IL-4/IL-13 pathway genetics strongly influence serum IgE levels and childhood asthma

被引:246
作者
Kabesch, M
Schedel, M
Carr, D
Woitsch, B
Fritzsch, C
Weiland, SK
von Mutius, E
机构
[1] Univ Munich, Childrens Univ Hosp, D-80337 Munich, Germany
[2] Univ Childrens Hosp, Leipzig, Germany
[3] Univ Ulm, Dept Epidemiol, Ulm, Germany
关键词
asthma; IgE; IL-4; IL-13; pathway; polymorphism;
D O I
10.1016/j.jaci.2005.10.024
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
Background: IgE production, a hallmark of asthma and atopic disease, may be under genetic control. Genes of the IL-4 and IL-13 pathway, central for IgE regulation, have so far only been assessed in studies of single gene effects. Objective: Here we analyzed combined extended haplotypes involving IL-4, IL-13, their shared receptor chain IL-4R alpha, and the intracellular signal transducer and activator of transcription, STAT6, to assess the combined effect of single nucleotide polymorphisms in this important immunological signaling pathway. Methods: We genotyped a large cross-sectional population of 1120 children age 9 to 11 years for 18 polymorphisms in the respective genes of the IL-4/IL-13 pathway. One polymorphism per gene was selected because of its putative functional role, and extended haplotypes were built in a stepwise procedure where gene-by-gene interactions were assessed by using a Cordell model. Results: Combining polymorphisms in all 4 major pathway genes in a stepwise procedure, the risk for high serum IgE levels increased 10.8-fold (P = .02) and the risk for the development of asthma increased by a factor of 16.8-fold (P = .005) compared with the maximum effect of any single polymorphism. Significant interactions in a model with additive and dominant effects, for both pair and triplet combinations for asthma (lowest P = .005), and for pairs of polymorphisms in IgE regulation were observed (lowest P = .054). Conclusion: These data indicate that only the combined analyses of genetic alterations in the IL-4/IL-13 pathway reveal its actual significance to the development of atopy and childhood asthma.
引用
收藏
页码:269 / 274
页数:6
相关论文
共 22 条
[1]   Epistasis: what it means, what it doesn't mean, and statistical methods to detect it in humans [J].
Cordell, HJ .
HUMAN MOLECULAR GENETICS, 2002, 11 (20) :2463-2468
[2]  
Corry DB, 1999, NATURE, V402, pB18
[3]   Common polymorphisms in the coding part of the IL4-receptor gene [J].
Deichmann, K ;
Bardutzky, J ;
Forster, J ;
Heinzmann, A ;
Kuehr, J .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1997, 231 (03) :696-697
[4]   STAT6 as an asthma candidate gene:: polymorphism-screening, association and haplotype analysis in a Caucasian sib-pair study [J].
Duetsch, G ;
Illig, T ;
Loesgen, S ;
Rohde, K ;
Klopp, N ;
Herbon, N ;
Gohlke, H ;
Altmueller, J ;
Wjst, M .
HUMAN MOLECULAR GENETICS, 2002, 11 (06) :613-621
[5]  
EXCOFFIER L, 1995, MOL BIOL EVOL, V12, P921
[6]   A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children [J].
Graves, PE ;
Kabesch, M ;
Halonen, M ;
Holberg, CJ ;
Baldini, M ;
Fritzsch, C ;
Weiland, SK ;
Erickson, RP ;
von Mutius, E ;
Martinez, FD .
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2000, 105 (03) :506-513
[7]   A novel polymorphism in the 5′ promoter region of the human interleukin-4 receptor α-chain gene is associated with decreased soluble interleukin-4 receptor protein levels [J].
Hackstein, H ;
Hecker, M ;
Kruse, S ;
Bohnert, A ;
Ober, C ;
Deichmann, KA ;
Bein, G .
IMMUNOGENETICS, 2001, 53 (04) :264-269
[8]   Genetic variants of IL-13 signalling and human asthma and atopy [J].
Heinzmann, A ;
Mao, XQ ;
Akaiwa, M ;
Kreomer, RT ;
Gao, PS ;
Ohshima, K ;
Umeshita, R ;
Abe, Y ;
Braun, S ;
Yamashita, T ;
Roberts, MH ;
Sugimoto, R ;
Arima, K ;
Arinobu, Y ;
Yu, B ;
Kruse, S ;
Enomoto, T ;
Dake, Y ;
Kawai, M ;
Shimazu, S ;
Sasaki, S ;
Adra, CN ;
Kitaichi, M ;
Inoue, H ;
Yamauchi, K ;
Tomichi, N ;
Kurimoto, F ;
Hamasaki, N ;
Hopkin, JM ;
Izuhara, K ;
Shirakawa, T ;
Deichmann, KA .
HUMAN MOLECULAR GENETICS, 2000, 9 (04) :549-559
[9]   Parasites, atopy, and the hygiene hypothesis: resolution of a paradox? [J].
Holt, PG .
LANCET, 2000, 356 (9243) :1699-1701
[10]   Gene-gene interaction in asthma:: IL4RA and IL13 in a Dutch population with asthma [J].
Howard, TD ;
Koppelman, GH ;
Xu, JF ;
Zheng, SQL ;
Postma, DS ;
Meyers, DA ;
Bleecker, ER .
AMERICAN JOURNAL OF HUMAN GENETICS, 2002, 70 (01) :230-236