A single nucleotide polymorphism on the promoter of eotaxin1 associates with its mRNA expression and asthma phenotypes.
Eotaxin1 plays a pivotal role in eosinophil-associated inflammation. Previously, we demonstrated 14 single-nucleotide polymorphisms (SNPs) in the human eotaxin1 gene and the association between the EOT+67G>A allele and the level of IgE. In this study, we investigated the association between the SNPs and plasma eotaxin1 levels, peripheral blood eosinophil counts, and PC20 methacholine values in normal and asthmatic subjects, and the effects of SNPs on the process of eotaxin1 production. The EOT-576C>T and EOT-384A>G polymorphisms and haplotypes (ht1 and ht4) were significantly associated with plasma eotaxin1 levels in the asthmatics (p < 0.001-0.040). The log [plasma eotaxin1] values correlated with the log [serum total IgE] values in the asthmatics and the normal controls (p = 0.012 and p = 0.004, respectively), and with the log [PC20 methacholine] values in the asthmatics (p = 0.014). A DNA-protein complex was formed with EOT-384A>G, but not with the other SNPs of the promoter. The interaction was stronger with the minor allele than with the common allele, and was reduced upon TNF-alpha exposure. TNF-alpha-stimulated PBMCs from the asthmatics with the minor allele homozygote expressed significantly lower levels of eotaxin1 mRNA than those from individuals with the common allele. The EOT+67G>A polymorphism, which substitutes alanine with threonine, did not affect eotaxin1 production or activity. Our data suggest that the EOT-384A>G SNP participates in the regulation of eotaxin1 expression by providing a potential binding site for a repressor, and that the ANOVA of EOT-384A>G may predict asthma phenotypes.
Chang
Hun Soo
HS
Division of Molecular and Life Sciences, Hanyang University, Ansan, Gyeonggi-do, Korea.
Kim
Jung Sun
JS
Lee
June Hyuk
JH
Cho
Jung Il
JI
Rhim
Tai Youn
TY
Uh
Soo-Taek
ST
Park
Byung Lae
BL
Chung
Il Yup
IY
Park
Choon-Sik
CS
Shin
Hyoung Doo
HD
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics; D001249:Asthma / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D001665:Binding Sites / Q000235:genetics; D001985:Bronchial Provocation Tests; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics*; D004804:Eosinophils / Q000166:cytology; D005260:Female; D006239:Haplotypes; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood*; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis*; D013912:Threonine / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C515456:CCL11 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D012333:RNA, Messenger; D014157:Transcription Factors; D013912:Threonine; D007073:Immunoglobulin E; D000409:Alanine