TY - JOUR
T1 - Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk—A re-analysis of eight GWASs
AU - Transdisciplinary Research in Cancer of the Lung (TRICL) Research Team
AU - Zhou, Fei
AU - Wang, Yanru
AU - Liu, Hongliang
AU - Ready, Neal
AU - Han, Younghun
AU - Hung, Rayjean J.
AU - Brhane, Yonathan
AU - McLaughlin, John
AU - Brennan, Paul
AU - Bickeböller, Heike
AU - Rosenberger, Albert
AU - Houlston, Richard S.
AU - Caporaso, Neil
AU - Landi, Maria Teresa
AU - Brüske, Irene
AU - Risch, Angela
AU - Ye, Yuanqing
AU - Wu, Xifeng
AU - Christiani, David C.
AU - Goodman, Gary
AU - Chen, Chu
AU - Amos, Christopher I.
AU - Wei, Qingyi
N1 - Publisher Copyright:
© 2016 Wiley Periodicals, Inc.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - Purpose: mRNA degradation is an important regulatory step for controlling gene expression and cell functions. Genetic abnormalities involved in mRNA degradation genes were found to be associated with cancer risks. Therefore, we systematically investigated the roles of genetic variants in the general mRNA degradation pathway in lung cancer risk. Experimental design: Meta-analyses were conducted using summary data from six lung cancer genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung and additional two GWASs from Harvard University and deCODE in the International Lung Cancer Consortium. Expression quantitative trait loci analysis (eQTL) was used for in silico functional validation of the identified significant susceptibility loci. Results: This pathway-based analysis included 6816 single nucleotide polymorphisms (SNP) in 68 genes in 14 463 lung cancer cases and 44 188 controls. In the single-locus analysis, we found that 20 SNPs were associated with lung cancer risk with a false discovery rate threshold of <0.05. Among the 11 newly identified SNPs in CNOT6, which were in high linkage disequilibrium, the rs2453176 with a RegulomDB score “1f” was chosen as the tagSNP for further analysis. We found that the rs2453176 T allele was significantly associated with lung cancer risk (odds ratio = 1.11, 95% confidence interval = 1.04–1.18) in the eight GWASs. In the eQTL analysis, we found that levels of CNOT6 mRNA expression were significantly correlated with the rs2453176 T allele, which provided additional biological basis for the observed positive association. Conclusion: The CNOT6 rs2453176 SNP may be a new functional susceptible locus for lung cancer risk.
AB - Purpose: mRNA degradation is an important regulatory step for controlling gene expression and cell functions. Genetic abnormalities involved in mRNA degradation genes were found to be associated with cancer risks. Therefore, we systematically investigated the roles of genetic variants in the general mRNA degradation pathway in lung cancer risk. Experimental design: Meta-analyses were conducted using summary data from six lung cancer genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung and additional two GWASs from Harvard University and deCODE in the International Lung Cancer Consortium. Expression quantitative trait loci analysis (eQTL) was used for in silico functional validation of the identified significant susceptibility loci. Results: This pathway-based analysis included 6816 single nucleotide polymorphisms (SNP) in 68 genes in 14 463 lung cancer cases and 44 188 controls. In the single-locus analysis, we found that 20 SNPs were associated with lung cancer risk with a false discovery rate threshold of <0.05. Among the 11 newly identified SNPs in CNOT6, which were in high linkage disequilibrium, the rs2453176 with a RegulomDB score “1f” was chosen as the tagSNP for further analysis. We found that the rs2453176 T allele was significantly associated with lung cancer risk (odds ratio = 1.11, 95% confidence interval = 1.04–1.18) in the eight GWASs. In the eQTL analysis, we found that levels of CNOT6 mRNA expression were significantly correlated with the rs2453176 T allele, which provided additional biological basis for the observed positive association. Conclusion: The CNOT6 rs2453176 SNP may be a new functional susceptible locus for lung cancer risk.
KW - lung cancer risk
KW - molecular epidemiology
KW - pathway analysis
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U2 - 10.1002/mc.22585
DO - 10.1002/mc.22585
M3 - Article
C2 - 27805284
AN - SCOPUS:85003702285
SN - 0899-1987
VL - 56
SP - 1227
EP - 1238
JO - Molecular Carcinogenesis
JF - Molecular Carcinogenesis
IS - 4
ER -