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A Polymorphism Affecting MYB Binding within the Promoter of the PDCD4 Gene is Associated with Severe Asthma in Children
Author(s) -
Binia Aristea,
Van Stiphout Nicole,
Liang Liming,
Michel Sven,
Bhavsar Pankaj K.,
Fan Chung K.,
Brightling Chris E.,
Barnes Peter J.,
Kabesch Michael,
Bush Andrew,
Cookson William O.C.,
Moffatt Miriam F.
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22340
Subject(s) - single nucleotide polymorphism , myb , biology , asthma , promoter , gene , transcription factor , proband , immunoglobulin e , genetics , immunology , genome wide association study , genotype , gene expression , antibody , mutation
A previous genome‐wide association study in asthma revealed putative associations that merit further investigation. In this study, the genome‐wide significant associations of SNP s at the 5% false discovery rate were examined in independent groups of severe asthmatics. The panel consisted of 397 severe asthmatic adults, 116 severe asthmatic children, and a collection of 207 family‐trios with an asthmatic proband. Three SNP s in the PDCD4 gene ( rs6585018:G>A , rs1322997:C>A , and rs34104444:G>A ) were significantly associated with severe childhood asthma ( P values: 0.003, 0.002, 0.004) and total immunoglobulin E (IgE) levels ( P values: 0.034, 0.041, 0.052). In an independent group of 234 asthmatic children and 652 controls, PDCD4 SNPs rs1407696:T>G and rs11195360:T>C were associated with total IgE levels ( P values: 0.006, 0.014). In silico analysis of PDCD4 locus showed that rs6585018:G>A had the potential to affect MYB transcription factor binding, shown to act as a PDCD 4‐transcription inducer. Electromobility shift assays and reporter assays revealed that rs6585018:G>A alters MYB binding thereby influencing the expression of PDCD 4. SNP s within MYB itself confer susceptibility to eosinophilia and asthma. Our association between a variant MYB binding site in PDCD4 and the severest form of childhood asthma therefore suggests that PDCD 4 is a novel molecule of importance to asthmatic inflammatory responses.