Association between common genetic variation in Cockayne syndrome A and B genes and nucleotide excision repair capacity among smokers.
Mutagen sensitivity in in vitro cultured lymphocytes challenged by benzo[a]pyrene diolepoxide (BPDE) has been validated as an intrinsic susceptibility factor for several cancers. Bulky BPDE-DNA adducts are repaired via either transcription-coupled repair or global genome nucleotide excision repair depending on the location of lesions. Cockayne syndrome A (CSA) and B (CSB) play essential roles in integrating the recognition of damage, chromatin remodeling, and the core nucleotide excision repair proteins. This study evaluated the hypothesis that common genetic variation in CSA and CSB is associated with mutagen sensitivity induced by BPDE in 276 cancer-free smokers. Tag single nucleotide polymorphisms (SNP; n = 37) selected across the entire coding and putative regulatory regions of CSA and CSB based on a high-density SNP database were genotyped by the Illumina Golden Gate assay. Major principal components of CSA and CSB that captured the linkage disequilibrium from multiple SNPs were globally associated with the number of breaks per cell at the threshold of 80% (P < or = 0.02 for both genes). Haplotype H125 in CSA and H97 in CSB as well as SNPs in high linkage disequilibrium with these two haplotypes were significantly associated with a 13% to 15% reduction in the mean number of chromatid breaks per cell (P < 0.05). A resampling-based omnibus test supported the significant association between SNPs and haplotypes in CSA and mutagen sensitivity induced by BPDE (P = 0.035). This study implicates transcription-coupled repair in protecting the cell from BPDE-induced DNA damage.
Leng
Shuguang
S
Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive South East, Albuquerque, NM 87108, USA.
Bernauer
Amanda
A
Stidley
Christine A
CA
Picchi
Maria A
MA
Sheng
Xin
X
Frasco
Melissa A
MA
Van Den Berg
David
D
Gilliland
Frank D
FD
Crowell
Richard E
RE
Belinsky
Steven A
SA
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity; D003057:Cockayne Syndrome / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D016014:Linear Models; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009152:Mutagenicity Tests; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000235:genetics*
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide