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Genetic variants in the liver kinase B1-AMP-activated protein kinase pathway genes and pancreatic cancer risk.

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Date
2019-04-17
Authors
Xu, Xinyuan
Qian, Danwen
Liu, Hongliang
Cruz, Diana
Luo, Sheng
Walsh, Kyle M
Abbruzzese, James L
Zhang, Xuefeng
Wei, Qingyi
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Abstract
The liver kinase B1-AMP-activated protein kinase (LKB1-AMPK) pathway has been identified as a new target for cancer therapy, because it controls the glucose and lipid metabolism in response to alterations in nutrients and intracellular energy levels. In the present study, we aimed to identify genetic variants of the LKB1-AMPK pathway genes and their associations with pancreatic cancer (PanC) risk using 15 418 participants of European ancestry from two previously published PanC genome-wide association studies. We found that six novel tagging single-nucleotide polymorphisms (SNPs) (i.e, MAP2 rs35075084 T > deletion, PRKAG2 rs2727572 C > T and rs34852782 A > deletion, TP53 rs9895829 A > G, and RPTOR rs62068300 G > A and rs3751936 G > C) were significantly associated with an increased PanC risk. The multivariate logistic regression model incorporating the number of unfavorable genotypes (NUGs) with adjustment for age and sex showed that carriers with five to six NUGs had an increased PanC risk (odds ratio = 1.24, 95% confidence interval = 1.16-1.32 and P < 0.0001), compared to those with zero to four NUGs. Subsequent expression quantitative trait loci (eQTL) analysis further revealed that these SNPs were associated with significantly altered mRNA expression levels either in 373 normal lymphoblastoid cell lines (TP53 SNP rs9895829, P < 0.05) or in whole blood cells of 369 normal donors from the genotype-tissue expression project (GTEx) database [RPTOR SNP rs60268947 and rs28434589, both in high linkage disequilibrium (r2  > 0.9) withRPTOR rs62068300, P < 0.001]. Collectively, our findings suggest that these novel SNPs in the LKB1-AMPK pathway genes may modify susceptibility to PanC, possibly by influencing gene expression.
Type
Journal article
Subject
genome-wide association study
pancreatic cancer risk
single-nucleotide polymorphism (SNP)
Permalink
https://hdl.handle.net/10161/18472
Published Version (Please cite this version)
10.1002/mc.23018
Publication Info
Xu, Xinyuan; Qian, Danwen; Liu, Hongliang; Cruz, Diana; Luo, Sheng; Walsh, Kyle M; ... Wei, Qingyi (2019). Genetic variants in the liver kinase B1-AMP-activated protein kinase pathway genes and pancreatic cancer risk. Molecular carcinogenesis. 10.1002/mc.23018. Retrieved from https://hdl.handle.net/10161/18472.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Abbruzzese

James Abbruzzese

D. C. I. Distinguished Professor of Medical Oncology
My research interests include the clinical study and treatment of pancreatic cancer.
Luo

Sheng Luo

Professor of Biostatistics & Bioinformatics
Walsh

Kyle Walsh

Associate Professor of Neurosurgery
Dr. Walsh is Associate Professor of Neurosurgery and Pathology, Director of the Division of Neuro-epidemiology, and a Senior Fellow in the Duke Center for the Study of Aging and Human Development. He leads Duke’s Neuro-epidemiology Lab, which integrates bench science with statistical methods to study the neurobiology of glial senescence and gliomagenesis. This research interrogates human genomic and epigenomic profiles to identify both heritable and modifiable factors that contribute to ne
Zhang

Xuefeng Zhang

Adjunct Associate Professor in the Department of Pathology
Alphabetical list of authors with Scholars@Duke profiles.
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