Genetic variation in the promoter region of chitinase 3-like 1 is associated with atopy.
BACKGROUND
Atopy or atopic syndrome is an allergic hypersensitivity subject to hereditary influences. Aberrant expression of chitinase 3-like 1 (CHI3L1), also known as YKL-40 or HC gp-39, is involved in the pathogenesis of inflammatory and allergic diseases.


OBJECTIVE
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.


RESULTS
In the case-control association analysis, the g.-247C/T polymorphism at the promoter region (rs10399805; 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.
Sohn
Myung Hyun
MH
Department of Pediatrics and Institute of Allergy, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
Lee
Ji Hyun
JH
Kim
Kyung Won
KW
Kim
So Won
SW
Lee
Sung Hee
SH
Kim
Kyu-Earn
KE
Kim
Kyung Hwan
KH
Lee
Chun Geun
CG
Elias
Jack A
JA
Lee
Min Goo
MG
D054392:Adipokines; D022762:CCAAT-Enhancer-Binding Proteins; D016022:Case-Control Studies; D002648:Child; D000071451:Chitinase-3-Like Protein 1; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005838:Genotype; D006023:Glycoproteins / Q000097:blood / Q000235:genetics*; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics*; D007073:Immunoglobulin E / Q000097:blood; D007723:Korea; D037102:Lectins; D008297:Male; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors
D054392:Adipokines; D022762:CCAAT-Enhancer-Binding Proteins; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D006023:Glycoproteins; D037102:Lectins; D012333:RNA, Messenger; D007073:Immunoglobulin E