Jung Dong, Wonmi Ku, Bucheon, Gyeonggi Do, Republic of Korea; 2 Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul, Republic of Korea; and 3 Division of Molecular and Life Science, The College of Science and Technology, Hanyang University, Sangrok Ku, Ansan, Gyeonggi Do, Republic of Korea Correspondence and requests for reprints should be addressed to Choon-Sik Park, M.D., Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, 1174, Jung-Dong, Wonmi-Ku, Bucheon, Kyeonggi-Do, 420-020, Korea. E-mail: mdcspark{at}unitel.co.kr Rationale: The CD40 protein plays important roles in cell-mediated and humoral immune responses, especially in immunoglobulin class-switching to IgE. Objectives: We tested the association of CD40 polymorphisms with the risk of asthma and the level of serum IgE and investigated the functional effect of associated polymorphisms on the expression of CD40. Methods: We identified 17 CD40 single-nucleotide polymorphisms (SNPs) in the Korean population by direct sequencing, and we genotyped 7 of these in 487 subjects with asthma and in 161 normal subjects. Cell-surface expression of CD40 for B-cell lines of various SNP genotypes was measured using flow cytometry. The effects of SNPs in the promoter and 5'-untranslated regions (UTRs) of CD40 were assessed using pGL3 luciferase and enhanced green fluorescent protein (EGFP) reporter systems, respectively.
Measurements and Results: None of the SNPs was associated with asthma risk, but total serum IgE levels were associated with the –580G>A and –1C>T polymorphisms in subjects with asthma (p = 0.007 and 0.005, respectively). The total amount of IgE was highest in the –580A or –1C homozygotes. More CD40 was expressed in B cells with the –1C allele than in those with the –1T allele (p < 0.001). EGFP expression from the CD40 5'-UTR–EGFP construct was higher for the –1C allele than the –1T allele. The –580G>A SNP did not affect promoter activity, even after IFN- Conclusions: CD40 gene polymorphisms exert a genetic effect on IgE production in patients with asthma through translational regulation of CD40 expression on B cells.
Key Words: CD40 • single nucleotide polymorphisms • asthma • IgE
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