Association of circulating fatty acids with cardiovascular disease risk: analysis of individual-level data in three large prospective cohorts and updated meta-analysis

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 associ