The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: a Mendelian randomization study

Abstract

Despite early interest, the evidence linking fatty acids to cardiovascular diseases (CVDs) remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the etiology of several CVD endpoints in up to 1 153 768 European (maximum 123 668 cases) and 212 453 East Asian (maximum 29 319 cases) ancestry individuals. As instruments, we selected single nucleotide polymorphisms mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple CVDs, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low-density lipoprotein (LDL) cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that PUFA and MUFA biosynthesis are involved in the etiology of CVDs and suggest LDL cholesterol as a potential mediating trait between PUFA biosynthesis and CVDs risk.

Figure 1

Overview of desaturation and elongation reactions involved in the conversion of MUFA from SFA and of longer-chain omega-3 and omega-6 PUFA from their shorter chain precursors. ^*D5D, D6D, ELOVL2 and SCD activities were explored in the current study. Abbreviations: Saturated fatty acids (SFA): PA: palmitic acid; SA: stearic acid. Monounsaturated fatty acids (MUFA): POA: palmitoleic acid; OA: oleic acid. ω-6 polyunsaturated fatty acids (PUFA): LA: linoleic acid; GLA: ϒ-linolenic acid; EDA: eicosadienoic acid; DGLA: dihomo-ϒ-linolenic acid; AA: arachidonic acid; ADA: adrenic acid; TTA: tetracosatetraenoic acid; TPA: tetracosapentaenoic acid; DPA: docosapentaenoic acid. ω-3 polyunsaturated fatty acids (PUFA): ALA: α-linolenic acid; SDA: stearidonic acid; ETE: eicosatrienoic acid; ETA: eicosatetraenoic acid; EPA: eicosapentaenoic acid; DPA: docosapentaenoic acid; TPA: tetracosapentaenoic acid; THA: tetracosahexaenoic acid; DHA: docosahexaenoic acid.

Figure 2

Schematic representation of scenarios leading to true (A) and spurious (B–E) findings in Mendelian randomization analyses on the effect of fatty acids biosynthesis and CVD risk. Image (A) represents vertical pleiotropy in which the effect of genetic instruments on CVD is mediated by fatty acids biosynthesis. Images (B–E) represent alternative mechanisms that could bias Mendelian randomization findings: (B) confounding by LD in which the selected genetic variant is in LD with another genetic variant influencing CVD independently; (C) horizontal pleiotropy in which the genetic variant influences fatty acids biosynthesis and CVD via two different biological pathways; (D) confounding by population stratification, assortative mating or indirect genetic effects, in which different phenomena can introduce spurious association between genetic variant and CVD in samples of unrelated individuals and (E) selection bias in which selection into the study creates a spurious association between the genetic variant and CVD owing to collider stratification bias. U: unobserved confounders; P: population phenomena (i.e. population stratification, assortative mating or indirect genetic effects); S: selection; SNP: single nucleotide polymorphism; CVD: cardiovascular diseases; LD: linkage disequilibrium.

Figure 3

Mendelian randomization results for the risk of CVDs related to increasing activity of enzymes coded by FADS1/2 (D5D/D6D), ELOVL2 (ELOVL2) and SCD (SCD) among individuals of European and East Asian ancestries. Results are expressed as odds ratio of CVDs per standard unit increase in the marker of enzyme activity for FADS1/2 (i.e. AA:DGLA ratio in Europeans and DGLA:LA ratio in East Asians), ELOVL2 (i.e. DHA:DPA ratio in Europeans) and SCD (i.e. POA:PA ratio in Europeans) loci. For individuals of European ancestry, SNP-CVDs association data were metanalyzed across multiple genetic association consortia, UK Biobank and FinnGen. For individuals of East Asian ancestry, SNP-CVDs association data were extracted from BioBank Japan. Full symbols indicate associations at P-value lower than the P-value threshold accounting for multiple testing (P < 0.00556). AA: arachidonic acid; DGLA: dihomo-ϒ-linolenic acid; DHA: docosahexaenoic acid; DPA: docosapentaenoic acid; LA: linoleic acid; PA: palmitic acid; POA: palmitoleic acid; SNP: single nucleotide polymorphism; FADS1/2: fatty acid desaturases 1 and 2; ELOVL2: elongase 2; SCD: stearoyl-CoA desaturase.

Figure 4

Genetic association plots for fatty acids enzyme activity (proxied by AA:DGLA, DHA:DPA and POA:PA ratios) and CVDs risk among individuals of European ancestry. Results for each trait are expressed as log₁₀  P-values for the FADS, ELOVL2 and SCD locus (columns 1, 2 and 3, respectively). AA: arachidonic acid; DGLA: dihomo-γ-linoleic acid; DHA: docosahexaenoic acid; DPA: docosapentaenoic acid; LA: linoleic acid; PA: palmitic acid; POA: palmitoleic acid; FADS: fatty acids desaturase; ELOVL2: elongase 2; SCD: stearoyl-CoA desaturase; CAD: coronary artery disease; AIS: any ischemic stroke; AHS: any haemorrhagic stroke; HF: heart failure; AF: atrial fibrillation; PAD: peripheral artery disease; AA: aortic aneurysm; VT: venous thromboembolism; AVS: aortic valve stenosis.

Figure 5

Mendelian randomization results for cardiovascular risk factors related to increasing activity of enzymes coded by FADS1/2 (D5D/D6D), ELOVL2 (ELOVL2) and SCD (SCD) among individuals of European and East Asian ancestries. Results are expressed as change in standard units (SD) or log odds ratio (logOR) of CVD risk factors per standard unit increase in the marker of enzyme activity for FADS1/2 (i.e. AA:DGLA ratio in Europeans and DGLA:LA ratio in East Asians), ELOVL2 (i.e. DHA:DPA ratio in Europeans) and SCD (i.e. POA:PA ratio in Europeans) loci. For individuals of European ancestry, data were extracted from UK Biobank or genetic association studies. For individuals of East Asian ancestry, data were extracted from BioBank Japan. Full symbols indicate associations at P-value lower than the P-value threshold accounting for multiple testing (P < 0.00625). Smoking is represent by pack years of smoking and number of cigarettes per day in European and East Asian ancestry individuals, respectively. AA: arachidonic acid; DGLA: dihomo-γ-linolenic acid; DHA: docosahexaenoic acid; DPA: docosapentaenoic acid; LA: linoleic acid; PA: palmitic acid; POA: palmitoleic acid; FADS1/2: fatty acid desaturases 1 and 2; ELOVL2: elongase 2; SCD: stearoyl-CoA desaturase; LDL-cholesterol: low-density lipoprotein-cholesterol.

Figure 6

Genetic association plots for fatty acids enzyme activity (proxied by AA:DGLA, DHA:DPA and POA:PA ratio) and CVD risk factors among individuals of European ancestry. Results for each trait are expressed as log₁₀  P-values for the FADS, ELOVL2 and SCD locus (columns 1, 2 and 3, respectively). AA: arachidonic acid; DGLA: dihomo-γ-linoleic acid; DHA: docosahexaenoic acid; DPA: docosapentaenoic acid; LA: linoleic acid; PA: palmitic acid; POA: palmitoleic acid; FADS: fatty acids desaturase; ELOVL2: elongase 2; SCD: stearoyl-CoA desaturase; LDL: low-density lipoprotein.

Figure 7

Phenome wide association scan of FADS1/2 (rs174546), ELOVL2 (rs3734398) and SCD (rs603424) genetic variants in European and East Asian ancestry individuals. Results are expressed as the Z-statistic for the variant-trait association for the allele increasing enzyme expression/activity. Red circles denote P-value < in Europeans and P-value < in East Asians. FADS1/2: fatty acid desaturases 1 and 2; ELOVL2: elongase 2; SCD: stearoyl-CoA desaturase.

Figure 8

Association of FADS1/2 (rs174546), ELOVL2 (rs3734398) and SCD (rs603424) genetic variants with cardiovascular risk factors among unrelated individuals and within siblings of European ancestry. Results are expressed as change in SD units (or risk difference), and 95% CI, of cardiovascular risk factors per allele increasing enzyme activity. FADS1/2: fatty acid desaturases 1 and 2; ELOVL2: elongase 2; SCD: stearoyl-CoA desaturase.