Higher circulating polyunsaturated fatty acids (PUFAs), especially omega-3 fatty acids, 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. This study aimed to investigate the observational and causal associations of circulating PUFAs with COVID-19 susceptibility and severity. 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 (blood samples collected from 2007 to 2010) 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, going beyond UK Biobank, we leveraged summary statistics from existing genome-wide association studies to perform bidirectional two-sample Mendelian randomization (MR) analyses to examine the causal associations of eight individual PUFAs, measured in either plasma or red blood cells, with COVID-19 susceptibility and severity. In the observational association analysis of each PUFA measure separately, total, omega-3, and 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. When omega-6, omega-3, and their ratio are jointly analyzed, only omega-3 PUFAs remained significantly and inversely associated with both susceptibility and severity. The forward MR analysis indicated that docosapentaenoic acid (DPA-n3) and arachidonic acid (AA) 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 0.89 (0.81, 0.99) and 0.96 (0.94, 0.99), respectively. The reverse MR analysis did not support any causal effect of COVID-19 on PUFAs. Our observational analysis supported that higher circulating omega-3 PUFAs, especially DHA, may lower the susceptibility to and alleviate the severity of COVID-19. Our MR analysis further supported causal associations of DPA-n3 and AA with a lower risk of severe COVID-19.

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.

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