Connelly, Katelyn E.Hullin, KatherineAbdolalizadeh, EhssanZhong, JunEiser, DainaO'Brien, AidanCollins, IreneDas, SudiptoDuncan, GerardPancreatic Cancer Cohort ConsortiumPancreatic Cancer Case-Control ConsortiumChanock, Stephen J.Stolzenberg-Solomon, Rachael Z.Klein, Alison P.Wolpin, Brian M.Hoskins, Jason W.Andresson, ThorkellSmith, Jill P.Amundadottir, Laufey T.2025-06-102025-06-102025Connelly KE, Hullin K, Abdolalizadeh E, Zhong J, Eiser D, O'Brien A, et al. Allelic effects on KLHL17 expression underlie a pancreatic cancer genome-wide association signal at chr1p36.33. Nat Commun. 2025 Apr 30;16(1):4055. DOI: 10.1038/s41467-025-59109-22041-1723http://hdl.handle.net/10230/70645Pancreatic 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 chr1p36.33 (tagged by rs13303010) identified through a genome wide association study (GWAS). One of the fine-mapped SNPs, rs13303160 (OR = 1.23 (95% CI 1.15-1.32), P-value = 2.74×10-9, LD r2 = 0.93 with rs13303010 in 1000 G EUR samples) demonstrated allele-preferential gene regulatory activity in vitro and 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 with vimentin and nestin as candidate substrates for degradation in PDAC-derived cells. In silico differential gene expression analysis of high and low KLHL17 expressing GTEx pancreas samples suggested an association between lower KLHL17 levels (risk associated) and pro-inflammatory pathways. We hypothesize that KLHL17 may mitigate cell injury and inflammation by recruiting nestin and vimentin for ubiquitination and degradation thereby influencing PDAC risk.application/pdfengOpen Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-025-59109-2Cancer geneticsGene regulationGenetic variationinfo:eu-repo/semantics/openAccess