Open AccessAssociations between genetic variants of KIF5B , FMN1 , and MGAT3 in the cadherin pathway and pancreatic cancer risk
Author(s) -
Zhao Lingling,
Liu Hongliang,
Luo Sheng,
Moorman Patricia G.,
Walsh Kyle M.,
Li Wei,
Wei Qingyi
Publication year - 2020
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.3603
Subject(s) - single nucleotide polymorphism , genome wide association study , odds ratio , genetics , genotyping , biology , epigenetics , genotype , expression quantitative trait loci , quantitative trait locus , genetic association , allele , mlh1 , locus (genetics) , gene , bioinformatics , medicine , dna mismatch repair , dna repair
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 ( p trend < 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.