两个全基因组相互作用位点改变了非甾体抗炎药与结直肠癌的关联。
Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.
发表日期：2024 May 31
作者：
David A Drew, Andre E Kim, Yi Lin, Conghui Qu, John Morrison, Juan Pablo Lewinger, Eric Kawaguchi, Jun Wang, Yubo Fu, Natalia Zemlianskaia, Virginia Díez-Obrero, Stephanie A Bien, Niki Dimou, Demetrius Albanes, James W Baurley, Anna H Wu, Daniel D Buchanan, John D Potter, Ross L Prentice, Sophia Harlid, Volker Arndt, Elizabeth L Barry, Sonja I Berndt, Emmanouil Bouras, Hermann Brenner, Arif Budiarto, Andrea Burnett-Hartman, Peter T Campbell, Robert Carreras-Torres, Graham Casey, Jenny Chang-Claude, David V Conti, Matthew A M Devall, Jane C Figueiredo, Stephen B Gruber, Andrea Gsur, Marc J Gunter, Tabitha A Harrison, Akihisa Hidaka, Michael Hoffmeister, Jeroen R Huyghe, Mark A Jenkins, Kristina M Jordahl, Anshul Kundaje, Loic Le Marchand, Li Li, Brigid M Lynch, Neil Murphy, Rami Nassir, Polly A Newcomb, Christina C Newton, Mireia Obón-Santacana, Shuji Ogino, Jennifer Ose, Rish K Pai, Julie R Palmer, Nikos Papadimitriou, Bens Pardamean, Andrew J Pellatt, Anita R Peoples, Elizabeth A Platz, Gad Rennert, Edward Ruiz-Narvaez, Lori C Sakoda, Peter C Scacheri, Stephanie L Schmit, Robert E Schoen, Mariana C Stern, Yu-Ru Su, Duncan C Thomas, Yu Tian, Konstantinos K Tsilidis, Cornelia M Ulrich, Caroline Y Um, Fränzel J B van Duijnhoven, Bethany Van Guelpen, Emily White, Li Hsu, Victor Moreno, Ulrike Peters, Andrew T Chan, W James Gauderman
来源：
CLINICAL PHARMACOLOGY & THERAPEUTICS
摘要：
定期、长期使用阿司匹林可能与遗传变异（尤其是机械相关途径中的遗传变异）产生协同作用，从而对结直肠癌（CRC）风险产生保护作用。我们利用 52 项临床试验、队列和病例对照研究（其中包括 30,806 名 CRC 病例和 41,861 名欧洲血统对照者）的汇总数据，对常规阿司匹林/非甾体抗炎药 (NSAID) 使用和估算之间进行全基因组相互作用扫描。遗传变异。在调整多重比较后，我们发现常规阿司匹林/NSAID 使用与 6q24.1（热门命中 rs72833769）中的变异之间存在统计上显着的相互作用，该变异有影响 TBC1D7（TSC1-TSC2 复合物的一个亚基，关键调节因子）表达的证据。 MTOR 活性），以及 5p13.1 的变体（热门 rs350047），其与 PTGER4（编码直接参与阿司匹林作用模式的细胞表面受体）的表达相关。具有功能影响的基因变异可能会调节定期使用阿司匹林的化学预防作用，我们的研究确定了先前未识别的推定目标，以进行额外的机械询问。
Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.