TY - JOUR
T1 - An analysis of single nucleotide polymorphisms of 125 DNA repair genes in the Texas genome-wide association study of lung cancer with a replication for the XRCC4 SNPs
AU - Yu, Hongping
AU - Zhao, Hui
AU - Wang, Li E.
AU - Han, Younghun
AU - Chen, Wei V.
AU - Amos, Christopher I.
AU - Rafnar, Thorunn
AU - Sulem, Patrick
AU - Stefansson, Kari
AU - Landi, Maria Teresa
AU - Caporaso, Neil
AU - Albanes, Demetrius
AU - Thun, Michael
AU - McKay, James D.
AU - Brennan, Paul
AU - Wang, Yufei
AU - Houlston, Richard S.
AU - Spitz, Margaret R.
AU - Wei, Qingyi
N1 - Funding Information:
We thank Min Zhao, Jianzhong He and Kejing Xu for their laboratory assistance, and Dakai Zhu for his technical support. This study was supported in part by National Institutes of Health grants ES11740 and CA131274 (to Q.W.), CA86390 and CA55769 (to M.R.S.), CA121197 (to C.A.), and CA 16672 (to The University of Texas M. D. Anderson Cancer Center). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
PY - 2011/4/3
Y1 - 2011/4/3
N2 - DNA repair genes are important for maintaining genomic stability and limiting carcinogenesis. We analyzed all single nucleotide polymorphisms (SNPs) of 125 DNA repair genes covered by the Illumina HumanHap300 (v1.1) BeadChips in a previously conducted genome-wide association study (GWAS) of 1154 lung cancer cases and 1137 controls and replicated the top-hits of XRCC4 SNPs in an independent set of 597 cases and 611 controls in Texas populations. We found that six of 20 XRCC4 SNPs were associated with a decreased risk of lung cancer with a P-value of 0.01 or lower in the discovery dataset, of which the most significant SNP was rs10040363 (P for allelic test=4.89×10-4). Moreover, the data in this region allowed us to impute a potentially functional SNP rs2075685 (imputed P for allelic test=1.3×10-3). A luciferase reporter assay demonstrated that the rs2075685G>T change in the XRCC4 promoter increased expression of the gene. In the replication study of rs10040363, rs1478486, rs9293329, and rs2075685, however, only rs10040363 achieved a borderline association with a decreased risk of lung cancer in a dominant model (adjusted OR=0.80, 95% CI=0.62-1.03 and P=0.079). In the final combined analysis of both the Texas GWAS discovery and replication datasets, the strength of the association was increased for rs10040363 (adjusted OR=0.77, 95% CI=0.66-0.89, Pdominant=5×10-4 and P for trend=5×10-4) and rs1478486 (adjusted OR=0.82, 95% CI=0.71-0.94, Pdominant=6×10-3 and P for trend=3.5×10-3). Finally, we conducted a meta-analysis of these XRCC4 SNPs with available data from published GWA studies of lung cancer with a total of 12,312 cases and 47,921 controls, in which none of these XRCC4 SNPs was associated with lung cancer risk. It appeared that rs2075685, although associated with increased expression of a reporter gene and lung cancer risk in the Texas populations, did not have an effect on lung cancer risk in other populations. This study underscores the importance of replication using published data in larger populations.
AB - DNA repair genes are important for maintaining genomic stability and limiting carcinogenesis. We analyzed all single nucleotide polymorphisms (SNPs) of 125 DNA repair genes covered by the Illumina HumanHap300 (v1.1) BeadChips in a previously conducted genome-wide association study (GWAS) of 1154 lung cancer cases and 1137 controls and replicated the top-hits of XRCC4 SNPs in an independent set of 597 cases and 611 controls in Texas populations. We found that six of 20 XRCC4 SNPs were associated with a decreased risk of lung cancer with a P-value of 0.01 or lower in the discovery dataset, of which the most significant SNP was rs10040363 (P for allelic test=4.89×10-4). Moreover, the data in this region allowed us to impute a potentially functional SNP rs2075685 (imputed P for allelic test=1.3×10-3). A luciferase reporter assay demonstrated that the rs2075685G>T change in the XRCC4 promoter increased expression of the gene. In the replication study of rs10040363, rs1478486, rs9293329, and rs2075685, however, only rs10040363 achieved a borderline association with a decreased risk of lung cancer in a dominant model (adjusted OR=0.80, 95% CI=0.62-1.03 and P=0.079). In the final combined analysis of both the Texas GWAS discovery and replication datasets, the strength of the association was increased for rs10040363 (adjusted OR=0.77, 95% CI=0.66-0.89, Pdominant=5×10-4 and P for trend=5×10-4) and rs1478486 (adjusted OR=0.82, 95% CI=0.71-0.94, Pdominant=6×10-3 and P for trend=3.5×10-3). Finally, we conducted a meta-analysis of these XRCC4 SNPs with available data from published GWA studies of lung cancer with a total of 12,312 cases and 47,921 controls, in which none of these XRCC4 SNPs was associated with lung cancer risk. It appeared that rs2075685, although associated with increased expression of a reporter gene and lung cancer risk in the Texas populations, did not have an effect on lung cancer risk in other populations. This study underscores the importance of replication using published data in larger populations.
KW - Genetic susceptibility
KW - Genome-wide association study
KW - Replication study
KW - Variant
KW - XRCC4
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U2 - 10.1016/j.dnarep.2011.01.005
DO - 10.1016/j.dnarep.2011.01.005
M3 - Article
C2 - 21296624
AN - SCOPUS:79952703141
SN - 1568-7864
VL - 10
SP - 398
EP - 407
JO - DNA Repair
JF - DNA Repair
IS - 4
ER -