| Title: | Allelic effects on KLHL17 expression underlie a pancreatic cancer genome-wide association signal at chr1p36.33 |
| Journal: | Nature Communications |
| Published: | 30 Apr 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40307206/ |
| DOI: | https://doi.org/10.1038/s41467-025-59109-2 |
| URL: | https://www.nature.com/articles/s41467-025-59109-2.pdf |
Publication 15442
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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 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.</p>
12 Keywords
- Alleles
- Carcinoma, Pancreatic Ductal
- Cell Line, Tumor
- Gene Expression Regulation, Neoplastic
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Lectins, C-Type
- Male
- Pancreatic Neoplasms
- Polymorphism, Single Nucleotide
- Quantitative Trait Loci
17 Authors
- Katelyn E. Connelly
- Katherine Hullin
- Ehssan Abdolalizadeh
- Jun Zhong
- Daina Eiser
- Aidan O'Brien
- Irene Collins
- Sudipto Das
- Gerard Duncan
- Stephen J. Chanock
- Rachael Z. Stolzenberg-Solomon
- Alison P. Klein
- Brian M. Wolpin
- Jason W. Hoskins
- Thorkell Andresson
- Jill P. Smith
- Laufey T. Amundadottir
1 Application
| Application ID | Title |
|---|---|
| 29565 | Genetic and epidemiologic risk factors for Pancreatic Cancer |
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