Allelic effects on KLHL17 expression likely mediated by JunB/D underlie a PDAC GWAS signal at chr1p36.33
Connelly, K. E.; Hullin, K.; Abdolalizadeh, E.; Zhong, J.; Eiser, D.; O'Brien, A.; Collins, I.; Das, S.; Duncan, G.; Pancreatic Cancer Cohort Consortium, ; Pancreatic Cancer Case-Control Consortium, ; Chanock, S.; Stolzenberg-Solomon, R. Z.; Klein, A.; Wolpin, B. M.; Hoskins, J. W.; Andresson, T.; Smith, J. P.; Amundadottir, L. T.
Show 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, 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.
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