Published ahead of print on January 25, 2007, doi:10.1164/rccm.200609-1286OC Am. J. Respir. Crit. Care Med., Volume 175, Number 8, April 2007, 775-782 A more recent version of this article appeared on April 15, 2007
Submitted on September 11, 2006 Association Analysis of CD40 Polymorphisms with Asthma and The Level of Serum Total IgEJu Hyun Park1,1 Genome Research Center for Allergy and Respiratory Diseases, Soonchunhyang University Hospital, Bucheon, Gyeonggi Do, Korea, Republic of, 2 Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul, Korea, Republic of, 3 Division of Molecular and Life Science, Hanyang University, The College of Science and Technology, Ansan, Gyeonggi Do, Korea, Republic of * To whom correspondence should be addressed. E-mail: mdcspark{at}unitel.co.kr.
Rationale; The CD40 protein plays important roles in both 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 SNPs in the Korean population by direct sequencing, and we genotyped seven of these in 487 asthmatic and 161 normal subjects. Cell-surface expression of CD40 for B-cell lines of various SNP genotypes was measured using flow cytometry. In addition, the effects of SNPs in the promoter and 5'-UTR regions of CD40 were assessed using pGL3 luciferase and pEGFP reporter systems, respectively.
Measurements and Results; None of the SNPs were associated with asthma risk, but total serum IgE levels were associated with the -580G >A and -1C>T polymorphisms in asthmatics (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'-UTREGFP construct was higher for the -1C allele than the -1T allele. The -580G >A SNP did not affect promoter activity, even after IFN- Key words: CD40, Single nucleotide polymirphisms, Asthma, IgE
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stimulation.
Conclusions; CD40 gene polymorphisms exert a genetic effect on IgE production in asthmatics through translational regulation of CD40 expression on B cells.
