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 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 on the same locus previously reported GWAS, we performed LD analysis, SNP functional prediction and further analysis for two independent SNPs: rs3769201 and rs722864 in ZAK. 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=1.03E-05 for rs3769201; OR=0.91, 95% CI=0.88–0.95, and P=2.03E-06 for rs722864). Finally, we performed an 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 possible functional susceptibility loci for lung cancer risk.

Genetic variants in Hippo pathway genes are associated with house dust mite‐induced allergic rhinitis in a Chinese population

“…Moreover, similar results were reported by Wang et al 24 . and Feng et al 25 . Hence, the rs754466 A allele in our study increased the expression of DLG5 in whole blood, lung, and cultured fibroblasts (Figure S4).…”

Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer

“…For this investigation we extracted the genotypes of 113 genomic variants (markers) assigned to 58 genes, previously associated with the risk for LC in European decent people or one of its histological subtypes through a wide variety of approaches [ 4 – 11 ] or proxies thereof (called LC-marker ), and 296 markers assigned to 7 genes involved in Wnt signalling and listed in Bahl et al [ 25 , 26 ] and Yilmaz et al [ 27 ] (called AhR / Wnt-marker ). Thus, we focused this analysis to genes previously investigated with respect to LC.…”

“…Genome-wide association studies (GWAS) have identified dozens of susceptibility loci throughout the genome that are associated with the susceptibility to lung cancer or one of its histological subtypes [ 4 – 11 ]. Genes related to Wnt signalling, one of the key pathway regulating cell development and stemness, were not detected as being associated to LC susceptibility in individuals of European descent so far, unlike TERT (5p15.33) that was one of the first for which a robust association was observed [ 12 ].…”

Gene-gene Interaction of AhR with and within the Wnt Cascade Affects Susceptibility to Lung Cancer

“…Genome-wide association studies (GWAS) have identified dozens of susceptibility loci throughout the genome that are associated with lung cancer (LC) or one of its histological subtypes. [1][2][3][4][5][6][7][8] Genes related to Wnt signalling, one of the key pathway regulating cell development and stemness, were not detected as being associated to LC susceptibility in individuals of European descent so far, unlike TERT (5p15.33) that was one of the first for which a robust association was observed. [9] Aberrant Wnt signalling is often observed in expression profiles of many cancers, but to date no association of Wnt/Ahr genes with susceptibility to cancer of any type has been observed.…”

“…For this investigation we extracted the genotypes of 113 genomic variants (markers) assigned to 58 genes, previously robustly associated with the risk for LC or one of its histological subtypes [1][2][3][4][5][6][7][8] or proxies thereof (called LC-marker), and 296 markers assigned to 7 genes involved in Wnt signalling and listed in Bahl et al [22,23] and Yilmaz et al [24] (called AhR/Wnt-marker). Thus, we focused this analysis to genes previously investigated with respect to LC.…”