title: 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.
abstract: 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 x 10⁻⁴). Moreover, the data in this region allowed us to impute a potentially functional SNP rs2075685 (imputed P for allelic test=1.3 x 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, P(dominant)=5 x 10⁻⁴ and P for trend=5 x 10⁻⁴) and rs1478486 (adjusted OR=0.82, 95% CI=0.71-0.94, P(dominant)=6 x 10⁻³ and P for trend=3.5 x 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.
authors.affiliation: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hongping
authors.initials: H
authors.lastname: Yu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.forename: Li-E
authors.initials: LE
authors.lastname: Wang
authors.forename: Younghun
authors.initials: Y
authors.lastname: Han
authors.forename: Wei V
authors.initials: WV
authors.lastname: Chen
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Thorunn
authors.initials: T
authors.lastname: Rafnar
authors.forename: Patrick
authors.initials: P
authors.lastname: Sulem
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Landi
authors.forename: Neil
authors.initials: N
authors.lastname: Caporaso
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.forename: Michael
authors.initials: M
authors.lastname: Thun
authors.forename: James D
authors.initials: JD
authors.lastname: McKay
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Yufei
authors.initials: Y
authors.lastname: Wang
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Spitz
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013781:Texas
chemical_list: D004268:DNA-Binding Proteins; C101467:XRCC4 protein, human