Objective To evaluate the causal relationship between polyunsaturated fatty acids (PUFA) and colorectal cancer (CRC) through a two-sample Mendelian randomization (MR) study.
Methods Based on genome-wide association study (GWAS) data, genetic variations related to PUFA were used as instrumental variables, and CRC was extracted from the GWAS dataset as the outcome indicator. The inverse-variance weighted method MR-Egger regression and weighted median method were used as the main analytical method to assess the causal relationship between omega-3 fatty acids, omega-6 fatty acids, the ratio of omega-3 to total fatty acids, the ratio of omega-6 to total fatty acids, and the omega-6 to omega-3 ratio with CRC risk.
Results The inverse variance weighting analysis showed that omega-3 fatty acids [OR=1.14, 95%CI(1.06, 1.23), P=0.014], omega-6 fatty acids [OR=1.10, 95%CI(1.03, 1.18), P=0.007], and the omega-6 to omega-3 ratio [OR=0.91, 95%CI(0.84, 0.99), P=0.006] have direct causal relationships with CRC. The ratio of omega-3 to total fatty acids [OR=1.09, 95%CI(0.94, 1.26), P=0.164] and the ratio of omega-6 to total fatty acids [OR=1.07, 95%CI(0.97, 1.18), P=0.226] have no causal relationship with CRC.
Conclusion The MR analysis results suggest that there are causal relationships between omega-3 fatty acids, omega-6 fatty acids, and the omega-6 to omega-3 ratio with CRC, while there is no causal relationship for the ratio of omega-3 to total fatty acids and the ratio of omega-6 to total fatty acids.
1.Thanikachalam K, Khan G. Colorectal cancer and nutrition[J]. Nutrients, 2019, 11(1): 164. DOI: 10.3390/nu11010164.
2.Zheng RS, Chen R, Han BF, et al. Cancer incidence and mortality in China, 2022[J]. Zhonghua Zhong Liu Za Zhi, 2024, 46(3): 221-231. DOI: 10.3760/cma.j.cn112152-20240119-00035.
3.Patel SG, Karlitz JJ, Yen T, et al. The rising tide of early-onset colorectal cancer: a comprehensive review of epidemiology, clinical features, biology, risk factors, prevention, and early detection[J]. Lancet Gastroenterol Hepatol, 2022, 7(3): 262-274. DOI: 10.1016/S2468-1253 (21)00426-X.
4.Aldoori J, Cockbain AJ, Toogood GJ, et al. Omega-3 polyunsaturated fatty acids: moving towards precision use for prevention and treatment of colorectal cancer[J]. Gut, 2022, 71(4): 822-837. DOI: 10.1136/gutjnl-2021- 326362.
5.Montecillo-Aguado M, Tirado-Rodriguez B, Huerta-Yepez S. The involvement of polyunsaturated fatty acids in apoptosis mechanisms and their implications in cancer[J]. Int J Mol Sci, 2023, 24(14): 11691. DOI: 10.3390/ijms 241411691.
6.Dierge E, Debock E, Guilbaud C, et al. Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects[J]. Cell Metab, 2021, 33(8): 1701-1715. DOI: 10.1016/j.cmet.2021.05.016.
7.Lange M, Olzmann JA. Ending on a sour note: lipids orchestrate ferroptosis in cancer[J]. Cell Metab, 2021, 33(8): 1507-1509. DOI: 10.1016/j.cmet.2021.07.011.
8.Sekula P, Del Greco MF, Pattaro C, et al. Mendelian randomization as an approach to assess causality using observational data[J]. J Am Soc Nephrol, 2016, 27(11): 3253-3265. DOI: 10.1681/ASN.2016010098.
9.谢朝荣, 陶庆锋, 胡缤予, 等. 孟德尔随机化研究及其在中医药领域的应用展望[J]. 中医杂志, 2023, 64(5): 438-442, 447. [Xie CR, Tao QF, Hu BY, et al. Mendelian randomization and its application in traditional Chinese medicine[J]. Journal of Traditional Chinese Medicine, 2023, 64(5): 438-442, 447.] DOI: 10.13288/j.11-2166/r.2023.05.002.
10.Bowden J, Holmes MV. Meta-analysis and Mendelian randomization: a review[J]. Res Synth Methods, 2019, 10(4): 486-496. DOI: 10.1002/jrsm.1346.
11.Sakaue S, Kanai M, Tanigawa Y, et al. A cross-population atlas of genetic associations for 220 human phenotypes[J]. Nat Genet, 2021, 53(10): 1415-1424. DOI: 10.1038/s41588-021-00931-x.
12.Kettunen J, Demirkan A, Würtz P, et al. Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA[J]. Nat Commun, 2016, 7: 11122. DOI: 10.1038/ncomms11122.
13.Richardson TG, Leyden GM, Wang Q, et al. Characterising metabolomic signatures of lipid-modifying therapies through drug target mendelian randomisation[J]. PLoS Biol, 2022, 20(2): e3001547. DOI: 10.1371/journal.pbio.3001547.
14.Xu Q, Ni JJ, Han BX, et al. Causal relationship between gut microbiota and autoimmune diseases: a two-sample Mendelian randomization study[J]. Front Immunol, 2022, 12: 746998. DOI: 10.3389/fimmu.2021.746998.
15.Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data[J]. Genet Epidemiol, 2013, 37(7): 658-665. DOI: 10.1002/gepi.21758.
16.Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression[J]. Int J Epidemiol, 2015, 44(2): 512-525. DOI: 10.1093/ije/dyv080.
17.Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator[J]. Genet Epidemiol, 2016, 40(4): 304-314. DOI: 10.1002/gepi.21965.
18.CSCO生物统计学专家委员会RWS方法学组. 孟德尔随机化模型及其规范化应用的统计学共识[J]. 中国卫生统计, 2021, 38(3): 471-475, 480. [CSCO Biostatistics Expert Committee RWS Methodology Group. Consensus on statistical methods for Mendelian randomization models and their standardized application[J]. Chinese Journal of Health Statistics, 2021, 38(3): 471-475, 480.] DOI: 10.11783/j.issn.1002-3674.2023.01.036.
19.Bowden J, Del Greco MF, Minelli C, et al. A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization[J]. Stat Med, 2017, 36(11): 1783-1802. DOI: 10.1002/sim.7221.
20.Gronau QF, Wagenmakers EJ. Limitations of Bayesian leave-one-out cross-validation for model selection[J]. Comput Brain Behav, 2019, 2(1): 1-11. DOI: 10.1007/s42113-018-0011-7.
21.Yue T, Xiong K, Deng J, et al. Meta-analysis of omega-3 polyunsaturated fatty acids on immune functions and nutritional status of patients with colorectal cancer[J]. Front Nutr, 2022, 9: 945590. DOI: 10.3389/fnut.2022.945590.
22.Shahidi F, Ambigaipalan P. Omega-3 polyunsaturated fatty acids and their health benefits[J]. Annu Rev Food Sci Technol, 2018, 9: 345-381. DOI: 10.1146/annurev-food-111317-095850.
23.Zhou Y, Lin Z, Xie S, et al. Interplay of chronic obstructive pulmonary disease and colorectal cancer development: unravelling the mediating role of fatty acids through a comprehensive multi-omics analysis[J]. J Transl Med, 2023, 21(1): 587. DOI: 10.1186/s12967-023-04278-1.
24.Khankari NK, Banbury BL, Borges MC, et al. Mendelian randomization of circulating polyunsaturated fatty acids and colorectal cancer risk[J]. Cancer Epidemiol Biomarkers Prev, 2020, 29(4): 860-870. DOI: 10.1158/1055-9965.EPI-19-0891.
25.王思平, 谢杰, 李红, 等. 结直肠癌患者血中多不饱和脂肪酸水平与其疾病的相关性分析[J]. 中国临床药理学杂志, 2013, 29(11): 810-811, 817. [Wang SP, Xie J, Li H, et al. Analysis the relationship between the levels of blood polyunsaturated fatty acid in patients with colorectal cancer and its cause of colorectal cancer[J]. The Chinese Journal of Clinical Pharmacology, 2013, 29(11): 810-811, 817.] DOI: 10.13699/j.cnki.1001-6821.2013.11.013.
26.董岩, 周迪, 谢亚书, 等. 多不饱和脂肪酸对结直肠癌细胞生物学功能的影响及其生物信息学分析[J]. 广东医学, 2023, 44(12): 1485-1491. [Dong Y, Zhou D, Xie YS, et al. Effect of polyunsaturated fatty acid on biological function of colorectal cancer cells and bioinformatics analysis[J]. Guangdong Medical Journal, 2023, 44(12): 1485-1491.] DOI: 10.13820/j.cnki.gdyx.20230711.
27.Yang K, Li H, Dong J, et al. Expression profile of polyunsaturated fatty acids in colorectal cancer[J]. World J Gastroenterol, 2015, 21(8): 2405-2412. DOI: 10.3748/wjg.v21.i8.2405.
28.Ference BA, Holmes MV, Smith GD. Using Mendelian randomization to improve the design of randomized trials[J]. Cold Spring Harb Perspect Med, 2021, 11(7): a040980. DOI: 10.1101/cshperspect.a040980.