Published ahead of print on September 22, 2005, doi:10.1164/rccm.200506-890OC Am. J. Respir. Crit. Care Med., Volume 172, Number 12, December 2005, 1505-1509 A more recent version of this article appeared on December 15, 2005
Submitted on June 9, 2005 Polymorphisms and Haplotypes of Acid Mammalian Chitinase are Associated with Bronchial AsthmaSibylle Bierbaum1,1 University Children's Hospital, University of Freiburg, Freiburg, Germany, 2 Department of Pediatric Pneumonology and Immunology, Charite - Humboldt University, Berlin, Germany * To whom correspondence should be addressed. E-mail: heinzmann{at}kikli.ukl.uni-freiburg.de.
Rationale: Chitinases are enzymes which cleave chitin, a polysaccharide contained in many parasites of man. Recent studies in mouse models of bronchial asthma have shown that acid mammalian chitinase (AMCase) is involved in the pathophysiology of asthma. It acts downstream of Interleukin 13; inhibition of AMCase leads to an abrogated T-helper cell 2 inflammation, less bronchial hyperreactivity and less eosinophils. Objectives: The aim of this study was to identify common genetic variants in human AMCase and to use them to test for association of AMCase with paediatric asthma. Methods: By sequencing the promotor region and all eleven exons on 30 individuals, 12 high-frequency polymorphisms were identified. Genotyping of six variants in exons and one promotor polymorphisms was performed on the following populations by means of restriction fragment length polymorphisms: 322 children with asthma, 270 randomly chosen adult controls, and a paediatric control population consisting of 565 children who, at age 10 yrs, had never wheezed and never being diagnosed having asthma. Measurements and Main Results: We identified three known and two new amino acid variants. Analyses by the Armitage's trend test using both controls populations showed association of the newly identified variant K17R and the nearby non-coding polymorphism rs3818822 with asthma (p=0.0031 and p=0.0003, respectively). In addition haplotype analyses revealed strong association of haplotypes with the disease (asthma population versus paediatric controls p<10-10). Conclusions: This newly described association between AMCase polymorphisms and asthma adds further evidence supporting the involvement of AMCase in the development of asthma. Key words: genetic, paediatric, asthma, AMCase
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