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Novel genetic variants in the P38MAPK pathway gene ZAK and susceptibility to lung cancer
Author(s) -
Feng Yun,
Wang Yanru,
Liu Hongliang,
Liu Zhensheng,
Mills Coleman,
Owzar Kouros,
Xie Jichun,
Han Younghun,
Qian David C.,
Hung RJ Rayjean J.,
Brhane Yonathan,
McLaughlin John,
Brennan Paul,
Bickeböller Heike,
Rosenberger Albert,
Houlston Richard S.,
Caporaso Neil,
Landi Maria Teresa,
Brüske Irene,
Risch Angela,
Ye Yuanqing,
Wu Xifeng,
Christiani David C.,
Amos Christopher I.,
Wei Qingyi
Publication year - 2018
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22748
Subject(s) - single nucleotide polymorphism , biology , genome wide association study , expression quantitative trait loci , lung cancer , carcinogenesis , genetics , gene , locus (genetics) , genetic association , quantitative trait locus , oncology , genotype , medicine
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.