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Long-Range Modulation of PAG1 Expression by 8q21 Allergy Risk Variants.

Abstract：

:The gene(s) whose expression is regulated by allergy risk variants is unknown for many loci identified through genome-wide association studies. Addressing this knowledge gap might point to new therapeutic targets for allergic disease. The aim of this study was to identify the target gene(s) and the functional variant(s) underlying the association between rs7009110 on chromosome 8q21 and allergies. Eight genes are located within 1 Mb of rs7009110. Multivariate association analysis of publicly available exon expression levels from lymphoblastoid cell lines (LCLs) identified a significant association between rs7009110 and the expression of a single gene, PAG1 (p = 0.0017), 732 kb away. Analysis of histone modifications and DNase I hypersensitive sites in LCLs identified four putative regulatory elements (PREs) in the region. Chromosome conformation capture confirmed that two PREs interacted with the PAG1 promoter, one in allele-specific fashion. To determine whether these PREs were functional, LCLs were transfected with PAG1 promoter-driven luciferase reporter constructs. PRE3 acted as a transcriptional enhancer for PAG1 exclusively when it carried the rs2370615:C allergy predisposing allele, a variant in complete linkage disequilibrium with rs7009110. As such, rs2370615, which overlaps RelA transcription factor (TF) binding in LCLs and was found to disrupt Foxo3a binding to PRE3, represents the putative functional variant in this locus. Our studies suggest that the risk-associated allele of rs2370615 predisposes to allergic disease by increasing PAG1 expression, which might promote B cell activation and have a pro-inflammatory effect. Inhibition of PAG1 expression or function might have therapeutic potential for allergic diseases.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Vicente CT,Edwards SL,Hillman KM,Kaufmann S,Mitchell H,Bain L,Glubb DM,Lee JS,French JD,Ferreira MA

doi

10.1016/j.ajhg.2015.06.010

subject

Has Abstract

pub_date

2015-08-06 00:00:00

pages

329-36

issue

2

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(15)00246-3

journal_volume

97

pub_type

杂志文章

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