Red Blood Cell Polyunsaturated Fatty Acids and Vascular Diseases: A Mendelian Randomization Study

Abstract

Abstract Objectives To evaluate the causal association of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs), as measured in red blood cells (RBC), with cardiovascular disease (CVD), cerebrovascular disease (CBVD), and peripheral vascular disease (PVD). Methods Applying a two-sample Mendelian Randomization approach, we first developed genetic instruments for RBC-PUFAs by utilizing summary statistics from previous genome-wide association study in the Framingham Heart Study. We then evaluated the association of these instrumental variables with CVD, CBVD, PVD, and their subtypes in the UK Biobank cohort. Results Strong evidence of causal association with at least one RBC-PUFAs was observed for the overall risk of PVD and three of its subtypes (aortic aneurysm and dissection, arterial embolism and thrombosis, and other PVDs), but only for two CVD subtypes (hypertensive heart disease, and chronic ischemic heart disease) and for two CBVD subtypes (stroke, and cerebral infarction). Based on their effects on all examined diseases, RBC-PUFAs clustered into two groups: a protective group with alpha-Linolenic acid (ALA), linoleic acid (LA), eicosadienoic acid (EDA), and dihomo-gamma-linolenic acid (DGLA); and the other risk group with docosapentaenoic acid (DPA), gamma-linolenic acid (GLA), arachidonic acid (AA), and adrenic acid (AdrA). PUFAs in the protective group are protective, while those in the risk group are risk-increasing, for all diseases with significant associations except for hypertensive heart diseases. In the metabolic pathway converting short-chain PUFAs into long-chain ones, the protective group is mapped to precursors of desaturases, while the risk group corresponds to their products. Conclusions Genetically regulated RBC-PUFAs are associated with the risk of PVD, and subtypes of PVD, CVD, and CBVD. Funding Sources University of Georgia Research Foundation.