Plasma Phospholipid Fatty Acids, FADS1 and Risk of 15 Cardiovascular Diseases: A Mendelian Randomisation Study

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Yuan, Shuai 
Bäck, Magnus 
Bruzelius, Maria 
Mason, Amy M 

jats:pWhether circulating fatty acids (FAs) play a causal role in the development of cardiovascular disease (CVD) remains unclear. We conducted a Mendelian randomisation study to explore the associations between plasma phospholipid FA levels and 15 CVDs. Summary-level data from the CARDIoGRAMplusC4D, MEGASTROKE, and Atrial Fibrillation consortia and UK Biobank were used. Sixteen single-nucleotide polymorphisms (SNPs) associated with ten plasma FAs were used as instrumental variables. SNPs in or close to the FADS1 gene were associated with most FAs. We performed a secondary analysis of the association between a functional variant (rs174547) in FADS1, which encodes ?5-desaturase (a key enzyme in the endogenous FA synthesis), and CVD. Genetic predisposition to higher plasma α-linolenic, linoleic, and oleic acid levels was associated with lower odds of large-artery stroke and venous thromboembolism, whereas higher arachidonic and stearic acid levels were associated with higher odds of these two CVDs. The associations were driven by SNPs in or close to FADS1. In the secondary analysis, the minor allele of rs174547 in FADS1 was associated with significantly lower odds of any ischemic stroke, large-artery stroke, and venous thromboembolism and showed suggestive evidence of inverse association with coronary artery disease, abdominal aortic aneurysm and aortic valve stenosis. Genetically higher plasma α-linolenic, linoleic, and oleic acid levels are inversely associated with large-artery stroke and venous thromboembolism, whereas arachidonic and stearic acid levels are positively associated with these CVDs. The associations were driven by FADS1, which was also associated with other CVDs.</jats:p>

?5-desaturase, FADS, Mendelian randomisation, cardiovascular disease, diet, fatty acids, Alleles, Arachidonic Acid, Cardiovascular Diseases, Data Analysis, Delta-5 Fatty Acid Desaturase, Fatty Acid Desaturases, Fatty Acids, Genetic Predisposition to Disease, Humans, Linoleic Acid, Mendelian Randomization Analysis, Odds Ratio, Oleic Acid, Phospholipids, Polymorphism, Single Nucleotide, Protective Factors, Risk Factors, Stearic Acids, alpha-Linolenic Acid
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Wellcome Trust (204623/Z/16/Z)
British Heart Foundation (None)
Medical Research Council (MC_UU_00002/7)
British Heart Foundation (RG/18/13/33946)
Funding for this study came from the Swedish Research Council for Health, Working Life and Welfare (Forte; Grant Number 2018-00123) and the Swedish Research Council (Vetenskapsrådet; Grant Number 2019-00977). SB is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 204623/Z/16/Z).