Fatty Acid Intake And Reduced Cardiovascular Event Risk
Overview
Recent research has raised questions about the purported benefits of Omega-3 fatty acids in improving endothelial thickness and preventing cardiovascular diseases like coronary atherosclerosis and hypertension. To address this, we conducted a rigorous analysis using Mendelian randomization, leveraging publicly available genetic data from genome-wide association studies (GWAS). Our study encompassed a vast dataset comprising millions of single nucleotide polymorphisms (SNPs) from thousands of individuals of European ancestry.
Employing a random-effects Inverse Variance Weighted (IVW) Mendelian Randomization approach, supplemented by sensitivity assessments to ensure the reliability of our findings, we explored the relationship between Omega-3 intake and the risk of hypertension. While our analysis did not yield a statistically significant trend linking Omega-3 intake to atherosclerosis (OR = 1.1198; 95% CI: 0.9641–1.3006, p = .130), we did observe a noteworthy negative association between Omega-3 fatty acid levels and hypertension risk (OR = 0.9006; 95% CI: 0.8179–0.9917, p = .033).
Furthermore, our investigation extended to exploring the potential causal link between atherosclerosis and hypertension, revealing a significant correlation (OR = 1.3036; 95% CI: 1.0672–1.5923, p = .009). In conclusion, our comprehensive Mendelian randomization analysis suggests that higher Omega-3 fatty acid levels may indeed be associated with a reduced risk of hypertension. However, while we found no direct evidence linking hypertension and atherosclerosis, the possibility of a subtle association warrants further investigation.
Introduction
Coronary atherosclerosis (AS), a significant health concern, presents as a complex ailment ranging from silent conditions to severe clinical scenarios like stable angina, Acute Coronary Syndrome (ACS), Heart Failure (HF), and Sudden Cardiac Death (SCD). While the World Health Organization (WHO) observes a trend towards younger individuals affected by AS, the elderly remain highly susceptible to acute cardiovascular incidents. Hypertension, the most prevalent chronic condition, plays a crucial role in AS development and is a leading cause of cardiovascular morbidity and premature mortality globally.
Recent studies highlight the prevalence of prehypertension and hypertension, particularly among men and women, emphasizing the importance of pharmacological management to control blood pressure levels. Vascular calcification (VC) emerges as a significant factor in both atherosclerosis and hypertension pathogenesis, further underscoring the need for strategic blood pressure reduction to mitigate associated risks.
Diagnostic criteria for hypertension, according to AHA/ACC guidelines, include systolic and/or diastolic blood pressure thresholds, with hypertension being a major risk factor for atherosclerotic cardiovascular disease (ASCVD). Elevated blood pressure disrupts the protective endothelial barrier, leading to lipid deposition and oxidative stress, contributing to ASCVD development. Additionally, hypertension is associated with increased angiotensin II activity and inflammatory pathways, further exacerbating ASCVD risk.
Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), derived from dietary sources like plant oils and marine organisms, offer potential benefits in blood pressure modulation and cardiovascular health. Omega-3 PUFAs facilitate vasoreactivity regulation, endothelial function enhancement, and triglyceride reduction, potentially leading to the regression of coronary plaques.
While the efficacy of dietary polyunsaturated fatty acids (PUFAs) remains debated, studies suggest a beneficial link between Omega-3 PUFA consumption and cardiovascular health. However, randomized trials present mixed findings, prompting further investigation into the protective mechanisms of Omega-3 against cardiovascular and coronary artery disease.
Recent evidence underscores the blood pressure-lowering, anti-thrombotic, anti-inflammatory, and endothelial-protective properties of Omega-3 fatty acids, suggesting their potential to improve the composition and stability of coronary atherosclerotic plaques.
This investigation employs a Mendelian randomization (MR) framework to explore potential causative links between Omega-3 fatty acids, hypertension, and coronary atherosclerosis, aiming to lay a foundational theory for understanding their intricate mechanisms and associated risk factors.
Method
The study’s methodology hinges on a concept known as Mendelian randomization (MR), which utilizes genetic variants as proxies for modifiable exposures, mimicking the randomization process in traditional clinical trials. By leveraging genetic variants associated with Omega-3 fatty acid levels as instrumental variables (IVs), the researchers aimed to investigate whether there’s a causal relationship between Omega-3 levels, hypertension, and atherosclerosis.
The study design drew upon data from prior studies, ensuring ethical compliance and informed consent from participants. Utilizing the FinnGen dataset, which contains genetic and health information from a population of Finnish individuals, the researchers accessed information on Omega-3 fatty acid levels, hypertension, and atherosclerosis.
To identify instrumental variables associated with Omega-3 levels, the researchers screened 49 single nucleotide polymorphisms (SNPs) meeting stringent significance thresholds. This process involved rigorous criteria to ensure the independence of the selected SNPs and to minimize the confounding effects of linkage disequilibrium (LD). By employing a genome-wide significance threshold and implementing criteria to assess SNP independence, the researchers aimed to reduce the risk of bias in their analysis.
Furthermore, the researchers assessed the relationship between instrumental variables and the exposure of interest (Omega-3 levels) using the F-statistic. SNPs with F-statistics greater than 10 were considered to provide unbiased estimates, further ensuring the validity of the MR approach.
By adopting this methodological framework, the study aimed to elucidate potential causal relationships between Omega-3 levels, hypertension, and atherosclerosis, contributing to our understanding of the underlying mechanisms involved in cardiovascular disease development. This meticulous approach, coupled with adherence to ethical standards, underscores the study’s commitment to robust scientific inquiry and its potential implications for clinical practice and public health interventions.
Statistical Analysis
The primary analytical method utilized in the study was the Inverse Variance Weighted (IVW) approach, which assumes all Single Nucleotide Polymorphisms (SNPs) are valid Instrumental Variables (IVs) for providing accurate estimates. When any SNP deviated from this assumption, a modified version called the random-effects IVW method was employed, adjusting estimates based on standard errors to address potential heterogeneity.
The Weighted Median approach required at least 50% of SNPs to be valid IVs for maintaining instrumental variable integrity. The median of the SNP distribution, ranked by weights and experimental outcomes, was determined accordingly. Additionally, the MR-Egger regression, independent of pleiotropic effects, was utilized to derive effect estimates. The pleiotropic effect extent was evaluated using the MR-Egger regression intercept, with a non-significant deviation indicating no directional pleiotropic bias.
Sensitivity analyses were conducted using various methods. The random-effects IVW method formed the foundation, amalgamating Wald ratio estimates to derive causal estimates, particularly reliable in the absence of pleiotropy. The Weighted Median method, requiring only half of SNPs as valid instruments, and the MR-Egger approach accommodating a non-zero intercept, indicative of pleiotropy, were employed. The MR-PRESSO test identified potential outliers, with adjustments made accordingly.
A two-stage Mendelian Randomization (MR) analysis evaluated mediation effects. The first stage used genetic instruments for the sex factor to estimate exposure’s causal impact on the mediator. The second stage employed genetic instruments for the mediator to ascertain the causal effect on developing hypertension and atherosclerosis.
Causal effects of Omega-3 on hypertension and atherosclerosis risk were presented as odds ratios (ORs), beta coefficients (β), and 95% confidence intervals (CIs). R software (version 4.2.1) and the “TwoSampleMR” package (version 0.5.6) facilitated MR and sensitivity analyses. A significance threshold of < 1.25 × 10^−2 (adjusted for multiple comparisons) was considered indicative of statistically significant causal relationships in univariate MR analyses.
Result
In this study, genetic markers associated with Omega-3 fatty acid levels were meticulously identified, with a total of 49 single nucleotide polymorphisms (SNPs) chosen as instrumental variables (IVs). These markers exhibited robust instrument strength and surpassed the threshold for genome-wide significance. The relationship between Omega-3 levels and atherosclerosis risk was assessed through Mendelian randomization (MR) analysis. While the IVW method suggested a potential reduction in atherosclerosis risk associated with elevated Omega-3 levels, the association did not reach statistical significance. Further analyses supported these findings, affirming the suitability of chosen SNPs as genetic instruments and confirming the absence of confounding factors.
Similarly, the impact of Omega-3 on hypertension was investigated using MR techniques. A set of 49 SNPs meeting genome-wide significance criteria served as instrumental variables. Results indicated a modest reduction in hypertension risk associated with higher Omega-3 levels, supported by alternative MR-Egger methods. Validation of the MR framework ensured the reliability of the relationship between Omega-3 levels and hypertension, free from confounding variables.
Additionally, the interrelation between hypertension and atherosclerosis was examined using MR analysis. A concise set of 5 SNPs associated with hypertension surpassed the genome-wide significance threshold, while their influence on atherosclerosis was explored. However, cautious interpretation was warranted due to nonsignificant trends in MR-Egger analysis.
Overall, the study provided a comprehensive genetic landscape of Omega-3 levels, hypertension, and coronary atherosclerosis, offering insights into their interrelationships while meticulously addressing methodological considerations to ensure the validity of findings.
Conclusion
Our study delves into the intricate biological pathways linking Omega-3 fatty acids to hypertension and coronary atherosclerosis. Through integrative GWAS analyses using the FinnGen database, we unveiled a direct impact of Omega-3 fatty acids on hypertension risk and an indirect role in coronary atherosclerosis development. This research advances our understanding of the causal relationships among Omega-3 fatty acids, hypertension, and coronary atherosclerosis within a genomic framework.
Consistent with existing literature, we found that monitoring the Omega-3 index could serve as a valuable indicator for managing hypertension and coronary atherosclerosis. High-dose EPA formulations offer cardiovascular protection beyond triglyceride reduction, encompassing various beneficial effects such as mitigating vascular inflammation, enhancing endothelial function, and lowering blood pressure.
Our investigation underscores the correlation between Omega-3 fatty acids and hypertension risk, suggesting their therapeutic potential in managing hyperlipidemia and hypertension. Elevating dietary Omega-3 levels may reduce mortality associated with hypertension and cardiovascular events.
Moreover, we elucidated the interconnection between hypertension and coronary atherosclerosis, highlighting the role of heightened blood pressure in exacerbating atherosclerotic conditions. Conversely, Omega-3 fatty acids have shown promise in reducing plaque formation and improving coronary atherosclerosis, presenting a potential therapeutic option for plaque regression in clinical practice.
Strengths of our study include robust Mendelian Randomization methods and the use of potent genetic variants as instrumental variables. However, limitations include the exclusive focus on subjects of European descent and the lack of detailed subgroup analyses for specific demographics.
In conclusion, our research provides a comprehensive understanding of the causal links between Omega-3 fatty acids, hypertension risk, and coronary atherosclerosis development.
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