Increased in vivo transcription of an IL-8 haplotype associated with respiratory syncytial virus disease-susceptibility

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Increased in vivo transcription of an IL-8 haplotype associated with respiratory syncytial virus disease-susceptibility. / Hacking, D; Knight, JC; Rockett, K; Fox, H; Frampton, Jonathan; Kwiatkowski, DP; Hull, J; Udalova, IA.

In: Genes and Immunity, Vol. 5, 15.04.2004, p. 274-82.

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Hacking, D ; Knight, JC ; Rockett, K ; Fox, H ; Frampton, Jonathan ; Kwiatkowski, DP ; Hull, J ; Udalova, IA. / Increased in vivo transcription of an IL-8 haplotype associated with respiratory syncytial virus disease-susceptibility. In: Genes and Immunity. 2004 ; Vol. 5. pp. 274-82.

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@article{7cd5652955874ba9874c15488595d6b4,
title = "Increased in vivo transcription of an IL-8 haplotype associated with respiratory syncytial virus disease-susceptibility",
abstract = "Interleukin-8 (IL-8) has been implicated in the pathogenesis of RSV-induced bronchiolitis. Previously, we have described an association between bronchiolitis disease severity and a specific IL-8 haplotype comprising six single-nucleotide polymorphisms (SNPs) (-251A/+396G/+781T/+1238delA/+1633T/+2767T, haplotype 2). Here we investigated the functional basis for this association by measuring haplotype-specific transcription in vivo in human primary cells. We found a significant increase in transcript level derived from the IL-8 haplotype 2 relative to the mirror haplotype 1 (-251T/+396T/+781C/+1238insA/+1633C/+2767A) in respiratory epithelial cells but not in lymphocytes. A promoter polymorphism, -251A, present on the high producer haplotype, had no significant affect on the allele-specific level of transcription when analyzed in reporter gene experiments in human respiratory epithelial A549 cells. We proceeded to systematically screen for allele-specific protein-DNA binding in this functional haplotype, which revealed significant differential binding at the +781T/C polymorphism. C/EBP beta was identified as being part of a transcription factor binding complex that preferentially bound in the presence of the +781 T allele. These results suggest that the mechanism for disease susceptibility to RSV-induced bronchiolitis may occur through a haplotype-specific increase in IL-8 transcription, which may be mediated by functional polymorphisms within that haplotype.",
keywords = "lung, allele-specific expression, chemokines, human",
author = "D Hacking and JC Knight and K Rockett and H Fox and Jonathan Frampton and DP Kwiatkowski and J Hull and IA Udalova",
year = "2004",
month = apr,
day = "15",
doi = "10.1038/sj.gene.6364067",
language = "English",
volume = "5",
pages = "274--82",
journal = "Genes and Immunity",
issn = "1466-4879",
publisher = "Nature Publishing Group",

}

RIS

TY - JOUR

T1 - Increased in vivo transcription of an IL-8 haplotype associated with respiratory syncytial virus disease-susceptibility

AU - Hacking, D

AU - Knight, JC

AU - Rockett, K

AU - Fox, H

AU - Frampton, Jonathan

AU - Kwiatkowski, DP

AU - Hull, J

AU - Udalova, IA

PY - 2004/4/15

Y1 - 2004/4/15

N2 - Interleukin-8 (IL-8) has been implicated in the pathogenesis of RSV-induced bronchiolitis. Previously, we have described an association between bronchiolitis disease severity and a specific IL-8 haplotype comprising six single-nucleotide polymorphisms (SNPs) (-251A/+396G/+781T/+1238delA/+1633T/+2767T, haplotype 2). Here we investigated the functional basis for this association by measuring haplotype-specific transcription in vivo in human primary cells. We found a significant increase in transcript level derived from the IL-8 haplotype 2 relative to the mirror haplotype 1 (-251T/+396T/+781C/+1238insA/+1633C/+2767A) in respiratory epithelial cells but not in lymphocytes. A promoter polymorphism, -251A, present on the high producer haplotype, had no significant affect on the allele-specific level of transcription when analyzed in reporter gene experiments in human respiratory epithelial A549 cells. We proceeded to systematically screen for allele-specific protein-DNA binding in this functional haplotype, which revealed significant differential binding at the +781T/C polymorphism. C/EBP beta was identified as being part of a transcription factor binding complex that preferentially bound in the presence of the +781 T allele. These results suggest that the mechanism for disease susceptibility to RSV-induced bronchiolitis may occur through a haplotype-specific increase in IL-8 transcription, which may be mediated by functional polymorphisms within that haplotype.

AB - Interleukin-8 (IL-8) has been implicated in the pathogenesis of RSV-induced bronchiolitis. Previously, we have described an association between bronchiolitis disease severity and a specific IL-8 haplotype comprising six single-nucleotide polymorphisms (SNPs) (-251A/+396G/+781T/+1238delA/+1633T/+2767T, haplotype 2). Here we investigated the functional basis for this association by measuring haplotype-specific transcription in vivo in human primary cells. We found a significant increase in transcript level derived from the IL-8 haplotype 2 relative to the mirror haplotype 1 (-251T/+396T/+781C/+1238insA/+1633C/+2767A) in respiratory epithelial cells but not in lymphocytes. A promoter polymorphism, -251A, present on the high producer haplotype, had no significant affect on the allele-specific level of transcription when analyzed in reporter gene experiments in human respiratory epithelial A549 cells. We proceeded to systematically screen for allele-specific protein-DNA binding in this functional haplotype, which revealed significant differential binding at the +781T/C polymorphism. C/EBP beta was identified as being part of a transcription factor binding complex that preferentially bound in the presence of the +781 T allele. These results suggest that the mechanism for disease susceptibility to RSV-induced bronchiolitis may occur through a haplotype-specific increase in IL-8 transcription, which may be mediated by functional polymorphisms within that haplotype.

KW - lung

KW - allele-specific expression

KW - chemokines

KW - human

UR - http://www.scopus.com/inward/record.url?scp=3242666120&partnerID=8YFLogxK

U2 - 10.1038/sj.gene.6364067

DO - 10.1038/sj.gene.6364067

M3 - Article

C2 - 15085176

VL - 5

SP - 274

EP - 282

JO - Genes and Immunity

JF - Genes and Immunity

SN - 1466-4879

ER -