Scherer Dominique, Koepl Lisel M, Poole Elizabeth M, Balavarca Yesilda, Xiao Liren, Baron John A, Hsu Li, Coghill Anna E, Campbell Peter T, Kleinstein Sarah E, Figueiredo Jane C, Lampe Johanna W, Buck Katharina, Potter John D, Kulmacz Richard J, Jenkins Mark A, Hopper John L, Win Aung K, Newcomb Polly A, Ulrich Cornelia M, Makar Karen W
Department of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, 69120, Heidelberg, Germany.
Genes Chromosomes Cancer. 2014 Jul;53(7):568-78. doi: 10.1002/gcc.22167. Epub 2014 Mar 28.
The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of colorectal neoplasia. Previous studies have reported that polymorphisms in NSAID-metabolizing enzymes central to NSAID metabolism including UDP-glucuronosyltransferases (UGT) and cytochrome P450 (CYP) 2C9 may modify this protective effect. We investigated whether 35 functionally relevant polymorphisms within CYP2C9 and UGT genes were associated with colorectal cancer risk or modified the protective effect of NSAIDs on colorectal cancer susceptibility, using 1,584 colorectal cancer cases and 2,516 unaffected sibling controls from the Colon Cancer Family Registry. A three-SNP genotype in UGT1A6 (G-A-A; Ala7-Thr181-Arg184) and the Asp85 variant in UGT2B15 increased the risk of colorectal cancer (OR 3.87; 95% CI 1.04-14.45 and OR 1.34; 95% CI 1.10-1.63, respectively). We observed interactions between UGT1A3 Thr78Thr (A>G) and NSAID use (P-interaction = 0.02), a three-SNP genotype within UGT2B4 and ibuprofen use (P-interaction = 0.0018), as well as UGT2B15 Tyr85Asp (T>G) and aspirin use (P-interaction = 0.01). The interaction with the UGT2B4 and the UGT2B15 polymorphisms were noteworthy at the 25% FDR level. This study highlights the need for further pharmacogenetic studies to identify individuals who might benefit from NSAID use as part of developing effective strategies for prevention of colorectal neoplasia. © 2014 Wiley Periodicals, Inc.
使用非甾体抗炎药（NSAIDs）与降低结直肠肿瘤发生风险相关。既往研究报道，参与NSAIDs代谢的酶（包括尿苷二磷酸葡萄糖醛酸基转移酶（UGT）和细胞色素P450（CYP）2C9）的基因多态性可能会改变这种保护作用。我们利用来自结肠癌家族登记处的1584例结肠癌病例和2516例未受影响的同胞对照，研究了CYP2C9和UGT基因中的35个功能相关多态性是否与结直肠癌风险相关，或是否改变了NSAIDs对结直肠癌易感性的保护作用。UGT1A6中的一个三单核苷酸多态性基因型（G-A-A；Ala7-Thr181-Arg184）和UGT2B15中的Asp85变体增加了结直肠癌风险（分别为OR 3.87；95%CI 1.04 - 14.45和OR 1.34；95%CI 1.10 - 1.63）。我们观察到UGT1A3 Thr78Thr（A>G）与NSAIDs使用之间存在相互作用（P相互作用 = 0.02），UGT2B4中的一个三单核苷酸多态性基因型与布洛芬使用之间存在相互作用（P相互作用 = 0.0018），以及UGT2B15 Tyr85Asp（T>G）与阿司匹林使用之间存在相互作用（P相互作用 = 0.01）。在25%的错误发现率水平上，UGT2B4和UGT2B15基因多态性之间的相互作用值得关注。本研究强调需要进一步开展药物遗传学研究，以确定哪些个体可能从使用NSAIDs中获益，这是制定预防结直肠肿瘤有效策略的一部分。© 2014威利期刊公司
