A population-based study of the Arg399Gln polymorphism in X-ray repair cross- complementing group 1 (XRCC1) and risk of pancreatic adenocarcinoma.
A population-based study of the Arg399Gln polymorphism in X-ray repair cross- complementing group 1 (XRCC1) and risk of pancreatic adenocarcinoma.
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发表时间：
2002-08
期刊：
影响因子：
11.2
通讯作者：
E. Duell;E. Holly;P. Bracci;J. Wiencke;K. Kelsey
中科院分区：
文献类型：
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作者：
E. Duell;E. Holly;P. Bracci;J. Wiencke;K. Kelsey
XRCC 1（X射线修复交叉互补组1）是一种碱基切除修复蛋白，在修复来自各种内源性和外源性氧化剂（包括烟草烟雾）的DNA链断裂和碱基损伤中发挥核心作用。一种遗传多态性（密码子399处的G->A，Arg->Gln）发生在聚（ADP-核糖）聚合酶结合区域内和XRCC 1的中心乳腺癌易感基因1产物COOH末端结构域内。XRCC 1的变异399 Gln等位基因与人类细胞中DNA损伤的生物标志物升高相关。我们使用基因组DNA和问卷信息对309例胰腺癌和964例对照进行了XRCC 1的Arg 399 Gln多态性分析，这些信息是1994年至2001年在旧金山弗朗西斯科湾区进行的基于人群的病例对照研究的一部分。我们使用基于质谱的方法对个体进行基因分型。由于吸烟和肥胖是已知和疑似的胰腺癌危险因素，并且与靶组织中的DNA损伤和氧化应激相关，因此我们估计了XRCC 1基因型和吸烟或体重指数（kg/m2）联合作用的比值比（OR），相互作用对比比（ICR）和95%置信区间。我们还评估了XRCC 1和CYP 1A 1，GSTT 1和GSTM 1多态性之间的潜在基因-基因相互作用。我们发现很少或没有证据表明XRCC 1基因型与高加索人，非洲裔美国人或亚洲人的胰腺癌之间存在关联。有证据表明XRCC 1 399 Gln和吸烟之间的相互作用在女性中比男性更强。相对于Arg/Arg基因型从不主动或被动吸烟者，年龄和种族校正的OR和ICR（95%置信限）（≥ 41包-年）：Gln/Gln或Arg/Gln基因型[女性OR = 7.0（2.4，21），ICR = 3.1（0.03，6.2）;男性OR = 2.4（1.1，5.0），ICR = 1.3（-0.20，2.8）];对于Arg/Arg基因型[女性OR = 2.2（0.73，6.4）;男性OR = 1.5（0.68，3.2）]。组合基因型的分析表明，XRCC 1（谷氨酰胺/谷氨酰胺或精氨酸/谷氨酰胺）和GSTT 1/GSTM 1-null/null之间的相互作用的女性，但不是男性。没有证据表明XRCC 1基因型和体重指数之间存在相互作用。我们的研究结果表明，XRCC 1 399 Gln等位基因是一个潜在的重要决定因素，吸烟诱导的胰腺癌的易感性。我们的研究结果，包括女性之间更强的关联和相互作用，需要在更多的研究人群中复制。
XRCC1 (X-ray repair cross-complementing group 1) is a base excision repair protein that plays a central role in the repair of DNA strand breaks and base damage from a variety of endogenous and exogenous oxidants including tobacco smoke. One genetic polymorphism (G-->A, Arg-->Gln at codon 399) occurs within a poly(ADP-ribose) polymerase binding region and within the central breast cancer susceptibility gene 1 product COOH terminus domain of XRCC1. The variant 399Gln allele of XRCC1 has been associated with elevated biomarkers of DNA damage in human cells. We conducted an analysis of the Arg399Gln polymorphism in XRCC1 using genomic DNA, and questionnaire information from 309 cases of pancreatic adenocarcinoma and 964 controls that were part of a population-based, case-control study conducted in the San Francisco Bay Area between 1994 and 2001. We genotyped individuals using a mass spectrometry-based method. Because smoking and obesity are known and suspected pancreas cancer risk factors, and have been associated with DNA damage and oxidative stress in target tissues, we estimated odds ratios (ORs), interaction contrast ratios (ICRs), and 95% confidence intervals for the combined effects of XRCC1 genotype and smoking or body mass index (in kg/m(2)). We also assessed potential gene-gene interactions between polymorphisms in XRCC1 and CYP1A1, GSTT1, and GSTM1. We found little or no evidence for an association between XRCC1 genotype and pancreatic cancer among Caucasians, African-Americans, or Asians. There was evidence for interaction between XRCC1 399Gln and smoking that was stronger among women than men. Relative to never active or passive smokers with the Arg/Arg genotype, the age- and race-adjusted ORs and ICRs (95% confidence limits) for heavy smoking (>or=41 pack-years) were: for Gln/Gln or Arg/Gln genotypes [women OR = 7.0 (2.4, 21), ICR = 3.1 (0.03, 6.2); men OR = 2.4 (1.1, 5.0), ICR = 1.3 (-0.20, 2.8)]; and for the Arg/Arg genotype [women OR = 2.2 (0.73, 6.4); men OR = 1.5 (0.68, 3.2)]. Analyses of combined genotypes suggested an interaction between XRCC1 (Gln/Gln or Arg/Gln) and GSTT1/GSTM1-null/null among women but not among men. There was no evidence of interaction between XRCC1 genotype and body mass index. Our results suggest that the XRCC1 399Gln allele is a potentially important determinant of susceptibility to smoking-induced pancreatic cancer. Our findings, including stronger associations and interactions among women, require replication in additional study populations.