多不饱和脂肪酸（PUFAs）对特定癌症的因果关系仍不确定。本研究采用Mendelian随机化（MR）框架，在欧洲和东亚血统的个体中评估了PUFAs对癌症风险的因果关系。我们将主要暴露定义为PUFA脱饱和酶活性，以FADS位点上的rs174546作为代理。次要暴露定义为可以由FADS区域外的基因多态性近似的ω-3和ω-6 PUFAs。我们的研究使用了由Fatty Acids in Cancer Mendelian Randomization Collaboration收集的10个PUFAs和67种癌症的汇总遗传数据，相应的案例和对照分别为562,871和1,619,465。我们估计了每一种基因近似PUFA暴露标准差增加的癌症比例比（ORs）。基因上升的PUFA脱饱和酶活性与结直肠癌（1.09 [1.07-1.11]）、食管鳞状细胞癌（1.16 [1.06-1.26]）、肺癌（1.06 [1.03-1.08]）和基底细胞癌（1.05 [1.02-1.07]）的风险显著相关（P ＜0.0007）。对于生殖癌（OR=1.00 [95% CI：0.99-1.01]；Pheterogeneity=0.25）、泌尿系统癌症（1.03 [0.99-1.06]，Pheterogeneity=0.51）、神经系统癌症（0.99 [0.95-1.03]，Pheterogeneity=0.92）或血液癌症（1.01 [0.98-1.04]，Pheterogeneity=0.09），几乎没有证据表明存在关联。对于结直肠癌和食管鳞状细胞癌的发现在敏感性分析中对违反假设的情况下与其因果关系保持一致。次要MR分析突出了ω-6 PUFAs（花生四烯酸，γ-亚麻酸和二十二碳六烯酸）作为潜在的介导因素。已知PUFA生物合成与阿司匹林相互作用，后者增加了出血和炎症性肠病的风险。在非肿瘤性疾病的表型广泛MR研究中，我们发现遗传性降低PUFA脱饱和酶活性，模拟减少癌症风险的假设干预，与炎症性肠病的风险增加显著相关（P ＜0.0006），但与出血无关联。PUFA生物合成途径可能是预防结直肠癌和食管鳞状细胞癌的干预目标，但可能增加炎症性肠病的风险。癌症研究英国（C52724/A20138，C18281/A19169）、英国医学研究委员会（MR/P014054/1）、英国国家卫生研究院（NIHR202411）、英国医学研究委员会（MC_UU_00011/1、MC_UU_00011/3、MC_UU_00011/6和MC_UU_00011/4）、美国国家癌症研究所（R00 CA215360）、国家卫生研究院（U01 CA164973、R01 CA60987、R01 CA72520、U01 CA74806、R01 CA55874、U01 CA164973和U01 CA164973）。版权所有©2023年作者。由Elsevier B.V.出版。保留所有权利。

The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain.Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures.Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activity, mimicking a hypothetical intervention to reduce cancer risk, was associated (P < 0.0006) with increased risk of inflammatory bowel disease but not bleeding.The PUFA biosynthesis pathway may be an intervention target for prevention of colorectal cancer and esophageal squamous cell carcinoma but with potential for increased risk of inflammatory bowel disease.Cancer Resesrch UK (C52724/A20138, C18281/A19169). UK Medical Research Council (MR/P014054/1). National Institute for Health Research (NIHR202411). UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4). National Cancer Institute (R00 CA215360). National Institutes of Health (U01 CA164973, R01 CA60987, R01 CA72520, U01 CA74806, R01 CA55874, U01 CA164973 and U01 CA164973).Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.