The association between genetically elevated polyunsaturated fatty acids and risk of cancer.
The association between genetically elevated polyunsaturated fatty acids and risk of cancer.
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DOI：
10.1016/j.ebiom.2023.104510
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发表时间：
2023-05
期刊：
影响因子：
11.1
通讯作者：
Martin, Richard M.
中科院分区：
文献类型：
--
作者：
Haycock, Philip C.;Borges, Maria Carolina;Burrows, Kimberley;Lemaitre, Rozenn N.;Burgess, Stephen;Khankari, Nikhil K.;Tsilidis, Konstantinos K.;Gaunt, Tom R.;Hemani, Gibran;Zheng, Jie;Truong, Therese;Birmann, Brenda M.;OMara, Tracy;Spurdle, Amanda B.;Iles, Mark M.;Law, Matthew H.;Slager, Susan L.;Hosnijeh, Fatemeh Saberi;Mariosa, Daniela;Cotterchio, Michelle;Cerhan, James R.;Peters, Ulrike;Enroth, Stefan;Gharahkhani, Puya;Le Marchand, Loic;Williams, Ann C.;Block, Robert C.;Amos, Christopher I.;Hung, Rayjean J.;Zheng, Wei;Gunter, Marc J.;Smith, George Davey;Relton, Caroline;Martin, Richard M.
关键词：
多不饱和脂肪酸(PUFAs)与特定部位癌症风险之间的因果关系仍不确定。使用孟德尔随机化(MR)框架，我们评估了多不饱和脂肪酸与欧洲和东亚血统个体患癌症风险的因果相关性。我们将主要暴露定义为多不饱和脂肪酸脱饱和酶活性，由FADS基因的rs174546代表。二次暴露被定义为omega 3和omega 6多不饱和脂肪酸，可以通过FADS区域外的遗传多态来替代。我们的研究使用了10种多不饱和脂肪酸和67种癌症的汇总遗传数据，对应于562,871例病例和1,619,465名对照，由癌症孟德尔随机化合作中的脂肪酸收集。我们估计了在基因代理的多不饱和脂肪酸暴露中癌症的优势比(OR)为每标准差增加。基因高的多不饱和脂肪酸去饱和酶活性与结直肠癌(1.09[1.07-1.11])、食道鳞状细胞癌(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])的高风险(OR[95%可信区间])相关(P<0.0007)。几乎没有证据表明与生殖系统癌症(OR=1.00[95%CI：0.99-1.01]；P异质性C=0.0.25)、泌尿系癌症(1.03[0.99-1.06]，P异质性C=0.51)、神经系统癌症(0.99[0.95-1.03]，P异质性C=0.92)或血癌(1.01[0.98-1.04]，P异质性C=10.09)有关。结直肠癌和食道鳞状细胞癌的研究结果仍然与违反假设的敏感性分析中的因果关系相一致。二次MR分析强调较高的omega 6 PUFAs(花生四烯酸、γ-亚麻酸和二高-γ-亚麻酸)是潜在的介体。已知多不饱和脂肪酸的生物合成与阿司匹林相互作用，这会增加出血和炎症性肠病的风险。在一项针对非肿瘤性疾病的表型磁共振研究中，我们发现，多不饱和脂肪酸脱氢酶活性的遗传降低与降低癌症风险的假想干预相关联(P<0.0006)，与炎症性肠病的风险增加有关，但与出血无关。PUFA生物合成途径可能是预防结直肠癌和食道鳞状细胞癌的干预靶点，但有可能增加炎症性肠病的风险。(C52724/A20138、C18281/A19169)。(MR/P014054/1)。(NIHR202411)。(MC_UU_00011/1、MC_UU_00011/3、MC_UU_00011/6和MC_UU_00011/4)。(R00 CA215360)。(U01 CA164973、R01 CA60987、R01 CA72520、U01 CA74806、R01 CA55874、U01 CA164973和U01 CA164973)。
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. (C52724/A20138, C18281/A19169). (MR/P014054/1). (NIHR202411). (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4). (R00 CA215360). (U01 CA164973, R01 CA60987, R01 CA72520, U01 CA74806, R01 CA55874, U01 CA164973 and U01 CA164973).
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影响因子：
14.9
作者：
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通讯作者：
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影响因子：
50.5
作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
Harris WS
DOI：
10.1002/ejlt.201400513
发表时间：
2015-09
期刊：
European journal of lipid science and technology : EJLST
影响因子：
--
作者：
Eilander A;Harika RK;Zock PL
通讯作者：
Zock PL