BACKGROUND: Development of asthma is likely to depend on a complex interaction between environmental and genetic factors. Several groups have suggested the gene of the IL-4 receptor alpha chain (IL4R) as a candidate gene for the development of asthma, although association with single polymorphisms has shown contradicting results. OBJECTIVE: We chose to analyse IL4R gene haplotypes and assess their possible relevance in susceptibility to asthma and to certain clinical phenotypes. METHODS: IL4R gene haplotypes were analysed, based on the three markers C-3223T, Q551R and I50V, using the expectation-maximization algorithm, in 170 atopic asthma patients and 350 controls, all adult Swedish Caucasians. RESULTS: Our data showed significantly higher levels of soluble IL-4R (sIL-4R) in asthma patients compared with controls (P<0.0001). Furthermore, we showed a significant association between the IL4R haplotype containing the alleles T-3223, V50 and R551 (TVR) of the IL4R gene, and susceptibility to atopic asthma, with a frequency of 6.5% in the patients compared with 1% in the controls (P<0.0005). A subgroup of patients with heterozygous or homozygous state for the T-3223, V50 and R551 alleles, also had lower levels of sIL-4R in their circulation compared with patients with homozygous state in the C-3223, I50 and Q551 alleles (P<0.05) and showed less severe asthma according to lung function test (P<0.05). Analysis of single markers showed the T-3223 IL4R allele to associate with lower serum levels of sIL-4 receptor (P<0.0001) and patients carrying the T allele also had more symptoms of active asthma (wheezing, P<0.01; coughing, P<0.05 and breathing difficulties, P<0.01). CONCLUSION: Our data suggest that asthmatic patients with low levels of sIL-4 receptor may represent a genetically distinct subgroup of atopic asthma. TVR haplotype analyses confirm the importance of IL4R as a candidate gene for susceptibility to asthma. This finding may have implications for the understanding of the pathogenesis of asthma and possibly for the development of more specific therapies.
BACKGROUND: Development of asthma is likely to depend on a complex interaction between environmental and genetic factors. Several groups have suggested the gene of the IL-4 receptor alpha chain (IL4R) as a candidate gene for the development of asthma, although association with single polymorphisms has shown contradicting results. OBJECTIVE: We chose to analyse IL4R gene haplotypes and assess their possible relevance in susceptibility to asthma and to certain clinical phenotypes. METHODS:IL4R gene haplotypes were analysed, based on the three markers C-3223T, Q551R and I50V, using the expectation-maximization algorithm, in 170 atopic asthmapatients and 350 controls, all adult Swedish Caucasians. RESULTS: Our data showed significantly higher levels of soluble IL-4R (sIL-4R) in asthmapatients compared with controls (P<0.0001). Furthermore, we showed a significant association between the IL4R haplotype containing the alleles T-3223, V50 and R551 (TVR) of the IL4R gene, and susceptibility to atopic asthma, with a frequency of 6.5% in the patients compared with 1% in the controls (P<0.0005). A subgroup of patients with heterozygous or homozygous state for the T-3223, V50 and R551 alleles, also had lower levels of sIL-4R in their circulation compared with patients with homozygous state in the C-3223, I50 and Q551 alleles (P<0.05) and showed less severe asthma according to lung function test (P<0.05). Analysis of single markers showed the T-3223 IL4R allele to associate with lower serum levels of sIL-4 receptor (P<0.0001) and patients carrying the T allele also had more symptoms of active asthma (wheezing, P<0.01; coughing, P<0.05 and breathing difficulties, P<0.01). CONCLUSION: Our data suggest that asthmatic patients with low levels of sIL-4 receptor may represent a genetically distinct subgroup of atopic asthma. TVR haplotype analyses confirm the importance of IL4R as a candidate gene for susceptibility to asthma. This finding may have implications for the understanding of the pathogenesis of asthma and possibly for the development of more specific therapies.
Authors: Christopher S Carlson; Patrick J Heagerty; Alex S Nord; David K Pritchard; Jane Ranchalis; Joshua M Boguch; Hangjun Duan; Thomas S Hatsukami; Stephen M Schwartz; Mark J Rieder; Deborah A Nickerson; Gail P Jarvik Journal: Hum Genet Date: 2006-11-18 Impact factor: 4.132
Authors: Natalie C Battle; Shweta Choudhry; Hui-Ju Tsai; Celeste Eng; Gunjan Kumar; Kenneth B Beckman; Mariam Naqvi; Kelley Meade; H George Watson; Michael Lenoir; Esteban González Burchard Journal: Am J Respir Crit Care Med Date: 2007-02-15 Impact factor: 21.405
Authors: Sally E Wenzel; Silvana Balzar; Elizabeth Ampleford; Gregory A Hawkins; William W Busse; William J Calhoun; Mario Castro; K Fan Chung; Serpil Erzurum; Benjamin Gaston; Elliot Israel; W Gerald Teague; Douglas Curran-Everett; Deborah A Meyers; Eugene R Bleecker Journal: Am J Respir Crit Care Med Date: 2006-12-14 Impact factor: 21.405
Authors: Raffi Tachdjian; Shadi Al Khatib; Andreas Schwinglshackl; Hong Sook Kim; Andrew Chen; Julie Blasioli; Clinton Mathias; Hye Young Kim; Dale T Umetsu; Hans C Oettgen; Talal A Chatila Journal: J Allergy Clin Immunol Date: 2010-04-14 Impact factor: 10.793
Authors: Raffi Tachdjian; Clinton Mathias; Shadi Al Khatib; Paul J Bryce; Hong S Kim; Frank Blaeser; Brian D O'Connor; Danuta Rzymkiewicz; Andrew Chen; Michael J Holtzman; Gurjit K Hershey; Holger Garn; Hani Harb; Harald Renz; Hans C Oettgen; Talal A Chatila Journal: J Exp Med Date: 2009-09-21 Impact factor: 14.307