Role of circulating polyunsaturated fatty acids on cardiovascular diseases risk: analysis using Mendelian randomization and fatty acid genetic association data from over 114,000 UK Biobank participants

Abstract

Background: Despite early interest in the health effects of polyunsaturated fatty acids (PUFA), there is still substantial controversy and uncertainty on the evidence linking PUFA to cardiovascular diseases (CVDs). We investigated the effect of plasma concentration of omega-3 PUFA (i.e. docosahexaenoic acid (DHA) and total omega-3 PUFA) and omega-6 PUFA (i.e. linoleic acid and total omega-6 PUFA) on the risk of CVDs using Mendelian randomization.

Methods: We conducted the largest genome-wide association study (GWAS) of circulating PUFA to date including a sample of 114,999 individuals and incorporated these data in a two-sample Mendelian randomization framework to investigate the involvement of circulating PUFA on a wide range of CVDs in up to 1,153,768 individuals of European ancestry (i.e. coronary artery disease, ischemic stroke, haemorrhagic stroke, heart failure, atrial fibrillation, peripheral arterial disease, aortic aneurysm, venous thromboembolism and aortic valve stenosis).

Results: GWAS identified between 46 and 64 SNPs for the four PUFA traits, explaining 4.8-7.9% of circulating PUFA variance and with mean F statistics >100. Higher genetically predicted DHA (and total omega-3 fatty acids) concentration was related to higher risk of some cardiovascular endpoints; however, these findings did not pass our criteria for multiple testing correction and were attenuated when accounting for LDL-cholesterol through multivariable Mendelian randomization or excluding SNPs in the vicinity of the FADS locus. Estimates for the relation between higher genetically predicted linoleic acid (and total omega-6) concentration were inconsistent across different cardiovascular endpoints and Mendelian randomization methods. There was weak evidence of higher genetically predicted linoleic acid being related to lower risk of ischemic stroke and peripheral artery disease when accounting by LDL-cholesterol.

Conclusions: We have conducted the largest GWAS of circulating PUFA to date and the most comprehensive Mendelian randomization analyses. Overall, our Mendelian randomization findings do not support a protective role of circulating PUFA concentration on the risk of CVDs. However, horizontal pleiotropy via lipoprotein-related traits could be a key source of bias in our analyses.

Keywords: Cardiovascular diseases; Fatty acids; Mendelian randomization.

Fig. 1

Association of genetically predicted DHA and linoleic acid on the circulating PUFA composition among individuals of European ancestry before and after excluding SNPs nearby the FADS locus. Results are expressed as z-statistics (i.e. effect estimate / standard error) for the variation in individual omega-3 and omega-6 fatty acids (y-axis) across multiple data sources (x-axis) according to genetically predicted DHA and linoleic acid. These are expressed using different shades of colours to indicate relative strengths of association; blue, red and grey boxes denote, respectively, decreases, increases and no change in individual PUFA, while white boxes represent missing data. Asterisks indicate P-value: < 5×10⁻⁸ (***), < 5×10⁻⁵ (**) and < 5×10⁻² (*). DHA: docosahexaenoic acid; FADS: fatty acid desaturase genes; ELOVL: elongase genes; SNP: single-nucleotide polymorphism; Plasma FA: plasma fatty acids; N: median sample size used for estimating SNP-fatty acid association; GC: gas chromatography; NMR: nuclear magnetic resonance; MS: mass spectrometry

Fig. 2

Multivariable regression and Mendelian randomization results for the risk of cardiovascular diseases associated with higher genetically predicted DHA and total omega-3 fatty acids among individuals of European ancestry. Results are expressed as odds ratio (OR) of cardiovascular diseases per standard unit increase in DHA and total omega-3 fatty acids with corresponding 95% confidence interval (CI). Full symbols indicate associations at P-value lower than the threshold accounting multiple testing (P < 0.006). Multivariable regression results are adjusted by for sex, age, BMI, fasting time, alcohol intake, frequency, statins use and total circulating fatty acids. DHA: docosahexaenoic acid; MV: multivariable regression; MR: Mendelian randomization; MVMR: multivariable Mendelian randomization; FA: fatty acids; TG: triglycerides; LDL: low-density lipoprotein cholesterol; ApoB: apolipoprotein B

Fig. 3

Multivariable regression and Mendelian randomization results for the risk of cardiovascular diseases associated with higher genetically predicted linoleic acid and total omega-6 fatty acids among individuals of European ancestry. Results are expressed as odds ratio of cardiovascular diseases per standard unit increase in linoleic acid and total omega-6 fatty acids with corresponding 95% confidence interval (CI). Full symbols indicate associations at P-value lower than the threshold accounting multiple testing (P < 0.006). Multivariable regression results are adjusted by for sex, age, BMI, fasting time, alcohol intake, frequency, statins use and total circulating fatty acids. MV: multivariable regression; MR: Mendelian randomization; MVMR: multivariable Mendelian randomization; FA: fatty acids; TG: triglycerides; LDL: low-density lipoprotein cholesterol; ApoB: apolipoprotein B