Miao Xiaoping, Zhang Xuemei, Zhang Lingqiang, Guo Yongli, Hao Bingtao, Tan Wen, He Fuchu, Lin Dongxin
Department of Etiology & Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Gastroenterology. 2006 Aug;131(2):420-7. doi: 10.1053/j.gastro.2006.05.050.
BACKGROUND & AIMS: Adenosine diphosphate ribosyl transferase (ADPRT) and x-ray repair cross-complementing 1 (XRCC1) are major DNA base excision repair proteins acting interactively in repair processes. This study examined the effects of ADPRT Val762Ala and XRCC1 Arg399Gln polymorphisms on ADPRT-XRCC1 interaction in vitro in cells and their contributions to gastric cardia adenocarcinoma (GCA) risk.
The ADPRT-XRCC1 interaction in cells transfected with ADPRT and XRCC1 variant complementary DNA (cDNA) constructs were examined by immunoprecipitation and immunoblotting analysis. Genotypes were analyzed in 500 patients and 1000 controls, and odds ratios (ORs) were estimated by logistic regression.
Interactions between ADPRT-762Val and XRCC1-399Arg or XRCC1-399Gln were robust, but interactions between ADPRT-762Ala and either XRCC1-399Arg or XRCC1-399Gln were very weak. A case-control analysis showed ORs of 2.17 (95% CI, 1.55-3.04) and 1.61 (95% CI, 1.06-2.44) for GCA in the ADPRT Ala/Ala or XRCC1 Gln/Gln genotype carriers, respectively, compared with noncarriers. Gene-gene interaction of ADPRT and XRCC1 polymorphisms increased the OR of GCA in a multiplicative manner (OR for the presence of both ADPRT Ala/Ala and XRCC1 Gln/Gln genotypes, 6.43; 95% CI, 1.80-22.97). A supermultiplicative joint effect between the ADPRT polymorphism and smoking was observed. The ORs (95% CIs) of the Ala/Ala genotype for nonsmokers and smokers who smoked < or = 24 or > 24 pack-years were 1.44 (0.89-2.32), 2.00 (1.09-3.67), or 3.19 (1.59-6.42), respectively (Ptrend test = .008).
The ADPRT and XRCC1 polymorphisms confer host susceptibility to GCA, which might result from reduced ADPRT-XRCC1 interaction and attenuated base excision repair capacity.
二磷酸腺苷核糖基转移酶（ADPRT）和X射线修复交叉互补蛋白1（XRCC1）是在修复过程中相互作用的主要DNA碱基切除修复蛋白。本研究检测了ADPRT Val762Ala和XRCC1 Arg399Gln多态性对细胞中ADPRT - XRCC1体外相互作用的影响及其对贲门腺癌（GCA）风险的影响。
通过免疫沉淀和免疫印迹分析检测用ADPRT和XRCC1变异互补DNA（cDNA）构建体转染的细胞中ADPRT - XRCC1的相互作用。对500例患者和1000例对照进行基因分型，并通过逻辑回归估计比值比（OR）。
ADPRT - 762Val与XRCC1 - 399Arg或XRCC1 - 399Gln之间的相互作用很强，但ADPRT - 762Ala与XRCC1 - 399Arg或XRCC1 - 399Gln之间的相互作用非常弱。病例对照分析显示，与非携带者相比，ADPRT Ala/Ala或XRCC1 Gln/Gln基因型携带者患GCA的OR分别为2.17（95%CI，1.55 - 3.04）和1.61（95%CI，1.06 - 2.44）。ADPRT和XRCC1多态性的基因 - 基因相互作用以乘法方式增加了GCA的OR（ADPRT Ala/Ala和XRCC1 Gln/Gln基因型均存在时的OR为6.43；95%CI，1.80 - 22.97）。观察到ADPRT多态性与吸烟之间存在超乘法联合效应。非吸烟者以及吸烟≤24或>24包年的吸烟者中，Ala/Ala基因型的OR（95%CI）分别为1.44（0.89 - 2.32）、2.00（1.09 - 3.67）或3.19（1.59 - 6.42）（趋势检验P = 0.008）。
ADPRT和XRCC1多态性使宿主易患GCA，这可能是由于ADPRT - XRCC1相互作用减弱和碱基切除修复能力降低所致。
