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

ABSTRACT: Whether 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 ?-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 ?-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.

SUBMITTER: Yuan S

PROVIDER: S-EPMC6950527 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Project description:AIMS/HYPOTHESIS:Epidemiological data on the associations of circulating fatty acid levels with type 2 diabetes are inconsistent. We conducted a two-sample Mendelian randomisation study to explore the causal associations of plasma levels of ten fatty acids with type 2 diabetes and glycaemic traits. METHODS:Thirteen SNPs associated with circulating levels of ten individual fatty acids at the genome-wide significance level (p?<?5?×?10-8) were selected as instrumental variables for the exposures. For the outcomes, summary-level data were obtained from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium for type 2 diabetes (898,130 individuals) and from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) for the glycaemic traits (up to 46,186 non-diabetic individuals). The inverse-variance weighted method was used for analyses. RESULTS:Genetic predisposition to higher plasma levels of eight of the ten fatty acids were statistically significantly associated with lower or higher odds of type 2 diabetes. The OR per one SD increment of each fatty acid was 0.93 (95% CI 0.90, 0.96; p?=?2.21?×?10-5) for ?-linolenic acid, 0.96 (95% CI 0.94, 0.98; p?=?1.85?×?10-4) for linoleic acid, 0.86 (95% CI 0.81, 0.91; p?=?6.68?×?10-7) for palmitoleic acid, 0.87 (95% CI 0.81, 0.93; p?=?2.21?×?10-5) for oleic acid, 1.08 (95% CI 1.03, 1.12; p?=?0.002) for eicosapentaenoic acid, 1.04 (95% CI 1.02, 1.07; p?=?0.001) for docosapentaenoic acid, 1.03 (95% CI 1.02, 1.05; p?=?2.51?×?10-5) for arachidonic acid and 1.09 (95% CI 1.03, 1.15; p?=?0.003) for stearic acid. The same eight fatty acids were also associated with fasting glucose levels and HOMA-B. The associations, except that for palmitoleic acid, were driven by variants in FADS1/2. CONCLUSIONS/INTERPRETATION:Genetic predisposition to higher circulating levels of eight out of ten fatty acids was associated with type 2 diabetes, fasting glucose and islet beta cell function. However, the associations, except that for palmitoleic acid, were driven by variants in FADS1/2, which encode enzymes with a key role in fatty acid metabolism.

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

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