Association of circulating fatty acids with cardiovascular disease risk: analysis of individual-level data in three large prospective cohorts and updated meta-analysis
Authors: Shi Fanchao , Chowdhury Rajiv , Sofianopoulou Eleni , Koulman Albert , Sun Luanluan , Steur Marinka , Aleksandrova Krasimira , Dahm Christina C , Schulze Matthias B , van der Schouw Yvonne T , Agnoli Claudia , Amiano Pilar , Boer Jolanda M A , Bork Christian S , Cabrera-Castro Natalia , Eichelmann Fabian , Elbaz Alexis , Farràs Marta , Heath Alicia K , Kaaks Rudolf , Katzke Verena , Keski-Rahkonen Pekka , Masala Giovanna , Moreno-Iribas Conchi , Panico Salvatore , Papier Keren , Petrova Dafina , Quirós J Ramón , Ricceri Fulvio , Severi Gianluca , Tjønneland Anne , Tong Tammy Y N , Tumino Rosario , Wareham Nicholas J , Weiderpass Elisabete , Di Angelantonio Emanuele , Forouhi Nita G , Danesh John , Butterworth Adam S , Kaptoge Stephen 
Published: October 2024

Abstract

Aims
Associations of saturated and unsaturated fatty acids (FAs) with cardiovascular disease (CVD) remain controversial. We therefore aimed to investigate the prospective associations of objectively measured FAs with CVD, including incident coronary heart disease (CHD) and stroke, as well as CVD mortality.

Methods and results
Circulating FA concentrations expressed as the percentage of total FAs were assayed in 172 891 participants without prior vascular disease at baseline from the European Prospective Investigation into Cancer and Nutrition-CVD (EPIC-CVD) (7343 CHD; 6499 stroke), UK Biobank (1825; 1474), and INTERVAL (285; 209) cohort studies. Hazard ratio (HR) per 1-standard deviation (SD) higher FA concentrations was estimated using Cox regression models and pooled by random-effects meta-analysis. Systematic reviews with meta-analysis published by 6 May 2023 on associations between FAs and CVDs were systematically searched and updated meta-analyses using random-effects model were conducted. Evidence from randomized controlled trials (RCTs) was also summarized. Higher concentrations of total saturated FAs (SFAs) were associated with higher cardiovascular risks in the combined analysis, with differential findings noted for SFA sub-types in further analysis restricted to EPIC-CVD: positive associations for even-chain SFA [HR for CHD 1.24 (95% CI: 1.18–1.32); stroke 1.23 (1.10–1.38)] and negative associations for odd-chain [0.82 (0.76–0.87); 0.73 (0.67–0.78)] and longer-chain [0.95 (0.80–1.12); 0.84 (0.72–0.99)] SFA. In the combined analysis, total n-3 polyunsaturated FA (PUFA) [0.91 (0.85–0.97)], including docosahexaenoic acid (DHA) [0.91 (0.84–0.98)], was negatively associated with incident CHD risk. Similarly, total n-6 PUFA [0.94 (0.91–0.98)], including linoleic acid (LA) [0.89 (0.83–0.95)], was negatively associated with incident stroke risk. In contrast, more detailed analyses in EPIC-CVD revealed that several downstream n-6 PUFAs of LA were positively associated with CHD risk. Updated meta-analyses of 37 FAs including 49 non-overlapping studies, involving between 7787 and 22 802 CHD cases and between 6499 and 14 221 stroke cases, showed broadly similar results as our combined empirical analysis and further suggested significant inverse associations of individual long-chain n-3 PUFAs and LA on both CHD and stroke. The findings of long-chain n-3 PUFAs were consistent with those from published RCTs on CHD despite insufficient evidence in monotherapy, while RCT evidence remained unclear for the rest of the explored FAs.

Conclusion
Our study provides an overview of the most recent evidence on the associations between objectively measured FAs and CVD outcomes. Collectively, the data reveal notable differences in associations by SFA sub-types and call for further studies, especially RCTs, to explore these links.