Allelic effects onKLHL17expression likely mediated by JunB/D underlie a PDAC GWAS signal at chr1p36.33

Abstract

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 (tagged by rs13303010) 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,Pvalue=2.74×10−9) demonstrated allele-preferential gene regulatory activityin vitroand allele-preferential binding of JunB and JunDin vitroandin vivo. Expression Quantitative Trait Locus (eQTL) analysis identifiedKLHL17as 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 silicodifferential 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.