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.

Keywords: SNP; ZAK; lung cancer risk; pathway analysis.

Figure 1.

Flowchart of SNP selection among the P38MAPK pathway genes

Figure 2.

Screening of SNPs in P38MAPKs pathway. (A) Manhattan plot of genome-wide association results of 14,904 SNPs in 108 P38MAPK pathway genes and lung cancer risk in the TRICL-ILCCO Consortium. SNPs are plotted on the X-axis according to their positions on each chromosome. The association P values with lung cancer risk are shown on the Y-axis (as -log₁₀ (P) values). The horizontal blue line represents FDR threshold 0.20. The horizontal red line represents P value of 0.05; (B) LD plots of the SNPs in ZAK with FDR < 0.20; (C) rs3769201 in ZAK with 500 kb up- and downstream of the gene region. (D) rs722864 in ZAK with 500 kb up- and downstream of the gene region. In (C) and (D), the left-hand y-axis shows the association P value of each SNP, which is plotted as -log₁₀ (P) against chromosomal base pair position; the right-hand y-axis shows the recombination rate estimated from the hg19/1000 Genomes European population.

Figure 3.

The correlations between identified SNPs and ZAK mRNA expression. A, rs3769201 in additive model, P = 2.86E-04; B, rs722864 in additive model, P = 1.68E-04.

Figure 4.

The mRNA expression of ZAK in the 109 paired lung cancer and normal adjacent tissue samples from the TCGA database (A, over all, P = 6.29E-08; B, squamous cell carcinoma, P = 0.069; C, adenocarcinoma, P = 1.55E-09).