流行病学和实验证据表明，摄入较高叶酸与结直肠癌（CRC）风险降低有关；但是，这种关系的机制尚不完全清楚。可能对叶酸代谢产生直接或间接影响的基因变异可以揭示叶酸在CRC中的作用。本研究旨在进行全基因组相互作用分析，以确定可能修改叶酸与CRC风险关联的遗传变异。我们应用传统的病例-对照逻辑回归、联合3自由度（3DF）和两步加权假设法，测试了从3个遗传协作（CCFR、CORECT、GECCO）的51个研究中的30,550例患者和42,336例对照中常见变异（等位基因频率> 1%）与饮食叶酸、叶酸酸补充剂使用和总叶酸在CRC风险方面的相互作用。发现饮食、总叶酸和叶酸酸补充剂与CRC呈负相关 [比值比：0.93（95%置信区间[CI]：0.90-0.96），0.91（0.89-0.94）每四分位摄入量增加，以及0.82（0.78-0.88）用户与非用户之间。使用传统的相互作用分析，叶酸酸补充剂和3p25.2位点变异（在Synapsin II（SYN2）/组织金属蛋白酶抑制因子4（TIMP4）区域）之间的相互作用（P相互作用<5×10-8）得到发现，位点rs150924902（位于SYN2上游）的变异呈最强交互作用。通过rs150924902基因型分层分析发现，在携带TT基因型的人群中，叶酸补充剂与降低CRC风险相关（OR = 0.82；95%CI：0.79-0.86），而在携带TA基因型的人群中，叶酸补充剂与增加CRC风险相关（OR = 1.63；95%CI：1.29-2.05），暗示存在定性相互作用（P相互作用= 1.4×10-8）。对于膳食和总叶酸没有观察到相互作用。3p25.2位点的变异可能修改叶酸补充剂与CRC风险的关联。有必要进行实验研究和融合其他相关的组学数据的研究来验证这一发现。版权所有 © 2023 作者（们）。由Elsevier Inc.发表。保留所有权利。

Epidemiological and experimental evidence suggests that higher folate intake is associated with a 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.Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk.We applied traditional case-control logistic regression, joint 3-degree of freedom (3DF), and a two-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).Inverse associations of dietary, total folate, and folic acid supplement with CRC were found [odds ratio: 0.93 (95% confidence intervals [CI]: 0.90-0.96), and 0.91 (0.89-0.94) per quartile higher intake, and 0.82 (0.78-0.88) for users vs. non-users, 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 the traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplement 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.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.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.