Effect of linoleic acid on ischemic heart disease and its risk factors: a Mendelian randomization study

The role of n-6 polyunsaturated fatty acids (PUFAs) in ischemic heart disease (IHD) is controversial, and dietary guidelines vary. Observationally, lower saturated fat intake and higher intake of vegetable oils rich in linoleic acid (LA), the main n-6 PUFA, is associated with lower IHD and diabetes; however, randomized controlled trials have not fully corroborated these benefits. We assessed how genetically predicted LA affected IHD and its risk factors, including diabetes, lipids, and blood pressure. We also assessed the role of LA in reticulocyte count, the red blood cell precursor, which has recently been identified as a possible causal factor in IHD.

Two-sample instrumental variable analysis with genetic instruments, i.e., Mendelian randomization, was used to obtain unconfounded estimates using genetic variants strongly (p value < 5 × 10^-8) and solely associated with LA, applied to an IHD case (n ≤ 76,014)-control (n ≤ 264,785) study (mainly based on the meta-analysis of CARDIoGRAMplusC4D 1000 Genomes and UK Biobank CAD SOFT GWAS), the DIAbetes Genetics Replication And Meta-analysis diabetes case (n = 26,676)-control (n = 132,532) study, lipids from the Global Lipids Genetics Consortium Results (n = 196,475), and reticulocyte count and blood pressure from the UK Biobank (n ≤ 361,194). A weighted median and Mendelian randomization Egger were used for sensitivity analysis.

Genetically predicted LA was not associated with IHD or systolic blood pressure. Genetically predicted higher serum LA was associated with lower diabetes (odds ratio (OR) 0.97 per percentage in total fatty acid increase in LA, 95% confidence interval (CI) 0.96 to 0.99) and lower lipids (low-density lipoprotein, high-density lipoprotein, and total cholesterol), but may be associated with higher diastolic blood pressure. The findings were robust to different single nucleotide polymorphism (SNP) selections, analytic methods, and correction for multiple testing.

Our novel study suggests a benefit of LA for diabetes and lipids but no benefit for IHD, blood pressure, or reticulocyte count. Explicating these paradoxical findings would facilitate identification of effective new interventions for diabetes and IHD.