Circulating Polyunsaturated Fatty Acids and COVID-19: a Prospective Cohort Study and Mendelian Randomization Analysis

Overview

Journal medRxiv

Date 2022 Feb 16

PMID 35169810

Authors

Yitang Sun

Radhika Chatterjee

Akash Ronanki

Kaixiong Ye

Affiliations

Soon will be listed here.

Abstract

Background: Higher circulating polyunsaturated fatty acids (PUFAs), especially omega-3 ones, have been linked to a better prognosis in patients of coronavirus disease 2019 (COVID-19). However, the effects and causality of pre-infection PUFA levels remain unclear.

Objective: To investigate the observational and causal associations of circulating PUFAs with COVID-19 susceptibility and severity.

Design: We first performed a prospective cohort study in UK Biobank, with 20,626 controls who were tested negative and 4,101 COVID-19 patients, including 970 hospitalized ones. Plasma PUFAs at baseline were measured by nuclear magnetic resonance, including total PUFAs, omega-3 PUFAs, omega-6 PUFAs, docosahexaenoic acid (DHA), linoleic acid (LA), and the omega-6/omega-3 ratio. Moreover, bidirectional two-sample Mendelian randomization (MR) analyses were performed to examine the causal associations of eight individual PUFAs, measured in either plasma or red blood cells, with COVID-19 susceptibility and severity using summary statistics from existing genome-wide association studies.

Results: In the observational association analysis, total PUFAs, omega-3 PUFAs, omega-6 PUFAs, DHA, and LA were associated with a lower risk of severe COVID-19. Omega-3 PUFAs and DHA were also associated with a lower risk of testing positive for COVID-19. The omega-6/omega-3 ratio was positively associated with risks of both susceptibility and severity. The forward MR analysis indicated that arachidonic acid (AA) and docosapentaenoic acid (DPA-n3) might be causally associated with a lower risk of severe COVID-19, with OR (95% CI) per one SD increase in the plasma level as 0.96 (0.94, 0.99) and 0.89 (0.81, 0.99), respectively. The reverse MR analysis did not support any causal effect of COVID-19 on PUFAs.

Conclusions: Our observational analysis supported that higher circulating PUFAs, either omega-3 or omega-6, are protective against severe COVID-19, while omega-3 PUFAs, especially DHA, were also associated with reducing COVID-19 susceptibility. Our MR analysis further supported causal associations of AA and DPA-n3 with a lower risk of severe COVID-19.

References

Bowden J, Davey Smith G, Haycock P, Burgess S . Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016; 40(4):304-14. PMC: 4849733. DOI: 10.1002/gepi.21965. View

Armstrong J, Rudkin J, Allen N, Crook D, Wilson D, Wyllie D . Dynamic linkage of COVID-19 test results between Public Health England's Second Generation Surveillance System and UK Biobank. Microb Genom. 2020; 6(7). PMC: 7478634. DOI: 10.1099/mgen.0.000397. View

Julkunen H, Cichonska A, Slagboom P, Wurtz P . Metabolic biomarker profiling for identification of susceptibility to severe pneumonia and COVID-19 in the general population. Elife. 2021; 10. PMC: 8172246. DOI: 10.7554/eLife.63033. View

Doaei S, Gholami S, Rastgoo S, Gholamalizadeh M, Bourbour F, Bagheri S . The effect of omega-3 fatty acid supplementation on clinical and biochemical parameters of critically ill patients with COVID-19: a randomized clinical trial. J Transl Med. 2021; 19(1):128. PMC: 8006115. DOI: 10.1186/s12967-021-02795-5. View

Ma M, Yang F, Wang Z, Bao Q, Shen J, Xie X . Association of plasma polyunsaturated fatty acids with arterial blood pressure: A Mendelian randomization study. Medicine (Baltimore). 2021; 100(3):e24359. PMC: 7837969. DOI: 10.1097/MD.0000000000024359. View

Perez-Torres I, Guarner-Lans V, Soria-Castro E, Manzano-Pech L, Palacios-Chavarria A, Valdez-Vazquez R . Alteration in the Lipid Profile and the Desaturases Activity in Patients With Severe Pneumonia by SARS-CoV-2. Front Physiol. 2021; 12:667024. PMC: 8144632. DOI: 10.3389/fphys.2021.667024. View

Tintle N, Pottala J, Lacey S, Ramachandran V, Westra J, Rogers A . A genome-wide association study of saturated, mono- and polyunsaturated red blood cell fatty acids in the Framingham Heart Offspring Study. Prostaglandins Leukot Essent Fatty Acids. 2014; 94:65-72. PMC: 4339483. DOI: 10.1016/j.plefa.2014.11.007. View

Liao L, Li W, Liu Y, Li J, Zhuang X, Liao X . Exploring the causal pathway from omega-6 levels to coronary heart disease: A network Mendelian randomization study. Nutr Metab Cardiovasc Dis. 2019; 30(2):233-240. DOI: 10.1016/j.numecd.2019.09.013. View

Sun Y, Zhou J, Ye K . White Blood Cells and Severe COVID-19: A Mendelian Randomization Study. J Pers Med. 2021; 11(3). PMC: 8002054. DOI: 10.3390/jpm11030195. View

10.

Chiang N, Serhan C . Specialized pro-resolving mediator network: an update on production and actions. Essays Biochem. 2020; 64(3):443-462. PMC: 7682745. DOI: 10.1042/EBC20200018. View

11.

Burgess S, Butterworth A, Thompson S . Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013; 37(7):658-65. PMC: 4377079. DOI: 10.1002/gepi.21758. View

12.

Zhao J, Schooling C . The role of linoleic acid in asthma and inflammatory markers: a Mendelian randomization study. Am J Clin Nutr. 2019; 110(3):685-690. DOI: 10.1093/ajcn/nqz130. View

13.

Torrinhas R, Calder P, Lemos G, Waitzberg D . Parenteral fish oil: An adjuvant pharmacotherapy for coronavirus disease 2019?. Nutrition. 2020; 81:110900. PMC: 7836308. DOI: 10.1016/j.nut.2020.110900. View

14.

Zhu N, Zhang D, Wang W, Li X, Yang B, Song J . A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020; 382(8):727-733. PMC: 7092803. DOI: 10.1056/NEJMoa2001017. View

15.

Asher A, Tintle N, Myers M, Lockshon L, Bacareza H, Harris W . Blood omega-3 fatty acids and death from COVID-19: A pilot study. Prostaglandins Leukot Essent Fatty Acids. 2021; 166:102250. PMC: 7816864. DOI: 10.1016/j.plefa.2021.102250. View

16.

Davey Smith G, Ebrahim S . 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?. Int J Epidemiol. 2003; 32(1):1-22. DOI: 10.1093/ije/dyg070. View

17.

Hemani G, Zheng J, Elsworth B, Wade K, Haberland V, Baird D . The MR-Base platform supports systematic causal inference across the human phenome. Elife. 2018; 7. PMC: 5976434. DOI: 10.7554/eLife.34408. View

18.

Zhang T, Zhao J, Schooling C . The associations of plasma phospholipid arachidonic acid with cardiovascular diseases: A Mendelian randomization study. EBioMedicine. 2021; 63:103189. PMC: 7804604. DOI: 10.1016/j.ebiom.2020.103189. View

19.

Wurtz P, Kangas A, Soininen P, Lawlor D, Davey Smith G, Ala-Korpela M . Quantitative Serum Nuclear Magnetic Resonance Metabolomics in Large-Scale Epidemiology: A Primer on -Omic Technologies. Am J Epidemiol. 2017; 186(9):1084-1096. PMC: 5860146. DOI: 10.1093/aje/kwx016. View

20.

Li S, Hua X . Modifiable lifestyle factors and severe COVID-19 risk: a Mendelian randomisation study. BMC Med Genomics. 2021; 14(1):38. PMC: 7856619. DOI: 10.1186/s12920-021-00887-1. View