Vol. 2 No. 2 (2025)

Research Articles

Evaluating The Causal Relationship Between Omega-3 Polyunsaturated Fatty Acids And Hypertension: Insights From A Two-Sample Mendelian Randomization Study

Published 2025-06-30

  • Weikun Zhao
    • ,
  • Xiaoping Li
    • ,
  • Yuechang Li

Weikun Zhao
Premium Healthcare Department, The First Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541004, China

Xiaoping Li
Department of Dermatology, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, Guangxi Zhuang Autonomous Region, China

Yuechang Li
Department of Cardiology, Chongqing University Fuling Hospital, Chongqing, China

Abstract

To investigate the causal relationship between dietary intake of omega-3 polyunsaturated fatty acids (ω-3 PUFA) and hypertension using a two-sample Mendelian randomization (MR) approach. Data from a comprehensive genome-wide association study (GWAS) database was used to identify single-nucleotide polymorphisms (SNPs) associated with ω-3 PUFA levels as instrumental variables. Five MR methods were employed for causal inference: MR-Egger regression, weighted median, inverse-variance weighted (IVW), simple mode, and weighted mode. The analysis was complemented by pleiotropy tests using the MR-Egger intercept and the MR-PRESSO method, alongside a 'leave-one-out' sensitivity analysis. The analysis showed no significant causal effects of ω-3 PUFA on hypertension across all methods (P > 0.05). The pleiotropy tests and sensitivity analysis confirmed the robustness of these findings. This MR study found no evidence supporting a causal relationship between ω-3 PUFA intake and hypertension, indicating that additional factors may modulate this association.

Keywords

Omega-3 Polyunsaturated Fatty Acids, Hypertension, Mendelian Randomization, Causal Inference

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References

  1. Mills, K. T., Stefanescu, A., & He, J. (2020). The global epidemiology of hypertension. ​Nature Reviews. Nephrology​, 16(4), 223–237. https://doi.org/10.1038/s41581-019-0244-2
  2. Oparil, S., Acelajado, M. C., Bakris, G. L., Berlowitz, D. R., Cífková, R., Dominiczak, A. F., Grassi, G., Jordan, J., Poulter, N. R., Rodgers, A., & Whelton, P. K. (2018). Hypertension. ​Nature Reviews. Disease Primers​, 4, 18014. https://doi.org/10.1038/nrdp.2018.14
  3. Xiang, R., Chen, J., Li, S., Yan, H., Meng, Y., Cai, J., Cui, Q., Yang, Y., Xu, M., Geng, B., & Yang, J. (2020). VSMC-specific deletion of FAM3A attenuated ang II-promoted hypertension and cardiovascular hypertrophy. ​Circulation Research​, 126(12), 1746–1759. https://doi.org/10.1161/CIRCRESAHA.119.315558
  4. Wu, Y., Ding, Y., Ramprasath, T., & Zou, M. H. (2021). Oxidative stress, GTPCH1, and endothelial nitric oxide synthase uncoupling in hypertension. ​Antioxidants & Redox Signaling​, 34(9), 750–764. https://doi.org/10.1089/ars.2020.8112
  5. Weinberg, R. L., Brook, R. D., Rubenfire, M., & Eagle, K. A. (2021). Cardiovascular impact of nutritional supplementation with omega-3 fatty acids: JACC focus seminar. ​Journal of the American College of Cardiology​, 77(5), 593–608. https://doi.org/10.1016/j.jacc.2020.11.060
  6. Bercea, C. I., Cottrell, G. S., Tamagnini, F., & McNeish, A. J. (2021). Omega-3 polyunsaturated fatty acids and hypertension: A review of vasodilatory mechanisms of docosahexaenoic acid and eicosapentaenoic acid. ​British Journal of Pharmacology​, 178(4), 860–877. https://doi.org/10.1111/bph.15336
  7. Zhang, X., Ritonja, J. A., Zhou, N., Chen, B. E., & Li, X. (2022). Omega-3 polyunsaturated fatty acids intake and blood pressure: A dose-response meta-analysis of randomized controlled trials. ​Journal of the American Heart Association​, 11(11), e025071. https://doi.org/10.1161/JAHA.121.025071
  8. Brosolo, G., Da Porto, A., Marcante, S., Picci, A., Capilupi, F., Capilupi, P., Bertin, N., Vivarelli, C., Bulfone, L., Vacca, A., Catena, C., & Sechi, L. A. (2023). Omega-3 fatty acids in arterial hypertension: Is there any good news? ​International Journal of Molecular Sciences​, 24(11), 9520. https://doi.org/10.3390/ijms24119520
  9. Colussi, G., Catena, C., Novello, M., Bertin, N., & Sechi, L. A. (2017). Impact of omega-3 polyunsaturated fatty acids on vascular function and blood pressure: Relevance for cardiovascular outcomes. ​Nutrition, Metabolism & Cardiovascular Diseases​, 27(3), 191–200. https://doi.org/10.1016/j.numecd.2016.07.011
  10. Hwang, H. J., Jung, T. W., Kim, J. W., Kim, J. A., Lee, Y. B., Hong, S. H., Roh, E., Choi, K. M., Baik, S. H., & Yoo, H. J. (2019). Protectin DX prevents H2O2-mediated oxidative stress in vascular endothelial cells via an AMPK-dependent mechanism. ​Cellular Signalling​, 53, 14–21. https://doi.org/10.1016/j.cellsig.2018.09.011
  11. Wang, H., Li, Q., Zhu, Y., & Zhang, X. (2021). Omega-3 polyunsaturated fatty acids: Versatile roles in blood pressure regulation. ​Antioxidants & Redox Signaling​, 34(10), 800–810. https://doi.org/10.1089/ars.2020.8108
  12. Rizos, E. C., Ntzani, E. E., Bika, E., Kostapanos, M. S., & Elisaf, M. S. (2012). Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: A systematic review and meta-analysis. ​JAMA​, 308(10), 1024–1033. https://doi.org/10.1001/2012.jama.11374
  13. Aung, T. et al. (2018). Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: Meta-analysis of 10 trials involving 77,917 individuals. ​JAMA Cardiology​, 3(3), 225–234. https://doi.org/10.1001/jamacardio.2017.5205
  14. Root, M., Collier, S. R., Zwetsloot, K. A., West, K. L., & McGinn, M. C. (2013). A randomized trial of fish oil omega-3 fatty acids on arterial health, inflammation, and metabolic syndrome in a young healthy population. ​Nutrition Journal​, 12, 40. https://doi.org/10.1186/1475-2891-12-40
  15. Minihane, A. M. et al. (2016). Consumption of fish oil providing amounts of eicosapentaenoic acid and docosahexaenoic acid that can be obtained from the diet reduces blood pressure in adults with systolic hypertension: A retrospective analysis. ​The Journal of Nutrition​, 146(3), 516–523. https://doi.org/10.3945/jn.115.220475
  16. Innes, J. K., & Calder, P. C. (2020). Marine omega-3 (n-3) fatty acids for cardiovascular health: An update for 2020. ​International Journal of Molecular Sciences​, 21(4), 1362. https://doi.org/10.3390/ijms21041362
  17. Matsumoto, C. et al. (2019). Fish and omega-3 fatty acid consumption and risk of hypertension. ​Journal of Hypertension​, 37(6), 1223–1229. https://doi.org/10.1097/HJH.0000000000002062
  18. Emdin, C. A., Khera, A. V., & Kathiresan, S. (2017). Mendelian randomization. ​JAMA​, 318(19), 1925–1926. https://doi.org/10.1001/jama.2017.17219
  19. Ahmed, M. et al. (2021). Adiposity and cancer: A Mendelian randomization analysis in the UK biobank. ​International Journal of Obesity​, 45(12), 2657–2665. https://doi.org/10.1038/s41366-021-00942-y
  20. Beeghly-Fadiel, A. et al. (2020). A Mendelian randomization analysis of circulating lipid traits and breast cancer risk. ​International Journal of Epidemiology​, 49(4), 1117–1131. https://doi.org/10.1093/ije/dyz242
  21. Hemani, G. et al. (2018). The MR-Base platform supports systematic causal inference across the human phenome. ​eLife​, 7, e34408. https://doi.org/10.7554/eLife.34408
  22. Burgess, S. et al. (2023). Guidelines for performing Mendelian randomization investigations: Update for summer 2023. ​Wellcome Open Research​, 4, 186. https://doi.org/10.12688/wellcomeopenres.15555.3
  23. Kanai, M., Tanaka, T., & Okada, Y. (2016). Empirical estimation of genome-wide significance thresholds based on the 1000 Genomes Project data set. ​Journal of Human Genetics​, 61(10), 861–866. https://doi.org/10.1038/jhg.2016.72
  24. Zehr, K. R., & Walker, M. K. (2018). Omega-3 polyunsaturated fatty acids improve endothelial function in humans at risk for atherosclerosis: A review. ​Prostaglandins & Other Lipid Mediators​, 134, 131–140. https://doi.org/10.1016/j.prostaglandins.2017.07.005
  25. Marston, N. A. et al. (2019). Association between triglyceride lowering and reduction of cardiovascular risk across multiple lipid-lowering therapeutic classes: A systematic review and meta-regression analysis of randomized controlled trials. ​Circulation​, 140(16), 1308–1317. https://doi.org/10.1161/CIRCULATIONAHA.119.041998
  26. Opoku, S. et al. (2019). Prevalence and risk factors for dyslipidemia among adults in rural and urban China: Findings from the China National Stroke Screening and Prevention Project (CNSSPP). ​BMC Public Health​, 19(1), 1500. https://doi.org/10.1186/s12889-019-7827-5
  27. Oh, D. Y. et al. (2010). GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. ​Cell​, 142(5), 687–698. https://doi.org/10.1016/j.cell.2010.07.041
  28. Thies, F. et al. (2003). Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: A randomised controlled trial. ​Lancet​, 361(9356), 477–485. https://doi.org/10.1016/S0140-6736(03)12468-3
  29. Limbu, R., Cottrell, G. S., & McNeish, A. J. (2018). Characterisation of the vasodilation effects of DHA and EPA, n-3 PUFAs (fish oils), in rat aorta and mesenteric resistance arteries. ​PLoS One​, 13(2), e0192484. https://doi.org/10.1371/journal.pone.0192484
  30. Williams, B. et al. (2018). 2018 ESC/ESH Guidelines for the management of arterial hypertension. ​European Heart Journal​, 39(33), 3021–3104. https://doi.org/10.1093/eurheartj/ehy339
  31. Whelton, P. K. et al. (2018). 2017 ACC/AHA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: Executive summary. ​Hypertension​, 71(6), 1269–1324. https://doi.org/10.1161/HYP.0000000000000066
  32. Nicholls, S. J. et al. (2020). Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: The STRENGTH randomized clinical trial. ​JAMA​, 324(22), 2268–2280. https://doi.org/10.1001/jama.2020.22258
  33. Manson, J. E. et al. (2019). Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. ​New England Journal of Medicine​, 380(1), 23–32. https://doi.org/10.1056/NEJMoa1811403
  34. ASCEND Study Collaborative Group et al. (2018). Effects of n-3 fatty acid supplements in diabetes mellitus. ​New England Journal of Medicine​, 379(16), 1540–1550. https://doi.org/10.1056/NEJMoa1804989
  35. Cicero, A. F., Ertek, S., & Borghi, C. (2009). Omega-3 polyunsaturated fatty acids: Their potential role in blood pressure prevention and management. ​Current Vascular Pharmacology​, 7(3), 330–337. https://doi.org/10.2174/157016109788340659
  36. Bürgin-Maunder, C. S. et al. (2016). Investigation of long chain omega-3 PUFAs on arterial blood pressure, vascular reactivity and survival in angiotensin II-infused Apolipoprotein E-knockout mice. ​Clinical and Experimental Pharmacology & Physiology​, 43(2), 174–181. https://doi.org/10.1111/1440-1681.12520
  37. Borghi, C., & Cicero, A. F. (2006). Omega-3 polyunsaturated fatty acids: Their potential role in blood pressure prevention and management. ​Heart International​, 2(2), 98. https://doi.org/10.4081/hi.2006.98
  38. Wang, X., & Cheng, Z. (2020). Cross-sectional studies: Strengths, weaknesses, and recommendations. ​Chest​, 158(1S), S65–S71. https://doi.org/10.1016/j.chest.2020.03.012
  39. Birney, E. (2022). Mendelian randomization. ​Cold Spring Harbor Perspectives in Medicine​, 12(4), a041302. https://doi.org/10.1101/cshperspect.a041302