title: Tagging single nucleotide polymorphisms in phosphoinositide-3-kinase-related protein kinase genes involved in DNA damage "checkpoints" and lung cancer susceptibility.
abstract: OBJECTIVE
  DNA damage checkpoints are initiated by its sensor proteins of the phosphoinositide-3-kinase-related protein kinase family, including ataxia-telangiectasia mutated, ataxia-telangiectasia and Rad3-related, and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). We hypothesized that polymorphisms in these genes may alter the regulation of DNA repair and the risk of lung cancer.
  
  
  METHODS
  We genotyped 12 tagging single nucleotide polymorphisms (tSNP) in these three phosphoinositide-3-kinase-related protein kinase genes in 500 incident lung cancer cases and 517 controls in a Chinese population by using the Illumina SNP genotyping BeadLab platform.
  
  
  RESULTS
  Single locus analyses revealed that some of the heterozygotes or variant homozygotes of DNA-PKcs tSNPs were associated with decreased risks of lung cancer compared with their wild-type homozygotes. In the combined analyses of two tSNPs (rs8178085 and rs12334811) with approaching dose-dependent effect on lung cancer predisposition, subjects carrying two to four risk genotypes were associated with a 43% decreased lung cancer risk compared with subjects carrying zero to one risk genotypes (adjusted odds ratio, 0.53; 95% confidence interval, 0.35-0.80). Moreover, the decreased risk associated with the combined genotypes of rs8178085 and rs12334811 was slightly more pronounced in nonsmokers and in carriers with ataxia-telangiectasia mutated rs228591 variant allele or ataxia-telangiectasia and Rad3-related rs6782400 wild-type homozygous genotype.
  
  
  CONCLUSIONS
  These results indicate, for the first time, that tSNPs in DNA-PKcs may play a protective role in lung cancer development.
authors.affiliation: Department of Epidemiology and Biostatistics, Cancer Research Center of Nanjing Medical University, Nanjing, China.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Hu
authors.forename: Hongliang
authors.initials: H
authors.lastname: Liu
authors.forename: Haifeng
authors.initials: H
authors.lastname: Wang
authors.forename: Ruifen
authors.initials: R
authors.lastname: Miao
authors.forename: Weiwei
authors.initials: W
authors.lastname: Sun
authors.forename: Guangfu
authors.initials: G
authors.lastname: Jin
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Hongxia
authors.initials: H
authors.lastname: Ma
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
authors.forename: Daru
authors.initials: D
authors.lastname: Lu
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Hongbing
authors.initials: H
authors.lastname: Shen
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D002681:China; D004249:DNA Damage / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011494:Protein Kinases / Q000235:genetics*
chemical_list: D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases