Novel genetic variants in the P38MAPK pathway gene ZAK and susceptibility to lung cancer.

Abstract

The P38MAPK pathway participates in regulating cell cycle, inflammation, development, cell death, cell differentiation, and tumorigenesis. Genetic variants of some genes in the P38MAPK pathway are reportedly associated with lung cancer risk. To substantiate this finding, we used six genome-wide association studies (GWASs) to comprehensively investigate the associations of 14 904 single nucleotide polymorphisms (SNPs) in 108 genes of this pathway with lung cancer risk. We identified six significant lung cancer risk-associated SNPs in two genes (CSNK2B and ZAK) after correction for multiple comparisons by a false discovery rate (FDR) <0.20. After removal of three CSNK2B SNPs that are located in the same locus previously reported by GWAS, we performed the LD analysis and found that rs3769201 and rs7604288 were in high LD. We then chose two independent representative SNPs of rs3769201 and rs722864 in ZAK for further analysis. We also expanded the analysis by including these two SNPs from additional GWAS datasets of Harvard University (984 cases and 970 controls) and deCODE (1319 cases and 26 380 controls). The overall effects of these two SNPs were assessed using all eight GWAS datasets (OR = 0.92, 95%CI = 0.89-0.95, and P = 1.03 × 10-5 for rs3769201; OR = 0.91, 95%CI = 0.88-0.95, and P = 2.03 × 10-6 for rs722864). Finally, we performed an expression quantitative trait loci (eQTL) analysis and found that these two SNPs were significantly associated with ZAK mRNA expression levels in lymphoblastoid cell lines. In conclusion, the ZAK rs3769201 and rs722864 may be functional susceptibility loci for lung cancer risk.

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Citation

Published Version (Please cite this version)

10.1002/mc.22748

Publication Info

Feng, Yun, Yanru Wang, Hongliang Liu, Zhensheng Liu, Coleman Mills, Kouros Owzar, Jichun Xie, Younghun Han, et al. (2018). Novel genetic variants in the P38MAPK pathway gene ZAK and susceptibility to lung cancer. Molecular carcinogenesis, 57(2). pp. 216–224. 10.1002/mc.22748 Retrieved from https://hdl.handle.net/10161/18517.

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Scholars@Duke

Owzar

Kouros Owzar

Professor of Biostatistics & Bioinformatics

cancer pharmacogenomics
drug induced neuropathy, neutropenia and hypertension
statistical genetics
statistical methods for high-dimensional data
copulas
survival analysis
statistical computing

Xie

Jichun Xie

Associate Professor of Biostatistics & Bioinformatics
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 variations in cell death. He is Editor-in-Chief of the open access journal "Cancer Medicine" and Associate Editor-in-Chief of the International Journal of Molecular Epidemiology and Genetics.

Area of Expertise: Epidemiology


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