Roles for circulating polyunsaturated fatty acids in ischemic stroke and modifiable factors: a Mendelian randomization study

Abstract

Background: Available data about the effects of circulating polyunsaturated fatty acids (PUFAs) on ischemic stroke (IS) and its main risk factors remains limited and conflicting. Therefore, we conducted Mendelian randomization (MR) to assess whether genetically predicted PUFA affected IS, lipids and blood pressure (BP).

Methods: Genetic instruments associated with IS were derived from ISGC Consortium (n = 29,633), with lipids were derived from GLGC(n = 188,577), with BP were derived from Neale Lab(n = 337,000). The inverse-variance weighted method was the main analysis to estimate the effect of exposure on outcome. Sensitivity analyses included principal components analysis, MR-Egger, weighted median, and weighted mode.

Results: Per SD increases in serum α-linolenic acid (ALA) were associated with lower IS risk, with odd ratio (OR) of 0.867(0.782,0.961), arachidonic acid (AA) were associated with higher IS risk (OR: 1.053(1.014,1.094)). Likewise, Per SD increases in ALA were associated with the lower-level low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC) (β:-0.122(- 0.144, - 0.101), - 0.159(- 0.182, - 0.135), - 0.148(- 0.171, - 0.126), respectively), AA were associated with the higher-level of LDL-C, HDL-C and TC (β:0.045(0.034,0.056), 0.059(0.050,0.067), 0.055(0.046,0.063), respectively). Linoleic acid (LA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) had little or no association with IS, lipids or BP at Bonferroni-corrected significance. Different analytic methods supported these findings. The intercept test of MR-Egger implied no pleiotropy.

Conclusions: High-level plasma ALA was protective for IS but AA was the opposite. LA, EPA, DHA, and DPA had no effects on IS.

Keywords: Blood pressure; Ischemic stroke; Lipids; Mendelian randomization; Omega-3 fatty acids; Omega-6 fatty acids.

Fig. 1

Associations of plasma LA with IS and lipids, BP estimated by IVW and PCA method. OR (95%) of ischemic stroke a per 1 SD increase in linoleic acid. β (95%) of risk factors b per 1 SD increase in linoleic acid. IVW, inverse-variance weighted. β, beta; CI, confidence interval; OR, odds ratio; PCA, principal components analysis. SNP, single nucleotide polymorphism. *Remained Bonferroni-corrected significance (p < 0.05/6 = 0.00833)

Fig. 2

Associations of plasma AA with IS and lipids, BP estimated by IVW and PCA method. OR (95%) of ischemic stroke a per 1 SD increase in arachidonic acid. β (95%) of risk factors b per 1 SD increase in arachidonic acid. IVW, inverse-variance weighted. β, beta; CI, confidence interval; OR, odds ratio; PCA, principal components analysis. SNP, single nucleotide polymorphism. *Remained Bonferroni-corrected significance (p < 0.05/6 = 0.00833)

Fig. 3

Associations of plasma ALA with IS and lipids, BP estimated by IVW and PCA method. OR (95%) of ischemic stroke a) per 1 SD increase in α-linolenic acid. β (95%) of risk factors b per 1 SD increase in α-linolenic acid. IVW, inverse-variance weighted. β, beta; CI, confidence interval; OR, odds ratio; PCA, principal components analysis. SNP, single nucleotide polymorphism. *Remained Bonferroni-corrected significance (p < 0.05/6 = 0.00833)

Fig. 4

Associations of plasma EPA with IS and lipids, BP estimated by IVW and PCA method. OR (95%) of ischemic stroke a per 1 SD increase in eicosapentaenoic acid. β (95%) of risk factors b per 1 SD increase in eicosapentaenoic acid. IVW, inverse-variance weighted. β, beta; CI, confidence interval; OR, odds ratio; PCA, principal components analysis. SNP, single nucleotide polymorphism. *Remained Bonferroni-corrected significance (p < 0.05/6 = 0.00833)

Fig. 5

Associations of plasma DHA with IS and lipids, BP estimated by IVW and PCA method. OR (95%) of ischemic stroke a per 1 SD increase in docosahexaenoic acid. β (95%) of risk factors b per 1 SD increase in docosahexaenoic acid. IVW, inverse-variance weighted. β, beta; CI, confidence interval; OR, odds ratio; PCA, principal components analysis. SNP, single nucleotide polymorphism. *Remained Bonferroni-corrected significance (p < 0.05/6 = 0.00833)

Fig. 6

Associations of plasma DPA with IS and lipids, BP estimated by IVW and PCA method. OR (95%) of ischemic stroke a per 1 SD increase in docosapentaenoic acid. β (95%) of risk factors b per 1 SD increase in docosapentaenoic acid. IVW, inverse-variance weighted. β, beta; CI, confidence interval; OR, odds ratio; PCA, principal components analysis. SNP, single nucleotide polymorphism. *Remained Bonferroni-corrected significance (p < 0.05/6 = 0.00833)