Coronary Atherosclerosis (AS), the foremost adversary to human health, manifests as a progressive and multifaceted ailment. Its spectrum ranges from silent conditions to clinical scenarios such as stable angina, Acute Coronary Syndrome (ACS), Heart Failure (HF), and Sudden Cardiac Death (SCD).1 World Health Organization (WHO) data indicates a trend towards a younger demographic being affected by AS, yet the elderly remain predominantly susceptible to acute cardiovascular incidents. Hypertension stands as the most prevalent chronic condition and a pivotal contributor to AS. It is a primary driver of cardiovascular morbidity and global premature mortality. A comprehensive study encompassing 250 741 individuals across 13 nations revealed a prehypertension prevalence of 40% in males, with 36.1% of hypertensive men and 62.1% of hypertensive women undergoing pharmacological management to mitigate blood pressure levels. Emerging evidence suggests that vascular calcification (VC) plays a significant role in the pathogenesis of both atherosclerosis and hypertension, with the latter being a critical element in coronary artery disease progression.2 Consequently, the strategic reduction of blood pressure is imperative in curtailing the risks associated with hypertension and coronary events.
According to the AHA/ACC guidelines, the diagnostic criteria for hypertension are systolic blood pressure (SBP) ≥130 mmHg and/or diastolic blood pressure (DBP) ≥80 mmHg, with SBP ≥140 mmHg or DBP ≥90 mmHg as the diagnostic criterion for grade 2 hypertension.Hypertension (HTN) is one of the major risk factors for atherosclerotic cardiovascular disease (ASCVD).Also, HTN is the world's leading modifiable risk factor for cardiovascular (CV) disease, stroke, disability and death.3 Firstly, it has been shown that when blood pressure is elevated, the protective endothelial barrier is impaired, which causes lipid deposition to form AS, and the process of AS is associated with oxidative stress (OS) and inflammatory immune response. In hypertensive patients, up-regulation of NADPH oxidase (NOX) increases reactive oxygen species (ROS) production, which further generates OS, and in the process induces low-density lipoprotein (ox-LDL) production, contributing to the development of ASCVD. In addition, HTN patients have higher angiotensin II activity, and Ang II-activated nuclear factor (HF)-κB inflammatory pathway can cause vascular endothelial dysfunction, which in turn induces ASCVD.4
Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), encompassing alpha-linolenic acid (ALA) and its metabolic progenies eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are classified as “essential” fatty acids. These are predominantly sourced from dietary inclusions such as plant oils, marine organisms, and commercial fish oil supplements.5 Omega-3 PUFAs orchestrate blood pressure modulation via diverse mechanisms. They facilitate vascular function regulation through the liberation of Omega-3 PUFA metabolites, including EPA and DHA derivatives (17,18-epoxy-EPA and 19,20-epoxy-DHA), which bolster vasoreactivity in cardiomyocytes, thus aiding in the management of cardiovascular conditions like hypertension. In endothelial cells (ECs), Omega-3 PUFAs, in concert with EPA, can enhance nitric oxide (NO) synthesis via endothelial NO synthase (eNOS) activation, promoting vasodilation in arterioles and contributing to antihypertensive effects.5 It has been shown that rapid and direct effects of Omega-3 PUFA include Ca2+-independent eNOS activation; translocation and dissociation of Caveolin-1 from eNOS in endothelial cells6; and activation of TRPV4-type Ca2+-permeable ion channels in endothelial cells, which improves flow-mediated vasodilatation7 and further protects cardiac and aortic tissue.8 Regarding AS, longitudinal studies have demonstrated that a 30-month regimen of EPA+DHA is associated with triglyceride reduction and the regression of coronary lipid-rich plaques.9
The efficacy of dietary polyunsaturated fatty acids (PUFAs), particularly linoleic acids (LAs), in thwarting CVD has been met with considerable debate. Syntheses of clinical trial data have yielded inconclusive results, suggesting that an increase in n-6 PUFA intake does not correlate with a diminished incidence of coronary heart disease events,10,11 and the robustness of this evidence has been questioned. While diets combining n-3 and n-6 PUFAs have been linked to favorable outcomes in some randomized controlled trials, diets rich exclusively in n6 PUFAs have not demonstrated the same protective benefits.12 Cohort studies have observed a beneficial link between n-3 PUFA consumption and cardiovascular health,13 yet randomized trials present a spectrum of findings.14,15 Notably, a substantial trial (n = 25 871) discerned that while daily n-3 PUFA supplementation (1 g/day) did not curtail major cardiovascular events, it significantly lowered the occurrence of cardiovascular diseases over an average span of 5.3 years, prompting further inquiry into the underlying protective mechanisms of Omega-3 against cardiovascular and coronary artery disease (CAD).16
In recent years it has been shown that Omega-3 fatty acids have blood pressure-lowering, antithrombotic, inflammatory status-improving, and endothelial-protective properties, which in turn suggests that Omega-3 fatty acids have a better efficacy in improving both the composition and stability of coronary atherosclerotic plaques,17 thus further demonstrating that Omega-3 fatty acids are associated with the additional benefit of lowering blood pressure.18
This investigation targets hypertension and coronary atherosclerosis as the outcomes, with Omega-3 fatty acids as the exposures of interest in a Mendelian randomization (MR) framework to discern potential causative links. The objective is to lay a foundational theory for subsequent inquiries into the intricate mechanisms and risk factors associated with Omega-3 fatty acids.
METHODS Study designTo elucidate the putative causal nexus between Omega-3 levels, hypertension, and atherosclerosis, a two-sample Mendelian randomization (MR) approach was adopted. The study harnessed single nucleotide polymorphisms (SNPs) as instrumental variables (IVs). This SNP-centric methodology mirrors the principles of randomized controlled trials and is instrumental in pinpointing causal relationships between the exposure factors—namely, Omega-3 and hypertension—and the outcome of atherosclerosis.
Study design drawingsA Mendelian Randomization Approach between Omega-3 Fatty Acids and cardiovascular disease.
The current investigation incorporated data from prior studies that had received approval from the appropriate institutional review boards. Participants in the original studies provided informed consent, as documented in ref. [18]. Therefore, no further ethical permissions were required for this analysis, as noted in ref. [19]. Nonetheless, we obtained ethical clearance from our institutional review board and ensured informed consent from all participants involved in our study.
Genetic instrument variants for exposureOur analysis employed 49 single nucleotide polymorphisms (SNPs) associated with Omega-3 fatty acid levels from the FinnGen dataset of Finland. The inclusion criterion for the SNPs was a significant association with Omega-3 fatty acids at a p-value threshold of less than 5 × 10−8.
GWAS summary data for hypertension and atherosclerosisFor hypertension, we accessed data from the FinnGen dataset, encompassing 16 379 784 SNPs. The comprehensive GWAS summary data for hypertension can be found at
Additionally, we utilized data on atherosclerosis from the same dataset. The diagnostic criteria for atherosclerosis were based on a comprehensive blood glucose and lipid profile assessment, evidence of calcium deposits via x-ray, atheromatous plaque presence confirmed by arteriography, or Doppler ultrasound detection. This dataset, which includes 23 363 cases and 195 429 controls, is accessible at
The selection of SNPs was conducted with scrupulous attention to detail. Initially, SNPs demonstrating a robust association with levothyroxine sodium were selected, meeting the genome-wide significance threshold of p < 5 × 10−8. To ensure the independence of the SNPs and to minimize the influence of linkage disequilibrium (LD), we ensured that the SNPs were independent by implementing a stringent r2 criterion of 0.01 within a 10 000 kb range. This step was critical to reduce the potential bias introduced by LD. Additionally, the relationship between the instrumental variables (IVs) and the exposure was quantified using the F-statistic for each SNP, with IVs exhibiting an F-statistic greater than 10 considered to provide unbiased estimates.
STATISTICAL ANALYSISThe primary method of analysis was the IVW approach, which is predicated on the assumption that all SNPs are valid IVs, thus providing the most accurate estimates. In instances where any SNP does not conform to the IV assumption, a modified version known as the random-effects IVW method is utilized. This method adjusts each estimate based on its standard error, thereby accounting for potential heterogeneity. The weighted median approach requires that a minimum of 50% of the SNPs are valid to maintain the integrity of the instrumental variable assumption. The median of the corresponding distribution was determined by ranking the SNPs according to their weights and examining the experimental outcomes. Furthermore, the MR-Egger regression, which does not depend on the absence of pleiotropic effects, was used to derive an effect estimate. The extent of the pleiotropic effect was assessed using the intercept from the MR-Egger regression, with a nonsignificant deviation from zero indicating no evidence of a directional pleiotropic bias.
SENSITIVITY ANALYSISThe random-effects IVW method served as the cornerstone of our analytical approach to discern the causal links between sex factors and Omega-3 fatty acid levels. This method amalgamates the Wald ratio estimates for each SNP to derive a causal estimate for each risk factor, yielding reliable estimates in the absence of pleiotropy. A suite of sensitivity analyses was conducted to corroborate the associations. The weighted median method was employed, which requires only half of the SNPs to be valid instruments, and the MR-Egger approach was utilized to accommodate a nonzero intercept, indicative of pleiotropy. The MR-PRESSO test was introduced to identify potential outliers, with adjustments made by excluding such SNPs. If the adjusted effect aligns with the uncorrected effect, the IVW-MR estimates are deemed robust. However, significant discrepancies warrant preference for the adjusted effects, as they are likely to be less biased and more reflective of the true relationship.
A two-stage MR analysis was implemented to evaluate mediation effects. The first stage involved using a genetic instrument for the sex factor to estimate the causal impact of exposure on the mediator. The second stage employed genetic instruments for the mediator to ascertain the causal effect on the risk of developing hypertension and atherosclerosis.
The causal effects of Omega-3 on the risk of hypertension and atherosclerosis were presented using odds ratios (ORs), beta coefficients (β), and 95% confidence intervals (CIs). MR and sensitivity analyses were performed using R software (version 4.2.1) and the “TwoSampleMR” package (version 0.5.6). In the univariate MR analyses, a p-value of < 1.25 × 10−2 (adjusted for multiple comparisons as 0.05 divided by the number of exposures and outcomes, 2 × 2) was considered indicative of a statistically significant causal relationship.
RESULTS Omega-3 fatty acids and their influence on atherosclerosis Selection of instrumental variables for Omega-3 fatty acid levelsThe genetic markers indicative of Omega-3 fatty acid levels are delineated in Figure 1. A total of 49 single nucleotide polymorphisms (SNPs) were meticulously chosen as instrumental variables (IVs). Each of these genetic markers surpassed the threshold for genome-wide significance (p < 5 × 10−8) and exhibited robust instrument strength (F-statistic > 10). The influence of each SNP on atherosclerosis risk is graphically represented in Forest Plot and Scatter Diagram (Figure 2).
Through the application of IVW analysis, MR-Egger regression, and weighted median approaches, we probed the potential causal link between Omega-3 fatty acid levels and atherosclerosis. The IVW method hinted at a potential reduction in atherosclerosis risk associated with elevated Omega-3 levels, although this association did not reach statistical significance (IVW, OR = 1.1198; 95% CI: 0.9641−1.3006, p = .130). Complementary analyses via MR-Egger regression yielded similar results (OR = 1.11937; 95% CI: 0.9069–1.3817, p = .290).
Verification of Mendelian randomization assumptionsOur analytical approach entailed a stringent selection of SNPs, adhering to the genome-wide significance criterion (p < 5 × 10−8). This strategy provided substantial evidence negating the presence of directional pleiotropy, thereby upholding the integrity of the second MR assumption (p = .996). Moreover, the MR heterogeneity test revealed significant variability in the data (p = 3.66E-52), underscoring the need for cautious interpretation. Collectively, our rigorous evaluation of MR's core postulates confirmed the suitability of the chosen SNPs as genetic instruments. Consequently, the inferred associations between Omega-3 levels predicted by these genetic markers and atherosclerosis remained unobscured by any discernible confounding factors or intermediaries.
The impact of Omega-3 on hypertension Determination of instrumental variables for Omega-3 levelsThe genetic determinants for Omega-3 levels are cataloged in Figure 1. From the pool of candidates, we identified and selected 49 SNPs to serve as instrumental variables (IVs). These genetic markers met the criteria for genome-wide significance (p < 5 × 10−8) and demonstrated sufficient statistical power (F-statistic > 10). The individual impact of these SNPs on hypertension is depicted in the corresponding Forest Plot and Scatter Diagram (Figure 2).
Mendelian randomization evaluation of Omega-3's effect on hypertensionUtilizing the IVW method, MR-Egger regression, and weighted median analysis, we investigated the causal influence of Omega-3 levels on hypertension. The IVW analysis indicated a modest reduction in the risk of hypertension associated with higher Omega-3 levels (IVW, OR = 0.9006; 95% CI: 0.8179−0.9917, p = .033). Results from alternative MR-Egger methods also supported this finding, albeit with wider confidence intervals (OR = 0.8984; 95% CI: 0.7845–1.0287, p = .130).
Validation of the Mendelian randomization frameworkOur SNP selection process was governed by the established genome-wide significance benchmark (p < 5 × 10−8), which provided a robust foundation for the absence of directional pleiotropy, thereby maintaining the validity of the second MR assumption (p = .958). The heterogeneity test within the MR framework also indicated significant variability (p = .004), warranting a nuanced interpretation of the results. In essence, our comprehensive validation of the MR methodology's core principles affirmed the appropriateness of the selected SNPs as genetic proxies. This ensured that the deduced relationship between Omega-3 levels and hypertension was free from the influence of unrecognized confounders or intermediate variables.
Interrelation of hypertension and atherosclerosis Selection of instrumental variables for hypertensionThe genetic imprints of hypertension are detailed in Figure 1. A concise set of 5 SNPs was meticulously chosen as instrumental variables (IVs). These genetic indicators surpassed the threshold for genome-wide significance (p < 5 × 10−8) and exhibited robust statistical strength (F-statistic > 10). The influence of these genetic variants on atherosclerosis is visually presented in (Figure 2), through Forest and Scatter plots.
Mendelian randomization analysis for atherosclerosisThe causal nexus between hypertension and atherosclerosis was scrutinized using methods such as IVW analysis, MR-Egger regression, and weighted median regression. The IVW method unveiled a paradoxical association, indicating a heightened risk of atherosclerosis in individuals with hypertension (IVW, OR = 1.3036; 95% CI: 1.0672−1.5923, p = .009). Conversely, MR-Egger analysis depicted a nonsignificant trend (OR = 0.6372; 95% CI: 0.3511–1.1565, p = .230), suggesting the need for cautious interpretation.
Verification of Mendelian randomization presumptionsOur SNP selection adhered to the stringent criterion of genome-wide significance (p < 5 × 10−8), which substantiated the nonexistence of directional pleiotropy, thereby upholding the integrity of the second MR postulate (p = .094). The MR heterogeneity test further revealed significant diversity within the observed effects (p = .002). Collectively, our meticulous evaluation of the MR framework's foundational postulates confirmed the suitability of the chosen SNPs as genetic instruments. Consequently, the deduced associations between genetically inferred hypertension and atherosclerosis remained unobscured by latent confounders or intermediaries.
In an extensive data retrieval exercise, our investigation cataloged 49 SNPs associated with omega3 levels. Moreover, a vast array of 16 380 466 SNPs were linked to hypertension, and a comparable magnitude of 16 379 784 SNPs were related to coronary atherosclerosis. This dataset included the magnitude of each SNP's effect on principal component analysis, effect sizes, and standard errors, providing a comprehensive genetic landscape of these conditions.
DISCUSSIONAcknowledging the multifaceted role of Omega-3 fatty acids, our study stands at the forefront of elucidating the intricate biological mechanisms that link these fatty acids to the risk of hypertension and coronary atherosclerosis. Leveraging the power of integrative GWAS analyses with the FinnGen database, we have uncovered a direct influence of Omega-3 fatty acids on hypertension risk, while also highlighting their indirect role in the development of coronary atherosclerosis. This research is instrumental in deepening our understanding of the causal relationships between Omega-3 fatty acids, hypertension, and coronary atherosclerosis pathogenesis, as well as the complex interplay between these conditions within a genomic context.
Moreover, our findings are in harmony with existing literature that identifies the Omega-3 index as a risk marker for sudden cardiac death, suggesting that monitoring the Omega-3 index could serve as a valuable indicator for the management of hypertension and coronary atherosclerosis.19–21 In line with our conclusions, other studies have demonstrated that high-dose EPA formulations confer significant cardiovascular protection, targeting the residual risk associated with triglyceride- rich lipoproteins.5 The benefits of Omega-3 PUFAs may transcend triglyceride reduction, encompassing a broad array of pleiotropic effects such as mitigating vascular inflammation and thrombosis, enhancing endothelial function, and lowering blood pressure.5,21 Empirical evidence from in vitro and in vivo studies, as well as human clinical trials, indicates that Omega-3 PUFAs can positively influence vascular responses, both endothelium-dependent and independent, potentially improving peripheral vascular resistance and thus offering therapeutic benefits for hypertension and coronary atherosclerosis.5,21 Secondly, it has been shown that Omega-3 PUFA can effectively improve the elasticity of large arteries by enhancing the production or release of NO, thereby further reducing blood pressure by vasodilating blood vessels.22 In addition, it has been concluded that in animal and human studies, Omega-3 PUFA improve normal and damaged endothelial function, and thus hypertension, primarily by increasing NO availability through activation of eNOS.23
Our investigation reveals a significant correlation between Omega-3 fatty acids and the heightened risk of hypertension development. Omega-3 fatty acids are recognized for their therapeutic application in managing hyperlipidemia and hypertension.24 Studies have indicated that an augmented intake of Omega-3 polyunsaturated fatty acids (N3-PUFA) correlates with a diminished risk of mortality from all causes and cardiovascular events in hypertensive adults within the United States. These findings propose that elevating dietary N3-PUFA levels could represent a viable approach to curtailing mortality associated with hypertension.25
Furthermore, our research delineates a direct correlation between the propensity for hypertension and the emergence of coronary atherosclerosis. The interconnection between blood pressure and atherosclerosis is evident, with increased arterial wall stress due to heightened blood pressure exacerbating atherosclerotic conditions. Conversely, atherosclerosis may arise from the development of atheromatous plaques in regions subjected to intensified stress as a result of elevated blood pressure.26 While hypertension is characterized by abnormally high blood pressure, numerous studies have substantiated that blood pressure reduction significantly mitigates the risk of atherosclerotic cardiovascular diseases and mortality.24 One particular study assessed carotid-femoral (cf) and femoral-ankle (fa) pulse wave velocities across 4166 adults, deducing that persistently elevated blood pressure contributes to the pathogenesis of arterial stiffness.27
In recent years, increased intake of Omega-3 fatty acids is effective in reducing plaque formation and thus improving coronary atherosclerosis. Omega-3 fatty acids such as eicosapentaenoic acid (EPA) are being attempted to intervene in coronary atherosclerotic disease, and it has been shown that patients treated with EPA have been found to have a greater increase in fibre volume and a greater decrease in liposome volume in both the studies, resulting in an intervention in coronary atherosclerosis.28 The EVAPORATE trial (2020), which treated 80 patients with either ethyl eicosapentaenoate (a purified ethyl EPA) or OMT and looked at plaque regression, concluded that the ethyl eicosapentaenoate group had significantly greater plaque regression (−9.0% vs. +11.0%; p < .05) and a reduction in low-attenuation plaques, fibrofatty volume and fibre volume 29. This seems to constitute an important therapeutic option for plaque abatement in future clinical practice.
The strengths of our two-sample Mendelian Randomization (MR) study are manifold. Primarily, we utilized robust MR analytical methods, selecting SNPs with a high association strength as instrumental variables, akin to the experimental framework of a randomized controlled trial. Secondly, we opted for independent, potent genetic variants as IVs to circumvent potential confounders and enhance the precision of our results.
However, our study is not without its limitations. The GWAS data encompassed subjects exclusively of European descent, necessitating additional research to ascertain the applicability of our conclusions to diverse populations. Moreover, the incidence of hypertension and coronary atherosclerosis exhibited gender-specific disparities. Regrettably, the public databases from which our data were sourced did not permit detailed subgroup analyses for particular demographics, such as age and gender.
In summation, our research provides a comprehensive demonstration of the causal links between Omega-3 fatty acids, hypertension risk, and coronary atherosclerosis development. We identified a negative association between Omega-3 fatty acids and hypertension risk, and a positive association between hypertension and coronary atherosclerosis, alongside a positive relationship between Omega-3s and coronary atherosclerosis. Omega-3 fatty acids may emerge as novel biomarkers, offering fresh perspectives on the treatment and prevention of cardiovascular diseases.
AUTHOR CONTRIBUTIONSQun Wang: Methodology. Yuchen Song: Formal analysis and investigation. Yuchen Song: Writing—original draft preparation. Lianqun Jia: Funding acquisition. Qun Wang: Resources. Lianqun Jia: Supervision. And all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
ACKNOWLEDGMENTSThis work was supported by the National Natural Science Foundation of China (81974548, 82074145, 82374423).
CONFLICT OF INTEREST STATEMENTThe authors declare that they have no competing interests.
DATA AVAILABILITY STATEMENTAll data generated or analyzed during this study are included in this published article (and its Supplementary Information files).
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Abstract
It has been suggested that Omega-3 fatty acids may improve endothelial thickness and thereby reduce the onset of cardiovascular diseases such as coronary atherosclerosis and hypertension. However, published observational epidemiological studies on the relationship between cardiovascular disease (CVD) and Omega-3 fatty acids remain inconclusive. Here, we performed a two-sample Mendelian randomisation analysis using publicly available GWAS pooled statistics to study a GWAS dataset of 16 380 466 SNPs in 23 363 cases and 195 429 controls (also of European ancestry) to determine genetic susceptibility to hypertension. We performed random-effects Inverse Variance Weighted (IVW) Mendelian Randomization (MR) analyses supplemented by a series of sensitivity assessments to measure the robustness of the findings and to detect any violations of the MR assumptions. During the course of the study, we used IVW, MR-Egger, and weighted median regression to infer that Omega-3 intake has a potentially adverse effect against atherosclerosis, although the trend was not significant (OR = 1.1198; 95%; CI: 0.9641–1.3006, p = .130). Meanwhile, our analyses showed a statistically significant negative association between Omega-3 fatty acid levels and risk of hypertension (OR = 0.9006; 95% CI: 0.8179–0.9917, p = .033). In addition, we explored the causal relationship between atherosclerosis and hypertension and found a significant correlation (OR = 1.3036; 95% CI: 1.0672–1.5923, p = .009). In conclusion, our extensive data investigated by MR suggest that elevated levels of Omega-3 fatty acids may be associated with an decreased risk of hypertension. Although there is no direct link between hypertension and atherosclerosis, the possibility of a subtle association cannot be categorically excluded.
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Details
1 College of Integrated Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China
2 Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Ministry of Education of China, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China