|
Genome-wide interaction analysis of folate for colorectal cancer risk Emmanouil Bouras, Andre E. Kim, Yi Lin, John Morrison, Mengmeng Du, Demetrius Albanes, Elizabeth L. Barry, James W. Baurley, Sonja I. Berndt, Stephanie A. Bien, Timothy D. Bishop, Hermann Brenner, Arif Budiarto, Andrea Burnett-Hartman, Peter T. Campbell, Robert Carreras-Torres, Graham Casey, Tjeng Wawan Cenggoro, Andrew T. Chan, Jenny Chang-Claude, David V. Conti, Michelle Cotterchio, Matthew Devall, Virginia Diez-Obrero, Niki Dimou, David A. Drew, Jane C. Figueiredo, Graham G. Giles, Stephen B. Gruber, Marc J. Gunter, Tabitha A. Harrison, Akihisa Hidaka, Michael Hoffmeister, Jeroen R. Huyghe, Amit D. Joshi, Eric S. Kawaguchi, Temitope O. Keku, Anshul Kundaje, Loic Le Marchand, Juan Pablo Lewinger, Li Li, Brigid M. Lynch, Bharuno Mahesworo, Satu Männistö, Victor Moreno, Neil Murphy, Polly A. Newcomb, Mireia Obón-Santacana, Jennifer Ose, Julie R. Palmer, Nikos Papadimitriou, Bens Pardamean, Andrew J. Pellatt, Anita R. Peoples, Elizabeth A. Platz, John D. Potter, Lihong Qi, Conghui Qu, Gad Rennert, Edward Ruiz-Narvaez, Lori C. Sakoda, Stephanie L. Schmit, Anna Shcherbina, Mariana C. Stern, Yu-Ru Su, Catherine M. Tangen, Duncan C. Thomas, Yu Tian, Caroline Y. Um, Franzel JB. van Duijnhoven, Bethany Van Guelpen, Kala Visvanathan, Jun Wang, Emily White, Alicja Wolk, Michael O. Woods, Cornelia M. Ulrich, Li Hsu, W James Gauderman, Ulrike Peters, Konstantinos K. Tsilidis The American Journal of Clinical Nutrition：2023/08/26 Background Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate’s role in CRC. Objectives Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. Methods We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). Results Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. Conclusions Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding. 背景流行病学和实验证据表明；叶酸；摄入与减少有关；癌症；（CRC）风险；然而，这种关系背后的机制尚不完全清楚。可能对；叶酸；代谢可以深入了解叶酸在CRC中的作用。目的我们的目的是进行全基因组相互作用分析，以确定可能改变叶酸与CRC风险相关性的遗传变异。方法采用传统病例对照法；逻辑回归、联合三自由度和两步加权假设方法，以测试来自3个遗传联合体（CCFR、CORECT、GECCO）的51项研究的30550例病例和42336名对照中基因组常见变异（等位基因频率>；1%）与饮食叶酸、叶酸补充剂使用和总叶酸与CRC风险的相互作用。结果膳食、总叶酸和叶酸补充与CRC呈负相关（优势比[OR]:0.93；95%置信区间[CI]:0.90，0.96；和0.91；95%置信度：0.89，0.94每四分位数摄入量高于非使用者，使用者分别为0.82（95%置信度0.78，0.88））。使用传统的相互作用分析发现叶酸补充剂与3p25.2基因座（Synapsin II[SYN2]/金属蛋白酶组织抑制剂4[TIMP4]区域）变异体的相互作用（P-相互作用<；5×10-8），变异体rs150924902（位于SYN2上游）显示出最强的相互作用。在rs150924902基因型的分层分析中，在携带TT基因型的人群中，叶酸补充与CRC风险降低相关（OR:0.82；95%CI:0.79，0.86），但在携带TA基因型的群体中，CRC风险增加（OR:1.63；95%CI:1.29，2.05），表明存在质性相互作用（P相互作用=1.4×10-8）。在饮食和总叶酸方面未观察到相互作用。结论3p25.2基因座的变异可能改变叶酸补充与CRC风险的关系。实验研究和包含其他相关研究的研究；组学；有必要提供数据来验证这一发现。 |
|
|
