MassIVE MSV000096025

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Allelic effects on KLHL17 expression likely mediated by JunB/D underlie a PDAC GWAS signal at chr1p36.33

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Description

Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the U.S. Both rare and common germline variants contribute to PDAC risk. Here, we fine-map and functionally characterize a common PDAC risk signal at 1p36.33 identified through a genome wide association study (GWAS). One of the fine-mapped SNPs, rs13303160 (r2=0.93 in 1000G EUR samples, OR=1.23, P value=2.74x10-9) demonstrated allele-preferential gene regulatory activity in vitro and allele-preferential binding of JunB and JunD in vitro and in vivo. Expression Quantitative Trait Locus (eQTL) analysis identified KLHL17 as a likely target gene underlying the signal. Proteomic analysis identified KLHL17 as a member of the Cullin-E3 ubiquitin ligase complex in PDAC-derived cells. In silico differential gene expression analysis of the GTExv8 pancreas data suggested an association between lower KLHL17 (risk associated) and pro-inflammatory pathways. We hypothesize that KLHL17 may mitigate inflammation by recruiting pro-inflammatory proteins for ubiquitination and degradation thereby influencing PDAC risk. [doi:10.25345/C5930P65Q] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: KLHL17, functional genetics, GWAS, (pancreatic) cancer

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Principal Investigators:
(in alphabetical order) 		Laufey Anumdadottir, NCI/DCEG, United States
Submitting User: ronholes7059
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