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.
Type
Journal articleSubject
HumansLung Neoplasms
Genetic Predisposition to Disease
Protein Kinases
p38 Mitogen-Activated Protein Kinases
Risk
Genotype
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Genome-Wide Association Study
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https://hdl.handle.net/10161/18517Published Version (Please cite this version)
10.1002/mc.22748Publication Info
Feng, Yun; Wang, Yanru; Liu, Hongliang; Liu, Zhensheng; Mills, Coleman; Owzar, Kouros;
... Wei, Qingyi (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.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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Show full item recordScholars@Duke
Zhensheng Liu
Assistant Professor of Medicine
Kouros Owzar
Professor of Biostatistics & Bioinformatics
cancer pharmacogenomicsdrug induced neuropathy, neutropenia and hypertensionstatistical
genetics statistical methods for high-dimensional data copulas survival analysis statistical
computing
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
Jichun Xie
Associate Professor of Biostatistics & Bioinformatics
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