From genotype to phenotype:: correlating XRCC1 polymorphisms with mutagen sensitivity
From genotype to phenotype:: correlating XRCC1 polymorphisms with mutagen sensitivity
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DOI：
10.1016/s1568-7864(03)00085-5
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发表时间：
2003-08-12
期刊：
影响因子：
3.8
通讯作者：
Wu, XF
中科院分区：
文献类型：
--
作者：
Wang, YF;Spitz, MR;Wu, XF
本研究相关的程度诱导体外染色体损伤，评估诱变剂敏感性试验，与基因型的X射线修复交叉互补组1（XRCC 1）基因，编码的碱基切除修复蛋白。有两种常见的多态性导致XRCC 1中的氨基酸取代，一种在外显子6的密码子194处，另一种在外显子10的密码子399处。我们在524名健康受试者中对这两种多态性进行了基因分型，并使用博莱霉素和苯并[a]芘-二醇-环氧化物（BPDE）作为激发诱变剂进行了诱变剂敏感性试验。我们的研究结果表明，具有野生型外显子6 Arg/Arg的个体比具有一个或两个变体Tip等位基因的个体表现出显著更高的每个细胞染色体断裂值（B/c）（博莱霉素P = 0.005，BPDE P = 0.05）。对于外显子10多态性，Gln/Gln纯合子受试者的B/c比其他基因型受试者高，有基因剂量效应的证据。当我们结合两个多态性位点，并使用外显子6 Arg/Trp和Trp/Trp和外显子10 Arg/Arg基因型作为参考类别时，这些差异在博莱霉素敏感性方面得到增强（趋势P = 0.032），但在BPDE敏感性方面没有增强（趋势P = 0.821）。这些数据在生物学上是合理的，因为密码子399位于BRCA 1C-末端功能结构域内，而密码子194位于XRCC 1 N-末端功能结构域的接头区。据我们所知，这是评价这些多态性的功能相关性的最大规模的研究。(C)2003 Elsevier Science B. V.保留所有权利。
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 Tip 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 BRCA1C-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. (C) 2003 Elsevier Science B.V. All rights reserved.