The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: a Mendelian randomization study.
Maria-Carolina BorgesPhillip HaycockJie ZhengGibran HemaniLaurence J HoweA Floriaan SchmidtJames R StaleyR Thomas LumbersAlbert HenryRozenn N LemaitreTom R GauntMichael V HolmesGeorge Davey SmithAroon D HingoraniDeborah A LawlorPublished in: Human molecular genetics (2022)
Despite early interest, the evidence linking fatty acids to cardiovascular diseases (CVDs) remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the etiology of several CVD endpoints in up to 1 153 768 European (maximum 123 668 cases) and 212 453 East Asian (maximum 29 319 cases) ancestry individuals. As instruments, we selected single nucleotide polymorphisms mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple CVDs, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low-density lipoprotein (LDL) cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that PUFA and MUFA biosynthesis are involved in the etiology of CVDs and suggest LDL cholesterol as a potential mediating trait between PUFA biosynthesis and CVDs risk.
Keyphrases
- fatty acid
- low density lipoprotein
- cell wall
- cardiovascular disease
- venous thromboembolism
- coronary artery disease
- magnetic resonance imaging
- magnetic resonance
- skeletal muscle
- type diabetes
- blood pressure
- left ventricular
- mass spectrometry
- cardiovascular risk factors
- adipose tissue
- cardiovascular events
- percutaneous coronary intervention
- coronary artery bypass grafting
- aortic valve
- patient reported outcomes