Circulating polyunsaturated fatty acids percentages and coronary artery disease incidence and mortality:...

The roles of polyunsaturated fatty acids (PUFAs) in preventing coronary artery disease (CAD) remain controversial. This study aimed to investigate the relationships between circulating PUFA percentages and CAD outcomes using observational and Mendelian randomization (MR) approaches.

We analyzed data from 203,373 UK Biobank participants without CAD at baseline. Four PUFA percentages (docosahexaenoic acid [DHA]%, omega-3%, linoleic acid [LA]%, and omega-6%) were examined in relation to incident CAD and CAD mortality. MR analyses included one-sample linear and nonlinear approaches, as well as two-sample univariable and multivariable methods. Observational and one-sample MR analyses were conducted overall and stratified by age and sex.

During a median follow-up of 13.2 years, 16,098 incident CAD cases and 1243 CAD deaths occurred. Observationally, all PUFA percentages were inversely associated with both CAD outcomes. In one-sample MR, genetically predicted DHA% was strongly associated with decreased risk of CAD mortality (hazard ratio [HR] 0.31, 95 % confidence interval [CI] 0.15-0.62, P = 9.71 × 10^-4), with a pronounced effect in individuals aged ≥58 years (HR 0.20, 95 % CI 0.09-0.43, P = 4.75 × 10^-5). Genetically predicted omega-6% was associated with a decreased risk of incident CAD (HR 0.84, 95 % CI 0.76-0.92, P = 1.26 × 10^-4), with a significant effect in females but not in males. Two-sample MR confirmed these findings, suggesting partial mediation through lipid pathways. Nonlinear MR analyses validated these linear associations without threshold effects.

Observational and genetically predicted high DHA% protects against CAD mortality, particularly in older adults. Omega-6% and incident CAD exhibited sex-specific inverse associations. These findings underscore the importance of considering age and sex in PUFA-based strategies for CAD prevention.