Browsing by Subject "risk analysis"

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    Associations between genetic variants of KIF5B, FMN1, and MGAT3 in the cadherin pathway and pancreatic cancer risk.
    (Cancer medicine, 2020-11-16) Zhao, Lingling; Liu, Hongliang; Luo, Sheng; Moorman, Patricia G; Walsh, Kyle M; Li, Wei; Wei, Qingyi
    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.
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    Associations of novel variants in PIK3C3, INSR and MAP3K4 of the ATM pathway genes with pancreatic cancer risk.
    (American journal of cancer research, 2020-01) Zhao, Ling-Ling; Liu, Hong-Liang; Luo, Sheng; Walsh, Kyle M; Li, Wei; Wei, Qingyi
    The ATM serine/threonine kinase (ATM) pathway plays important roles in pancreatic cancer (PanC) development and progression, but the roles of genetic variants of the genes in this pathway in the etiology of PanC are unknown. In the present study, we assessed associations between 31,499 single nucleotide polymorphisms (SNPs) in 198 ATM pathway-related genes and PanC risk using genotyping data from two previously published PanC genome-wide association studies (GWASs) of 15,423 subjects of European ancestry. In multivariable logistic regression analysis, we identified three novel independent SNPs to be significantly associated with PanC risk [PIK3C3 rs76692125 G>A: odds ratio (OR)=1.26, 95% confidence interval (CI)=1.12-1.43 and P=2.07×10-4, INSR rs11668724 G>A: OR=0.89, 95% CI=0.84-0.94 and P=4.21×10-5 and MAP3K4 rs13207108 C>T: OR=0.83, 95% CI=0.75-0.92, P=2.26×10-4]. The combined analysis of these three SNPs exhibited an increased PanC risk in a dose-response manner as the number of unfavorable genotypes increased (P trend<0.0001). The risk-associated rs76692125 A allele was correlated with decreased PIK3C3 mRNA expression levels, while the protective-associated rs11668724 A allele was correlated with increased INSR mRNA expression levels, but additional mechanistic studies of these SNPs are warranted. Once validated, these SNPs may serve as biomarkers for PanC risk in populations of European ancestry.