PDF(Pubmed)
Abstract：
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.
摘要：
常规,长期使用阿司匹林可能与遗传变异协同作用，特别是那些机械相关的途径，赋予对结直肠癌（CRC）风险的保护作用。我们利用了52项临床试验的汇总数据，队列,病例对照研究包括30,806例CRC病例和41,861例欧洲血统对照，在常规阿司匹林/非甾体抗炎药（NSAID）使用和估算的遗传变异之间进行全基因组相互作用扫描。调整多次比较后，我们在6q24.1中发现了常规阿司匹林/NSAID使用与变体之间的统计学显着相互作用（排名最高的rs72833769），有影响TBC1D7（TSC1-TSC2复合物的亚基，MTOR活动的关键调节器)，和5p13.1中的变体（最高命中rs350047），它与PTGER4（编码直接参与阿司匹林作用模式的细胞表面受体）的表达有关。具有功能影响的遗传变异可能会调节常规使用阿司匹林的化学预防作用，我们的研究确定了推定的先前未识别的目标，以进行额外的机械询问。
