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

Zhao, Lingling

Liu, Hongliang

Luo, Sheng

Moorman, Patricia G

Walsh, Kyle M

Li, Wei

Wei, Qingyi

2020-12-01T14:26:54Z

2020-12-01T14:26:54Z

2020-11-16

2020-12-01T14:26:50Z

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.

2045-7634

2045-7634

https://hdl.handle.net/10161/21772

eng

Wiley

Cancer medicine

10.1002/cam4.3603

cadherin pathway

pancreatic cancer

risk analysis

single-nucleotide polymorphism

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

Journal article

Luo, Sheng|0000-0003-4214-5809

Moorman, Patricia G|0000-0002-2978-6495

Walsh, Kyle M|0000-0002-5879-9981

Wei, Qingyi|0000-0002-3845-9445|0000-0003-4115-4439

School of Medicine

Duke Cancer Institute

Population Health Sciences

Pathology

Neurosurgery

Duke

Institutes and Centers

Basic Science Departments

Clinical Science Departments

Duke Global Health Institute

Medicine, Medical Oncology

University Institutes and Centers

Institutes and Provost's Academic Units

Medicine

Duke Clinical Research Institute

Biostatistics & Bioinformatics

Published