Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 179, Issue 6, Pages 449-456Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.200809-1422OC
Keywords
chitinase-like proteins; genetic association; YKL-40; hypersensitivity
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Funding
- Korea Health 21 R&D Project, Ministry of Health and Welfare, Korea [A030001]
- Korea Research Foundation, Korea [KRF-2008-013-E00032]
- National Research Foundation of Korea [2008-013-E00032] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Rationale Atopy or atopic syndrome is an allergic hypersensitivity subject to hereditary influences. Aberrant expression of chitinase 3-like I (CHI3L1), also known as YKL-40 or HC gp-39, is involved in the pathogenesis of inflammatory and allergic diseases. Objectives: The genetic contribution of CHI3L1 gene to atopic susceptibility was investigated using an integrated population genetic and molecular analysis. Methods: Genetic variations in CHI3L1 were identified and genotyped in 295 unrelated patients with atopy and 180 control subjects. Serum YKL-40 and IgE levels were analyzed according to genotype. The effects of a promoter polymorphism (g.-247C/T) on promoter activity were examined in reporter and protein binding assays. Measurements and Main Results: In the case-control association analysis, the g.-247C/T polymorphism at the promoter region (rsl 0399805; P = 0.0062) and the IVS7+82C/T polymorphism at intron 7 (rs2275353; P = 0.0056) of CHI3L1 showed a significant association with atopy. Subjects with the g.-247T risk allele had significantly higher serum YKL-40 (P < 0.0001) and IgE (P = 0.012) levels. An in vitro promoter assay using THP-1 human monocyte cells revealed that the C to T conversion at g.-247 induced a more than twofold increase of reporter gene expression. Moreover, the g.-247T allele showed an increased affinity for CCAAT enhancer-binding protein, a well known transcriptional activator, by electrophoretic mobility shift assay. Accordingly, subjects with the g.-247TT genotype showed a 2.5-fold increase in CHI3L1 mRNA expression in peripheral blood cells compared with those with the g.-247CC genotype. Conclusions: These results strongly suggest that the g.-247C/T polymorphism in the CHI3L1 promoter region is associated with the risk of atopy.
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