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Associations between genetic variants of KIF5B, FMN1, and MGAT3 in the cadherin pathway and pancreatic cancer risk.

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Date
2020-11-16
Authors
Zhao, Lingling
Liu, Hongliang
Luo, Sheng
Moorman, Patricia G
Walsh, Kyle M
Li, Wei
Wei, Qingyi
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Abstract
Because the cadherin-mediated signaling pathway promotes cancer progression, we assessed associations between genetic variants in 109 cadherin-related genes and risk of pancreatic cancer (PanC) by using genotyping data from publically available genome-wide association studies (GWAS) datasets comprising 15,423 individuals of European ancestry. After initial single-locus analyses and subsequent meta-analysis with multiple testing correction for 29,963 single-nucleotide polymorphisms (SNPs), 11 SNPs remained statistically significant (p < 0.05). In the stepwise logistic regression analysis, three independent PanC risk-associated SNPs (KIF5B rs211304 C > G, FMN1 rs117648907 C > T, and MGAT3 rs34943118 T > C) remained statistically significant (p < 0.05), with odds ratios of 0.89 (95% confidence interval = 0.82-0.95 and p = 6.93 × 10-4 ), 1.33 (1.13-1.56 and 2.11 × 10-4 ), and 1.11 (1.05-1.17 and 8.10 × 10-5 ), respectively. Combined analysis of unfavorable genotypes of these three independent SNPs showed an upward trend in the genotype-risk association (ptrend  < 0.001). Expression quantitative trait loci analyses indicated that the rs211304 G and rs34943118 C alleles were associated with increased mRNA expression levels of KIF5B and MGAT3, respectively (all p < 0.05). Additional bioinformatics prediction suggested that these three SNPs may affect enhancer histone marks that likely have an epigenetic effect on the genes. Our findings provide biological clues for these PanC risk-associated SNPs in cadherin-related genes in European ancestry populations, possibly by regulating the expression of the affected genes. However, our findings need to be validated in additional population, molecular and mechanistic investigations.
Type
Journal article
Subject
cadherin pathway
pancreatic cancer
risk analysis
single-nucleotide polymorphism
Permalink
https://hdl.handle.net/10161/21772
Published Version (Please cite this version)
10.1002/cam4.3603
Publication Info
Zhao, Lingling; Liu, Hongliang; Luo, Sheng; Moorman, Patricia G; Walsh, Kyle M; Li, Wei; & Wei, Qingyi (2020). Associations between genetic variants of KIF5B, FMN1, and MGAT3 in the cadherin pathway and pancreatic cancer risk. Cancer medicine. 10.1002/cam4.3603. Retrieved from https://hdl.handle.net/10161/21772.
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

Luo

Sheng Luo

Professor of Biostatistics & Bioinformatics
Moorman

Patricia Gripka Moorman

Professor Emeritus in Family Medicine and Community Health
Dr. Moorman's research focuses on the epidemiology of women's health issues. Her work includes research on ovarian cancer, breast cancer and hysterectomy. Areas of particular interest include disparities in cancer risk factors and outcomes and the effects of hysterectomy on ovarian function.  As part of the Duke Evidence Synthesis group, she has also been involved in systematic reviews and meta-analyses related to ovarian cancer, breast cancer and infertility.
Walsh

Kyle Walsh

Associate Professor in 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
Wei

Qingyi Wei

Professor in Population Health Sciences
Qingyi Wei, MD, PhD, Professor in the Department of Medicine, is Associate Director for Cancer Control and Population Sciences, Co-leader of CCPS and Co-leader of Epidemiology and Population Genomics (Focus Area 1). He is a professor of Medicine and an internationally recognized epidemiologist focused on the molecular and genetic epidemiology of head and neck cancers, lung cancer, and melanoma. His research focuses on biomarkers and genetic determinants for the DNA repair deficient phenotype and
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