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Feng, Y.* ; Wang, Y.* ; Liu, H.* ; Liu, Z.* ; Mills, C.* ; Owzar, K.* ; Xie, J.* ; Han, Y.* ; Qian, D.C.* ; Rj, R.J.H.* ; Brhane, Y.* ; McLaughlin, J.* ; Brennan, P.* ; Bickeböller, H.* ; Rosenberger, A.* ; Houlston, R.S.* ; Caporaso, N.* ; Landi, M.T.* ; Brüske, I. ; Risch, A.* ; Ye, Y.* ; Wu, X.* ; Christiani, D.C.* ; Amos, C.I.* ; Wei, Q.*

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

Mol. Carcinog. 57, 216-224 (2018)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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 (1,319 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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Snp ; Zak ; Lung Cancer Risk ; Pathway Analysis; Genome-wide Association; Functional Variation; Risk; Kinase; P38; Protein; Metaanalysis; Activation; Stress; Jnk
ISSN (print) / ISBN 0899-1987
e-ISSN 1098-2744
Journal Molecular Carcinogenesis
Quellenangaben Volume: 57, Issue: 2, Pages: 216-224 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Hoboken
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)