From genotype to phenotype: correlating XRCC1 polymorphisms with mutagen sensitivity.
This study correlated the extent of induced in vitro chromosomal damage, assessed by the mutagen sensitivity assay, with genotypes of the X-ray repair cross complementing group 1 (XRCC1) gene, which encodes for a base excision repair protein. There are two common polymorphisms that cause amino acid substitutions in XRCC1, one at codon 194 in exon 6 and another at codon 399 in exon 10. We genotyped these two polymorphisms in 524 healthy subjects and performed mutagen sensitivity assays using both bleomycin and benzo[a]pyrene-diol-epoxide (BPDE) as challenge mutagens. Our results showed that individuals with the wildtype exon 6 Arg/Arg exhibited significantly higher values of chromosomal breaks per cell (b/c) than those with one or two variant Trp alleles (P=0.005 for bleomycin and P=0.05 for BPDE). For the exon 10 polymorphism, subjects who were Gln/Gln homozygotes had higher b/c than did those with other genotypes, with evidence of a gene dosage effect. When we combined the two polymorphic sites and used the exon 6 Arg/Trp and Trp/Trp and exon 10 Arg/Arg genotypes as the reference category, these differences were enhanced for bleomycin sensitivity (P for trend = 0.032), but not for BPDE sensitivity (P for trend = 0.821). These data are biologically plausible since codon 399 is located within the BRCA1 C-terminus functional domain and codon 194 is in the linker region of the XRCC1 N-terminal functional domain. To our knowledge, this is the largest study conducted evaluating the functional relevance of these polymorphisms.
Wang
Yunfei
Y
Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Spitz
Margaret R
MR
Zhu
Yong
Y
Dong
Qiong
Q
Shete
Sanjay
S
Wu
Xifeng
X
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D000328:Adult; D001761:Bleomycin; D017931:DNA Primers; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D009152:Mutagenicity Tests; D010641:Phenotype; D011110:Polymorphism, Genetic; D012907:Smoking / Q000235:genetics; D044465:White People; D000076105:X-ray Repair Cross Complementing Protein 1
D017931:DNA Primers; D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D001761:Bleomycin; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide