Association of plasma polyunsaturated fatty acids with arterial blood pressure: A Mendelian randomization study.

ABSTRACT: High polyunsaturated fatty acids (PUFAs) intake is recommended for primary and secondary prevention of cardiovascular disease (CVD). However, the association of PUFAs with blood pressure (BP) is still controversial. In the present study, two-sample Mendelian randomization (MR) analysis was performed to investigate the causal relationship of PUFAs with BP, including systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP).Genetic instruments and summary statistics for two-sample MR analysis were obtained from 3 large-scale genome-wide association studies (GWASs). Eight single nucleotide polymorphisms (SNPs) significantly (P < 5 × 10-8) related to 6 PUFAs were used as instrumental variables. Conventional inverse-variance weighted method was adopted to evaluate the causality of PUFAs with BP; the Weighted Median, MR-egger, and Leave-one-out method were used for sensitivity analyses.As a result, there was no evidence of a causal association between all PUFAs and SBP. In addition, arachidonic acid (AA, ß = -0.04, P < .001) and eicosapentaenoic acid (EPA, ß = -0.47, P = .02) were negatively associated with DBP, while linoleic acid (LA, ß = 0.03, P = .005) and α-linolenic acid (ALA, ß = 3.83, P < .001) were positively associated with DBP. There was no evidence of a causal relationship between either docosapentaenoic acid (DPA) or docosahexaenoic acid (DHA) with DBP.In conclusion, a genetic predisposition to plasma polyunsaturated fatty acid (PUFA) had a divergent effect on DBP, independent of SBP. It suggested that it is helpful for lower DBP level to supplemental intake of AA and EPA or promote the conversion of LA and ALA to AA and EPA respectively, which need to be further validated with randomized controlled studies.

Sex-Specific Genetically Predicted Iron Status in relation to 12 Vascular Diseases: A Mendelian Randomization Study in the UK Biobank.

BACKGROUND: Iron overload has been implicated in the pathogenesis of varicose veins (VVs). However, the association of serum iron status with other vascular diseases (VDs) is not well understood, which might be a potential target for VD prevention. This study was aimed at investigating the causal associations between iron status and VDs using the Mendelian randomization (MR) method. METHODS: A two-sample MR was designed to investigate whether iron status was associated with VDs, based on iron data from a published genome-wide association study meta-analysis of 48,972 subjects of European descent and VD data obtained from the UK Biobank, including 361,194 British subjects (167,020 males and 194,174 females). We further explored whether there was sex difference in the associations between genetically predicted iron status and VDs. RESULTS: The results demonstrated that iron status had a significant causal effect on VVs of lower extremities (P < 0.001) and a potential effect on coronary atherosclerosis (P < 0.05 for serum iron, ferritin, and transferrin saturation, respectively), but not on other VDs. Furthermore, higher iron status exerted a detrimental effect on VVs of lower extremities in both genders (P < 0.05) and a protective effect on male patients with coronary atherosclerosis (P < 0.05 for serum iron, ferritin, and transferrin saturation, respectively). CONCLUSIONS: This MR study provides robust evidence that higher iron status increases the risk of VVs of lower extremities, whereas it reduces the incidence of coronary atherosclerosis in the male population, which indicates that iron has divergent effects on vascular pathology.

The impact of growth differentiation factor 15 on the risk of cardiovascular diseases: two-sample Mendelian randomization study.

BACKGROUND: Growth differentiation factor 15 (GDF-15), a stress responsive cytokine, belongs to transforming growth factor ß cytokine superfamily. Some evidence support that it's involved in inflammation, coagulation, oxidative stress, endothelial dysfunction, and hemostasis. However, it's still controversial whether GDF-15 directly contributes to the morbidity and mortality of patients suffered with cardiovascular disease (CVD). Besides prospective cohort study and randomized controlled trial, Mendelian randomization (MR) is a genetic epidemiological method that exploits genetic variants as unbiased proxies for modifiable to determine the causal relationships between exposures and health outcomes. Herein, we introduced a two-sample MR approach to evaluate the causal relationships of circulating GDF-15 levels with major CVDs incidence. METHODS: Genetic instruments and summary statistics for two-sample MR analysis were obtained from 5 independent large genome-wide association studies (GWAS) to investigate the causal correlation between circulating GDF-15 levels and 9 CVDs, respectively. Conventional inverse variance weighted method was adopted to evaluate the causality of GDF-15 with different outcomes; weighted median and MR egger were used for sensitivity analyses. RESULTS: Among 9 SNPs identified from 5 GWASs in 2.6 million individuals, 5 SNPs (rs1227731, rs3195944, rs17725099, rs888663, rs749451) coming from chromosome 19 and containing the PGPEP1 and GDF-15 genes were employed. Based on the instruments, circulating GDF-15 levels significantly linked to the increased risk of cardioembolic stroke, atrial fibrillation, coronary artery disease and myocardial infarction. However, no significant causal association was observed for circulating GDF-15 levels with the incidence of any ischemic stroke, large-artery atherosclerotic stroke, small vessel stroke, heart failure and nonischemic cardiomyopathy. CONCLUSIONS: The MR study provides with genetic evidence for the causal relationship of circulating GDF-15 levels with the increased risk of cardioembolic stroke, atrial fibrillation, coronary artery disease and myocardial infarction, but not any ischemic stroke, large-artery atherosclerotic stroke, small vessel stroke, heart failure and nonischemic cardiomyopathy. It indicates that GDF-15 might be a promising biomarker or potential therapeutic target for some CVDs.