The relationship of fatty acids to ischaemic heart disease and lifespan in men and women using Mendelian randomization

Background: Observationally, polyunsaturated fatty acids (PUFAs) have health benefits compared with saturated fatty acids (SFAs); randomized controlled trials suggest fewer benefits. We used uni-and multi-variable Mendelian randomization to assess the association of major fatty acids and their sub-species with ischaemic heart disease (IHD) overall and sex-specifically and with lifespan sex-specifically, given differing lifespan by sex. Methods: We obtained strong (P <5x10-8), independent (r2<0.001) genetic predictors of fatty acids from genome-wide association studies (GWAS) in a random subset of 114 999 UK Biobank participants. We applied these genetic predictors to the Cardiogram IHD GWAS (cases = 60 801, controls = 123 504) and to the Finngen consortium GWAS (cases = 31 640, controls = 187 152) for replication and to the UK Biobank for sex-specific IHD and for lifespan based on parental attained age (fathers = 415 311, mothers = 412 937). We used sensitivity analysis and assessed sex differences where applicable. Results: PUFAs were associated with IHD [odds ratio 1.23, 95% confidence interval (CI) 1.05 to 1.44] and lifespan in men (-0.76 years, 95% CI-1.34 to-0.17) but not women (0.20, 95% CI-0.32 to 0.70). Findings were similar for omega-6 fatty acids and linoleic acid. Independent associations of SFAs, mono-unsaturated fatty acids or omega-3 fatty acids with IHD overall or lifespan in men and women were limited. Conclusions: PUFAs, via specific subspecies, may contribute to disparities in lifespan by sex. Sex-specific dietary advice might be a start towards personalized public health and addressing inequities.