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Polyunsaturated fatty acid biosynthesis pathway and genetics. implications for interindividual variability in
Kumar S D Kothapalli1, Hui Gyu Park1, J Thomas Brenna2
1Dell Pediatric Research Institute, Depts of Pediatrics, of Chemistry, and of Nutrition, University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX, United States.
Insights
Genetic variations influence fatty acid balance, impacting COVID-19 severity. Fast desaturators may face higher risk, suggesting omega-3 fatty acids could mitigate severe SARS-CoV-2 responses.
Area of Science:
- Genetics and Molecular Biology
- Immunology
- Nutritional Science
Background:
- COVID-19 can cause severe inflammation and thrombosis via cytokine and thrombotic storms.
- SARS-CoV infection upregulates Cox-2, producing eicosanoids and docosanoids from highly unsaturated fatty acids (HUFA) that mediate inflammation and thrombosis.
Purpose of the Study:
- To investigate the role of genetic polymorphisms in FADS1 and their impact on HUFA balance.
- To explore the relationship between genetic variations, HUFA levels, and COVID-19 severity.
- To predict potential therapeutic interventions for SARS-CoV-2 infection.
Main Methods:
- Analysis of genetic polymorphisms, specifically insertion-deletion (Indel) rs66698963 and FADS gene cluster haplotypes in Europeans.
- Measurement of circulating arachidonic acid (AA) and other HUFA levels.
- Correlation of fatty acid profiles with desaturation efficiency and potential COVID-19 risk.
Main Results:
- Specific genetic variations (Indel rs66698963, FADS haplotypes) significantly alter circulating AA levels (>50%) and the AA/HUFA balance (47-84%).
- These variations are linked to differential desaturation at the FADS1-mediated 20:3→20:4 step, consistent with evolutionary selection possibly related to diet.
- Populations with high linoleic acid and low alpha-linoleic acid diets tend to drive net HUFA balance.
Conclusions:
- Genetic predisposition, particularly fast desaturators (insertion allele at rs66698963), may increase susceptibility to severe COVID-19 pathological responses.
- High-dose omega-3 HUFA supplementation is predicted to potentially reduce the risk and severity of SARS-CoV-2 infection in susceptible individuals.
Abstract:
COVID-19 symptoms vary from silence to rapid death, the latter mediated by both a cytokine storm and a thrombotic storm. SARS-CoV (2003) induces Cox-2, catalyzing the synthesis, from highly unsaturated fatty acids (HUFA), of eicosanoids and docosanoids that mediate both inflammation and thrombosis. HUFA balance between arachidonic acid (AA) and other HUFA is a likely determinant of net signaling to induce a healthy or runaway physiological response. AA levels are determined by a non-protein coding regulatory polymorphisms that mostly affect the expression of FADS1, located in the FADS gene cluster on chromosome 11. Major and minor haplotypes in Europeans, and a specific functional insertion-deletion (Indel), rs66698963, consistently show major differences in circulating AA (>50%) and in the balance between AA and other HUFA (47-84%) in free living humans; the indel is evolutionarily selective, probably based on diet. The pattern of fatty acid responses is fully consistent with specific genetic modulation of desaturation at the FADS1-mediated 20:3→20:4 step. Well established principles of net tissue HUFA levels indicate that the high linoleic acid and low alpha-linoleic acid in populations drive the net balance of HUFA for any individual. We predict that fast desaturators (insertion allele at rs66698963; major haplotype in Europeans) are predisposed to higher risk and pathological responses to SARS-CoV-2 could be reduced with high dose omega-3 HUFA.
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