MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, University of Bristol, Bristol, United Kingdom.
MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, University of Bristol, Bristol, United Kingdom.
EBioMedicine. 2023 May;91:104510. doi: 10.1016/j.ebiom.2023.104510. Epub 2023 Apr 20.
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]; P = 0.25), urinary system cancers (1.03 [0.99-1.06], P = 0.51), nervous system cancers (0.99 [0.95-1.03], P = 0.92) or blood cancers (1.01 [0.98-1.04], P = 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).
多不饱和脂肪酸 (PUFA) 与特定部位癌症风险的因果关系仍不确定。
使用孟德尔随机化 (MR) 框架，我们评估了 PUFAs 对欧洲和东亚人群癌症风险的因果关系。我们将主要暴露定义为 FADS 基因座上 rs174546 代表的 PUFA 去饱和酶活性。次要暴露定义为可由 FADS 区域外的遗传多态性来代表的 omega 3 和 omega 6 PUFAs。我们的研究使用了癌症孟德尔随机化脂肪酸合作组织收集的 10 种 PUFAs 和 67 种癌症的汇总遗传数据，对应 562871 例病例和 1619465 例对照。我们估计了每标准偏差增加遗传上代表性 PUFAs 暴露的癌症比值比 (OR)。
遗传上升高的 PUFA 去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]) 风险升高相关 (P<0.0007)。与生殖系统癌症 (OR=1.00 [95%CI：0.99-1.01]；P=0.25)、泌尿系统癌症 (1.03 [0.99-1.06]，P=0.51)、神经系统癌症 (0.99 [0.95-1.03]，P=0.92) 或血液癌症 (1.01 [0.98-1.04]，P=0.09) 的关联几乎没有证据。在对违反假设的情况进行敏感性分析时，结直肠癌和食管鳞状细胞癌的结果仍然符合因果关系。二级 MR 分析强调了更高的 omega 6 PUFAs（花生四烯酸、γ-亚麻酸和二高-γ-亚麻酸）作为潜在的介质。PUFA 生物合成已知与阿司匹林相互作用，阿司匹林会增加出血和炎症性肠病的风险。在一项非肿瘤性疾病的表型广泛 MR 研究中，我们发现，模拟降低癌症风险的假设干预的 PUFA 去饱和酶活性降低与炎症性肠病风险增加相关 (P<0.0006)，但与出血无关。
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靶点，但可能会增加炎症性肠病的风险。
英国癌症研究中心 (C52724/A20138、C18281/A19169)。英国医学研究理事会 (MR/P014054/1)。国家卫生研究院 (NIHR202411)。英国医学研究理事会 (MC_UU_00011/1、MC_UU_00011/3、MC_UU_00011/6 和 MC_UU_00011/4)。国家癌症研究所 (R00 CA215360)。美国国立卫生研究院 (U01 CA164973、R01 CA60987、R01 CA72520、U01 CA74806、R01 CA55874、U01 CA164973 和 U01 CA164973)。
