Oily Fish Intake and Cardiovascular Diseases: A Mendelian Randomization Study

doi:10.21203/rs.3.rs-4710125/v1

Download PDF

Article

Oily Fish Intake and Cardiovascular Diseases: A Mendelian Randomization Study

https://doi.org/10.21203/rs.3.rs-4710125/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Studies have shown a link between oily fish intake and a lower risk of cardiovascular disease (CVD). The potential causal relationship is unclear. The purpose of this study was to investigate the association between oily fish intake and eight CVDs, including coronary heart disease (CHD), heart failure (HF), myocardial infarction (MI), atrial fibrillation (AF), essential primary hypertension (EH), stroke, deep venous thrombosis (DVT), and peripheral artery disease (PDA), through a two-step Mendelian randomization (MR). Genome-wide association study (GWAS) statistics for oily fish intake and CVD were collected from the UK Biobanks and the European Bioinformatics Institute. Single nucleotide polymorphisms (SNP) are used as instrumental variables. In this analysis, the methods for evaluating causality were the inverse-variance weighted, weighted median, and simple median. To evaluate the consistency and dependability of the findings, sensitivity analyses and heterogeneity tests are carried out. MR analysis indicated that genetically predicted oily fish intake is associated with reduced risk of CHD (OR = 0.43, 95% CI, 0.27–0.71, p = 0.0009) and HF (OR = 0.79, 95% CI, 0.65–0.97, p = 0.0245).However, there was no association observed between oily fish intake and MI (OR = 1.00, 95% CI, 0.99–1.01, p = 0.9089), AF (OR = 0.95, 95% CI, 0.79–1.14, p = 0.5475), stroke (OR = 0.99, 95% CI, 0.99–1.00, p = 0.0116), EH (OR = 1.00, 95% CI, 1.00–1.00, p = 0.0009), DVT (OR = 1.00, 95% CI, 0.99–1.01, p = 0.5407), and PAD (OR = 1.00, 95% CI, 0.99–1.00, p = 0.2819). This MR study found a causal connection between oily fish intake and a lower incidence of CHD and HF, but did not affect MI, AF, stroke, EH, DVT, or PAD.

Health sciences/Cardiology

Health sciences/Medical research/Epidemiology

Biological sciences/Genetics

Health sciences/Health care

Mendelian randomization

Cardiovascular disease

Oily fish intake

Causal relationship

Genetic Variants

Causal Inference

A comprehensive global epidemiological survey on cardiovascular diseases underscores their alarming prevalence and significant burden worldwide ¹. While there has been a decline in the mortality rate of cardiovascular disease (CVD) in certain developed nations, the situation remains grave in numerous developing countries ². Despite consistent reductions in age-standardized CVD mortality and incidence over the long term, the global tally of prevalent CVD cases continues to soar ². By 2019, this tally had escalated to a staggering 523 million individuals ². Additionally, about 127.9 million Americans, or 48.6% of the population over the age of 20, are thought to have CVD, which includes hypertension, heart failure, stroke, and coronary heart disease ³.

Extensive research, including in vivo assays with animal models ⁴, clinical trials ⁵, prospective studies ⁶, and meta-analyses ⁷, has revealed a positive correlation between increased consumption of oily fish and numerous health benefits, encompassing cardiovascular protection ⁸, neuroprotection ⁹, pain reduction ¹⁰, and improved cognitive abilities ⁹. This is especially related to the high content of omega-3 long-chain polyunsaturated fatty acids (LC-PUFAs) found in oily fish, including docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and docosapentaenoic acid (DPA) ¹¹. Owing to its potential to prevent CVD, eating oily fish has been recommended in numerous national dietary guidelines ¹². Consequently, the American College of Cardiology and the American Heart Association have listed fish intake as one of the top 10 primary prevention measures for CVD ¹³. While the quality and quantity of evidence supporting these benefits have notably improved, it should be noted that reverse causality and residual confounding factors frequently have an impact on observational research. Currently, there is a lack of research exploring the combined effects of oily fish consumption and genetic polymorphism on the risk of CVD.

Mendelian randomization (MR) is a powerful technique that uses genetic variants' random distribution as instrumental variables to investigate the causal relationship between an exposure and its outcome ¹⁴. Uniquely, it exerts its influence solely on the exposure itself, thereby removing the possibility of reverse causality and confounding variables, which frequently afflict observational studies. Eliminating the expensive and labor-intensive costs required for randomized trials ¹⁵. Unaffected by other potential confounders, the findings of MR research exhibit directness, immunity to environmental interferences, scalability for large-scale investigations, and stability, making them invaluable references worthy of trust ¹⁴.

To date, MR studies have provided compelling evidence of a causal link between certain eating habits and CVD, encompassing meat consumption ¹⁶, cereal intake ¹⁷, dark chocolate ¹⁸, and caffeinated beverage intake ¹⁹. Therefore, this study will leverage the two-sample Mendelian randomization approach to delve into the possible causal relationship between oily fish intake and CVD.

We used a two-sample MR method to investigate the potential causal relationship between oily fish intake and CVD. This investigation followed the STROBE-MR recommendations ²⁰.Only if three fundamental presumptions are followed when conducting the analysis will the MR study lead to a compelling conclusion. First, the exposure (oily fish intake) should be strongly correlated with the genetic instrumental variables (IVs). Second, there should be no connection between the genetic IVs and potential confounders like body mass index (BMI), diabetes, and the lipoproteins associated with cardiovascular disease (total cholesterol, triglycerides, low-density lipoprotein, and high-density lipoprotein). Third, oily fish is the only way that the genetic IVs influence the outcome (CVD). An outline of the three main MR hypotheses is shown in Fig. 1.

Data sources

For the analysis in this study, we used publicly available GWAS summary statistics (https://gwas.mrcieu.ac.uk/). GWAS summary statistics for oily fish intake included a total of 460,443 European participants with 9,851,867 single nucleotide polymorphisms (SNP). The outcomes include coronary heart disease (CHD), heart failure (HF), myocardial infarction (MI), atrial fibrillation (AF), essential primary hypertension (EH), stroke, deep venous thrombosis (DVT), and peripheral artery disease (PDA). The GWAS database provided us with summary-level data related to the outcome events. Table 1 provides information about the GWAS database for exposure and outcome.

Table 1

Basic details regarding the exposure and outcomes in the GWAS database. *CHD* coronary heart disease, HF heart failure, MI myocardial infarction, AF atrial fibrillation, EH Essential (primary) hypertension, *DVT* deep venous thrombosis, *PDA* peripheral artery disease.
Trait	GWAS-ID	Year	Population	Number of SNPs	Sample size	Build
Oily fish intake	ukb-b-2209	2018	European	9,851,867	460,443	HG19/GRCh37
CHD	ieu-a-8	2011	European	2,420,361	ncase:22233	HG19/GRCh37
CHD	ieu-a-8	2011	European	2,420,361	ncontrol:64762	HG19/GRCh37
HF	ebi-a-GCST009541	2020	European	7,773,021	ncase:47309	HG19/GRCh37
HF	ebi-a-GCST009541	2020	European	7,773,021	ncontrol:930014	HG19/GRCh37
MI	ukb-d-I9_MI	2018	European	12,640,541	ncase:7018	HG19/GRCh37
MI	ukb-d-I9_MI	2018	European	12,640,541	ncontrol:361194	HG19/GRCh37
AF	ebi-a-GCST006414	2018	European	33,519,037	ncase:60620	HG19/GRCh37
AF	ebi-a-GCST006414	2018	European	33,519,037	ncontrol:970216	HG19/GRCh37
EH	ukb-a-531	2017	European	10,894,596	ncase:500	HG19/GRCh37
EH	ukb-a-531	2017	European	10,894,596	ncontrol:336699	HG19/GRCh37
Stroke	ukb-b-8714	2018	European	9,851,867	ncase:7055	HG19/GRCh37
Stroke	ukb-b-8714	2018	European	9,851,867	ncontrol:454825	HG19/GRCh37
DVT	ukb-a-65	2,017	European	9,851,867	ncase:6767	HG19/GRCh37
DVT	ukb-a-65	2,017	European	9,851,867	ncontrol:330392	HG19/GRCh37
PAD	ukb-d-I9_PAD	2,018	European	9,637,467	ncase:1230	HG19/GRCh37
PAD	ukb-d-I9_PAD	2,018	European	9,637,467	ncontrol:359964	HG19/GRCh37

IVs selection and evaluation

We used four criteria to control IVs and select SNPs related to oily fish intake. First, SNPs with a statistical significance of P < 5E − 08 across the genome ²¹.Second, chosen SNPs were independent by using linkage disequilibrium, r² > 0.001 and clump windows < 10 Mb. Third, for F-statistics > 10, the F-statistic F= (N-2)R2/1-R2, where R2 is the variability in oily fish intake explained by each SNP, was used to confirm the power sizes of the IVs ²², to calculate R² use the following formula:

R² = 2×(1-EAF)×EAF×β²/2×(1-EAF)×EAF×β² + 2×(1-EAF)×EAF×SE²×N

Where EAF is the effect allele frequency, β is the estimated genetic effect of oily fish intake, and SE is the standard error of the genetic effect ^[19]. Last, we used linkage disequilibrium (LD) to eliminate the impact of possible confounders. (https://ldlink.nih.gov/?tab=ldtrait) LD matrix (R² = 0.8, P < 5E-08).

Mediation MR analysis

Three techniques were employed to determine the associations between genetic variants linked to oily fish intake and CVD, aiming to assess the impact of oily fish consumption on CVD. Our primary analytical technique for determining the causal relationship between oily fish consumption and CVD was inverse variance weighted Mendelian randomization (IVW MR) ²³. This method combines the Wald ratios for each SNP through a meta-analytical procedure to obtain a comprehensive estimate, leveraging genotype data ²³. By estimating the impact of each SNP on exposure and outcome risk, the IVW technique provides the most accurate estimate. In addition, we supplemented the sample median and the weighted median ²⁴ to ensure the robustness of the results. Compared to the inverse variance weighted methods, the median-based methods are more resilient to individual genetic variants with substantially outlier causal estimates. Formally, the simple median method provides a consistent estimate of the causal effect when at least 50% of the genetic variants are valid instrumental variables. In the case of the weighted median method, this consistency is achieved when 50% of the total weight comes from valid instrumental variables. Finally, we calculated the statistical power using an online tool available at https://shiny.cnsgenomics.com/mRnd/41²⁵.

Sensitivity analysis

We conducted sensitivity analyses ²⁶using the MR-Egger test ²⁷, inverse variance weighted test, Egger intercept test, leave-one-out analysis, and funnel plots to evaluate the robustness and potential bias of our results. Causal estimations were presented as odds ratios (ORs) and 95% confidence intervals (CIs). If either of the following scenarios occurs, indicating the presence of horizontal pleiotropy, the results of the Mendelian randomization study are not reliable: (1) horizontal pleiotropy is detected in the MR-Egger intercept test (P < 0.05); (2) significant results are found in the MR-PRESSO global test (P < 0.05). All analyses were conducted using the TwoSampleMR (version 0.5.11) and MRPRESSO (version 1.0) packages in R (version 4.4.0).The entire Mendelian randomization research design is shown in Fig. 2.

The causal effect of cardiovascular disease

At the threshold of P < 5E-08, there are 10,368 SNPs in the genome that are strongly associated with oily fish intake. The Manhattan plot is shown in Fig. 3. We got 63 SNPs related to oily fish intake based on the screening criteria. Then, we eliminated 12 SNPs (rs10510554, rs1876245, rs11986122, rs9886779, rs10828250, rs703987, rs61882686, rs1951286, rs12983532, rs4002471, rs1421085, rs608975) related to CAD, BMI, diabetes, and cardiovascular disease lipoproteins. Eventually, 51 SNPs were selected. Details of the SNPs are presented in Table 2.

The two-sample MR analysis using three methods for the association of oily fish intake with CVD is shown in Fig. 4. The IVW analysis results showed that the oily fish intake had a suggestive positive association with CHD (OR = 0.43, 95% CI, 0.27–0.71, p = 0.0009) and HF (OR = 0.79, 95% CI, 0.65–0.97, p = 0.0245). In contrast, there was no association observed between oily fish intake and MI (OR = 1.00, 95% CI, 0.99–1.01, p = 0.9089), AF (OR = 0.95, 95% CI, 0.79–1.14, p = 0.5475), EH (OR = 1.00, 95% CI, 1.00–1.00, p = 0.0009), Stroke (OR = 0.99, 95% CI, 0.99–1.00, p = 0.0116), DVT (OR = 1.00, 95% CI, 0.99–1.01, p = 0.5407), and PAD (OR = 1.00, 95% CI, 0.99–1.00, p = 0.2819).

The MR power of oily fish intake on CHD and HF stood at 0.98 and 0.82, respectively, while the MR power on all other outcomes was all below 0.8.The details of MR powers are presented in Supplementary Table 1.

Table 2

Summary information on SNPs linked to oily fish intake in the Mendelian randomization analyses. *SNP* single nucleotide polymorphism, OA other allele, EA effect allele, *EAF* effect allele frequency, SE standard error, R² represents the proportion of variance explained for the association between the SNP and the exposure variable, *F-statistic* the power sizes of the IVs.
SNP	OA	EA	EAF	Beta	SE	P value	R^2	F-statistic
rs67474621	A	T	0.5118	0.0128	0.0020	1.60E-10	8.89E-05	40.94459498
rs45501495	C	T	0.2360	0.0157	0.0023	3.70E-12	0.000104803	48.2607095
rs55930451	C	T	0.1080	-0.0171	0.0031	2.90E-08	6.68E-05	30.74440302
rs17050031	C	T	0.4801	-0.0120	0.0019	3.50E-10	8.55E-05	39.35459678
rs55985303	G	A	0.2411	0.0130	0.0022	6.60E-09	7.31E-05	33.65654817
rs275160	T	C	0.7006	0.0121	0.0021	8.00E-09	7.23E-05	33.27222024
rs13070166	T	A	0.2286	0.0142	0.0023	4.40E-10	8.45E-05	38.91055726
rs114497213	G	T	0.0548	0.0273	0.0042	1.10E-10	9.03E-05	41.60225077
rs10513136	G	A	0.0654	-0.0233	0.0039	1.60E-09	7.92E-05	36.45098184
rs905575	C	G	0.8240	0.0139	0.0025	3.60E-08	6.59E-05	30.36772581
rs9841174	T	C	0.3739	0.0148	0.0020	8.50E-14	0.00012094	55.6923151
rs1201289	T	G	0.3945	-0.0107	0.0020	4.40E-08	6.51E-05	29.96564652
rs7683782	C	G	0.8334	0.0145	0.0026	1.90E-08	6.87E-05	31.63527034
rs11135351	G	A	0.3816	0.0112	0.0020	1.10E-08	7.08E-05	32.61293147
rs10061973	G	T	0.5139	-0.0109	0.0019	1.50E-08	6.97E-05	32.08069327
rs16891727	C	A	0.1298	-0.0237	0.0028	6.80E-17	0.000151441	69.74012996
rs1053924	T	C	0.6861	-0.0125	0.0021	1.40E-09	7.97E-05	36.71308207
rs12663865	G	A	0.7582	0.0128	0.0022	1.10E-08	7.11E-05	32.73224525
rs4869859	T	C	0.4499	0.0140	0.0019	3.10E-13	0.000115372	53.12801429
rs6465487	A	G	0.3998	-0.0124	0.0020	2.70E-10	8.66E-05	39.87641644
rs11767283	A	G	0.2217	0.0177	0.0023	2.50E-14	0.000126082	58.06049068
rs790564	A	C	0.7230	0.0147	0.0021	7.90E-12	0.000101608	46.78925435
rs10991192	C	T	0.5364	-0.0117	0.0019	1.10E-09	8.07E-05	37.17308439
rs510161	C	G	0.3104	-0.0113	0.0021	4.50E-08	6.50E-05	29.90996687
rs4278546	A	G	0.4411	0.0126	0.0019	9.30E-11	9.11E-05	41.96929771
rs11607886	T	C	0.5844	-0.0115	0.0019	2.90E-09	7.65E-05	35.22113412
rs631490	G	C	0.7091	-0.0151	0.0021	6.00E-13	0.000112598	51.85062399
rs303817	A	G	0.7511	0.0136	0.0022	8.00E-10	8.20E-05	37.76976478
rs35287743	G	T	0.1159	-0.0282	0.0030	7.00E-21	0.000190775	87.8572004
rs1361016	T	G	0.8449	0.0150	0.0027	1.70E-08	6.90E-05	31.78421934
rs3124402	A	G	0.7333	-0.0220	0.0022	1.90E-24	0.000226008	104.086833
rs9597870	T	G	0.2458	-0.0127	0.0022	1.10E-08	7.09E-05	32.64991835
rs9301837	C	A	0.1433	-0.0157	0.0027	8.10E-09	7.22E-05	33.24249511
rs12855717	C	T	0.5268	-0.0122	0.0019	2.00E-10	8.79E-05	40.45676784
rs4982738	G	A	0.5829	0.0109	0.0020	3.50E-08	6.60E-05	30.41385849
rs12896749	G	C	0.3847	-0.0110	0.0020	2.50E-08	6.75E-05	31.0989794
rs28533540	G	A	0.5342	0.0146	0.0019	2.80E-14	0.000125665	57.86855741
rs9889161	G	T	0.3579	-0.0133	0.0020	2.80E-11	9.62E-05	44.289614
rs11859365	A	C	0.2538	0.0226	0.0022	9.40E-25	0.000229135	105.5273024
rs28623270	A	T	0.1487	-0.0178	0.0027	7.30E-11	9.22E-05	42.43670223
rs1053651	A	C	0.7332	0.0120	0.0022	3.10E-08	6.66E-05	30.65203946
rs7225002	A	G	0.4144	-0.0139	0.0019	8.10E-13	0.000111301	51.25341418
rs9958909	T	G	0.1397	0.0158	0.0028	1.40E-08	6.99E-05	32.18930541
rs7243428	A	G	0.2246	-0.0130	0.0023	1.50E-08	6.96E-05	32.06016275
rs59355765	C	T	0.1601	-0.0163	0.0026	4.70E-10	8.42E-05	38.78417628
rs7254235	A	G	0.5773	-0.0106	0.0019	4.30E-08	6.52E-05	30.02203598
rs75887709	A	G	0.1359	-0.0159	0.0028	1.60E-08	6.94E-05	31.95038854
rs6033437	C	A	0.2573	0.0125	0.0022	1.70E-08	6.91E-05	31.83599689
rs6059844	A	G	0.4951	0.0110	0.0019	9.20E-09	7.17E-05	33.01232423
rs2827161	T	G	0.4228	0.0107	0.0019	3.20E-08	6.64E-05	30.57356991
rs9606833	T	C	0.2436	0.0170	0.0022	2.70E-14	0.000125888	57.97107742

Sensitivity analysis of Mendelian randomization

The Cochran’s Q test shows heterogeneity among the MI (P = 0.018) and AF (P = 0.036) employed SNPs. There was no indication of horizontal pleiotropy in the MR study, according to the MR-Egger intercept test. However, MR-PRESSO global test analysis results reveal a pleiotropy between oily fish intake and MI and AF. Horizontal pleiotropy persisted even after repeating the MR analysis following the elimination of outliers identified by MR-PRESSO, with MI (P = 0.003) and AF (P = 2.000E-04). This indicates that the MR analysis results for MI and AF are not robust and have low reliability. Details of the sensitivity analyses are shown in Table 3. Additionally, based on the MR results, no causal relationships were found between oily fish intake and MI or AF. The leave-one-out analysis results in Fig. 5 indicate that no single SNP significantly impacted either CHD or HF. Multiple sensitivity analyses supported these conclusions, highlighting the robustness of our research. Supplementary Fig. 1, 2, and 3 present the scatter plot, forest plot, and funnel plot of individual SNPs, illustrating the relationship between oily fish intake and CVD.

Table 3

Three sensitivity analyses for the associations of oily fish intake with eight CVD. *IVW_Q* corresponding to Cochran’s Q test, *egger Intercept* the intercept of MR-Egger regression.
Outcomes	IVW_Q(pval)	MR-Egger Intercept (pval)	Pval of MR-PRESSO global test
Coronary heart disease	0.453	-0.015 (0.436)	0.460
Heart failure	0.232	-0.007 (0.285)	0.240
Myocardial infarction	0.018	0.000 (0.175)	0.003
Atrial fibrillation	0.036	0.001 (0.861)	2.000E-04
Essential (primary) hypertension	0.421	8,61E-05 (0.185)	0.427
Stroke	0.390	2.80E-05 (0.876)	0.404
Deep venous thrombosis	0.089	5.38E-05 (0.840)	0.093
Peripheral artery disease	0.167	0.000 (0.200)	0.158

Extensive studies have indicated the efficacy of fish intake on CVD prevention ^28,29.Our MR analysis results confirm there is a significant association between genetically oily fish intake and a lower risk of CHD and HF, but not with MI, AF, EH, stroke, DVT, or PAD. Most studies support that the intake of oily fish is beneficial to CHD and HF, but there are different conclusions in the studies of MI, AF, EH, and stroke ^30,31. Our research findings align with those of a recent meta-analysis, indicating that the consumption of oily fish can reduce the incidence, mortality, and overall mortality rates of CHD, while lean fish did not show a significant correlation ³².

Omega-3 PUFAs, such as EPA and DHA found in fish oil, are well known for their capacity to reduce triglyceride (TG) levels ³³. These omega-3 fatty acids can improve endothelial function and possess anti-inflammatory qualities, helping to protect the cardiovascular system. In the United States, approximately 19 million adults ³⁴, including one in five individuals over 60, take fish oil supplements for heart health. However, recent research has highlighted the intricate effects of omega-3 PUFAs on cardiovascular health, particularly their potential impact on AF and acute myocardial infarction (AMI) ³⁵. The cardiovascular benefits of oily fish, a natural source of omega-3 fatty acids, are well-documented; however, the efficacy of fish oil supplements remains a topic of ongoing debate ³⁶. Several studies have indicated that fish oil supplementation may elevate the risk of AF and stroke ³⁷. A recent meta-analysis revealed that marine omega-3 PUFA supplementation is associated with an increased risk of AF, especially in trials where the dosage exceeds 1 g/day ³⁷. Conversely, dietary intake of EPA, DHA, and DPA, as assessed through food frequency questionnaires ³⁸, showed no significant association with an increased risk of AF and might even reduce the risk within certain intake ranges. A randomized controlled trial (RCT) investigating AMI demonstrated that supplementation with omega-3PUFAs can enhance lipid metabolism and endothelial function by modulating eicosanoid metabolism during the post-AMI recovery period ³⁹. Nonetheless, another subsequent RCT involving elderly patients who received 1.8g of omega-3 PUFAs daily for two years failed to demonstrate a reduction in clinical events post-AMI, indicating that omega-3 PUFAs may not provide the anticipated cardiovascular benefits in this context ⁴⁰.

Over the past two decades, omega-3 levels in farmed fish have been in decline ⁴¹. Moreover, quality issues such as persistent organic pollutants (POPs) ⁴², chlorinated paraffins (CPs) ⁴³, and excessive heavy metals ⁴⁴ in fish oil supplements present significant concerns. The potential health risks posed by polycyclic aromatic hydrocarbons (PAHs) ⁴², classified as class I carcinogens, in certain fish oil supplements further underscore the need for vigilance. Consequently, the search for alternative sources of omega-3 supplements has gained importance. Omega-3 polyunsaturated fatty acid (PUFA)-enriched chicken meat and eggs represent a promising alternative, demonstrating significant improvements in omega-3 levels and reductions in diastolic blood pressure ⁴¹. Flaxseed oil presents another effective option, as supplementation with both flaxseed oil and fish oil has demonstrated significant improvements in cardiovascular risk parameters in diabetic patients with coronary heart disease ⁴⁵.

Intake of oily fish and fish oil supplements both provide EPA and DHA; regular oily fish consumption is consistently associated with reduced cardiovascular events ⁴⁶. Conversely, fish oil supplements have shown mixed results in clinical trials. Fish oil supplements have potential benefits for cardiovascular health; their effects may be dependent on factors such as dosage ⁴⁷, sources ⁴⁸, intake time ⁴⁹, and individual differences ⁵⁰. Although a large prospective cohort study ⁵¹ shows that habitual use of fish oil seems to be associated with a lower risk of all causes and CVD mortality and to provide a marginal benefit against CVD events among the general population, due to limited regulation and quality issues, the FDA still doesn't recommend using fish oil supplements as a suitable alternative to treat heart disease with high triglycerides or prevent heart problems ³⁴. While high-quality fish oil supplements can be a beneficial alternative for those unable to consume sufficient oily fish, it seems that choosing a balanced diet rich in natural food sources is more appropriate.

This study primarily focused on populations of European descent, and considering the ethnic specificity of genetic background, dietary habits, and disease patterns, our findings may not be directly generalizable to populations of other ethnicities or regions regarding potential associations between oily fish intake and CVD. The pooled data used in this study were not stratified for specific factors such as age and sex; thus, our conclusions are largely based on general observations. It is worth noting that since questionnaire-based recall-type surveys were used for most of the intake of a particular food item, potential issues such as recall bias should not be overlooked. However, thanks to the larger sample size, our findings were somewhat enhanced in terms of representativeness and accuracy, partially compensating for this shortcoming. At the same time, we cannot ignore the bias caused by the possible overlap between GWAS samples and exposure factors. Although previous studies have shown that the two-sample MR method usually provides reliable results in similar situations, MR analyses exclude the influence of some confounders. We still need to be alert to possible confounders that may impact the interpretation of the results. Therefore, these potential limitations and uncertainties need to be carefully considered when interpreting and applying the results of this study. The strengths of this study reside in its groundbreaking utilization of MR to delve into the potential causal link between oily fish consumption and eight CVDs, thereby offering a deeper understanding of the cardiovascular health benefits associated with consuming oily fish. Additionally, this MR analysis harnesses large-scale datasets from reputable sources such as the UK Biobank and the European Bioinformatics Institute (EBI), ensuring both the reliability and extensive representativeness of the results.

We discovered a causal link between oily fish intake and a reduced risk of CHD and HF in the European population using MR methods. According to our research, consuming enough oily fish may help with CVD primary prevention and may have significant implications for public health in improving the understanding of diet-related CVD risk.

Data availability

The genetic data of oily fish intake and cardiovascular disease are available at IEU Open GWAS. (URL: https://gwas.mrcieu.ac.uk/datasets; Accession number: ukb-b-2209, ieu-a-8, ukb-d-I9_MI, ukb-a-531, ukb-a-65, ebi-a-GCST009541, ebi-a-GCST006414 and ukb-d-I9_PAD).

Acknowledgements

We extend our gratitude to the IEU Open GWAS Project Database for providing the GWAS data used in this study. We also appreciate the assistance from medical writers, proofreaders, and editors.

Author contributions

Material preparation, data collection and analysis were performed by X.L., A.K., and Yating. Z.Y. and C.Z. was responsible for research design. The first draft of the manuscript was written by Xin Liu and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. All authors contributed to this article and approved the submitted version.

Funding

This work was supported by the Young Scientists Fund of the National Natural Science Foundation of China (No.82205295).

Competing interests

The authors declare no competing interests.

Roth, G. A., Mensah, G. A. & Fuster, V. The Global Burden of Cardiovascular Diseases and Risks: A Compass for Global Action. J Am Coll Cardiol 76, 2980–2981 (2020).
Nedkoff, L., Briffa, T., Zemedikun, D., Herrington, S. & Wright, F. L. Global Trends in Atherosclerotic Cardiovascular Disease. Clin Ther 45, 1087–1091 (2023).
Martin, S. S. et al. 2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association. Circulation 149, e347–e913 (2024).
Kontostathi, M. et al. Influence of Omega-3 Fatty Acid-Rich Fish Oils on Hyperlipidemia: Effect of Eel, Sardine, Trout, and Cod Oils on Hyperlipidemic Mice. J Med Food 24, 749–755 (2021).
Manson, J. E. et al. Vitamin D, Marine n-3 Fatty Acids, and Primary Prevention of Cardiovascular Disease Current Evidence. Circ Res 126, 112–128 (2020).
Zhou, J. et al. Association of oily fish and nonoily fish intakes with all-cause mortality and cause-specific mortality: a large population-based prospective study. J Transl Med 21, 280 (2023).
Bosomworth, N. J. Indications for omega-3 fatty acid supplementation in prevention of cardiovascular disease: From fish to pharmaceuticals. Can Fam Physician 69, 459–468 (2023).
Innes, J. K. & Calder, P. C. Marine Omega-3 (N-3) Fatty Acids for Cardiovascular Health: An Update for 2020. Int J Mol Sci 21, 1362 (2020).
Del Brutto, O. H., Mera, R. M., Gillman, J., Zambrano, M. & Ha, J. Oily Fish Intake and Cognitive Performance in Community-Dwelling Older Adults: The Atahualpa Project. J Community Health 41, 82–86 (2016).
Carballo-Casla, A., García-Esquinas, E., Banegas, J. R., Rodríguez-Artalejo, F. & Ortolá, R. Fish consumption, omega-3 fatty acid intake, and risk of pain: the Seniors-ENRICA-1 cohort. Clin Nutr 41, 2587–2595 (2022).
F, C. et al. Health Benefits of Oily Fish: Illustrated with Blue Shark (Prionace glauca), Shortfin Mako Shark (Isurus oxyrinchus), and Swordfish (Xiphias gladius). Nutrients 15, (2023).
Zhu, Y. et al. Types of fish consumption differ across socioeconomic strata and impact differently on plasma fish-based omega-3 fatty acids: a cross-sectional study. Eur J Nutr 63, 435–443 (2024).
Arnett, D. K. et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 140, e596–e646 (2019).
Richmond, R. C. & Davey Smith, G. Mendelian Randomization: Concepts and Scope. Cold Spring Harb Perspect Med 12, a040501 (2022).
Ference, B. A., Holmes, M. V. & Smith, G. D. Using Mendelian Randomization to Improve the Design of Randomized Trials. Cold Spring Harb Perspect Med 11, a040980 (2021).
Hu, B. et al. Red and processed meat intake and risk of cardiovascular disease: A two-sample Mendelian randomization study. Clin Nutr ESPEN 60, 289–297 (2024).
Liu, J. & Cai, D. Causal relationship of cereal intake and type with cardiovascular disease: a Mendelian randomization study. Front Nutr 10, 1320120 (2023).
Yang, J. et al. Dark chocolate intake and cardiovascular diseases: a Mendelian randomization study. Sci Rep 14, 968 (2024).
Lin, T., Mao, H. & Jin, Y. Caffeinated beverages intake and risk of deep vein thrombosis: A Mendelian randomization study. PLoS One 19, e0298123 (2024).
Cao, Y., Feng, Y., Xia, N. & Zhang, J. Causal associations of particulate matter 2.5 and cardiovascular disease: A two-sample mendelian randomization study. PLoS One 19, e0301823 (2024).
Panagiotou, O. A., Ioannidis, J. P. A., & Genome-Wide Significance Project. What should the genome-wide significance threshold be? Empirical replication of borderline genetic associations. Int J Epidemiol 41, 273–286 (2012).
Burgess, S., Thompson, S. G., & CRP CHD Genetics Collaboration. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol 40, 755–764 (2011).
Burgess, S., Butterworth, A. & Thompson, S. G. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol 37, 658–665 (2013).
Bowden, J., Davey Smith, G., Haycock, P. C. & Burgess, S. Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol 40, 304–314 (2016).
Brion, M.-J. A., Shakhbazov, K. & Visscher, P. M. Calculating statistical power in Mendelian randomization studies. Int J Epidemiol 42, 1497–1501 (2013).
Burgess, S., Bowden, J., Fall, T., Ingelsson, E. & Thompson, S. G. Sensitivity Analyses for Robust Causal Inference from Mendelian Randomization Analyses with Multiple Genetic Variants. Epidemiology 28, 30–42 (2017).
Bowden, J., Davey Smith, G. & Burgess, S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol 44, 512–525 (2015).
Chen, J., Jayachandran, M., Bai, W. & Xu, B. A critical review on the health benefits of fish consumption and its bioactive constituents. Food Chem 369, 130874 (2022).
Costabile, G. et al. An Oily Fish Diet Improves Subclinical Inflammation in People at High Cardiovascular Risk: A Randomized Controlled Study. Molecules 26, 3369 (2021).
Liao, J., Xiong, Q., Yin, Y., Ling, Z. & Chen, S. The Effects of Fish Oil on Cardiovascular Diseases: Systematical Evaluation and Recent Advance. Front Cardiovasc Med 8, 802306 (2021).
Tutor, A. et al. Omega-3 fatty acids in primary and secondary prevention of cardiovascular diseases. Prog Cardiovasc Dis S0033-0620(24)00054–9 (2024) doi:10.1016/j.pcad.2024.03.009.
Giosuè, A. et al. Relations between the Consumption of Fatty or Lean Fish and Risk of Cardiovascular Disease and All-Cause Mortality: A Systematic Review and Meta-Analysis. Adv Nutr 13, 1554–1565 (2022).
Austin, G. et al. Postprandial lipaemia following consumption of a meal enriched with medium chain saturated and/or long chain omega-3 polyunsaturated fatty acids. A randomised cross-over study. Clin Nutr 40, 420–427 (2021).
Sherratt, S. C. R., Lero, M. & Mason, R. P. Are dietary fish oil supplements appropriate for dyslipidemia management? A review of the evidence. Curr Opin Lipidol 31, 94–100 (2020).
Chen, G. et al. Regular use of fish oil supplements and course of cardiovascular diseases: prospective cohort study. BMJ Med 3, e000451 (2024).
Asfaw, A., Minhas, S., Khouzam, A. R., Khouzam, N. R. & Khouzam, R. N. Fish Oil Dilemma: Does It Increase the Risk of Ventricular Arrhythmias and Death? Can Fish Oil Kill You? Curr Probl Cardiol 46, 100718 (2021).
Gencer, B. et al. Effect of Long-Term Marine ɷ-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis. Circulation 144, 1981–1990 (2021).
Guardino, E. T. et al. Dietary ω-3 fatty acids and the incidence of atrial fibrillation in the Million Veteran Program. Am J Clin Nutr 118, 406–411 (2023).
Yuan, M. et al. Omega-3 polyunsaturated fatty acid supplementation improves lipid metabolism and endothelial function by providing a beneficial eicosanoid-pattern in patients with acute myocardial infarction: A randomized, controlled trial. Clin Nutr 40, 445–459 (2021).
Kalstad, A. A. et al. Effects of n-3 Fatty Acid Supplements in Elderly Patients After Myocardial Infarction: A Randomized, Controlled Trial. Circulation 143, 528–539 (2021).
Stanton, A. V. et al. Omega-3 index and blood pressure responses to eating foods naturally enriched with omega-3 polyunsaturated fatty acids: a randomized controlled trial. Sci Rep 10, 15444 (2020).
Drábová, L., Pulkrabová, J., Hrbek, V., Kocourek, V. & Hajšlová, J. POPs and PAHs in fish oil-based food supplements at the Czech market. Food Addit Contam Part B Surveill 16, 197–208 (2023).
Tomasko, J. et al. Are fish oil-based dietary supplements a significant source of exposure to chlorinated paraffins? Sci Total Environ 833, 155137 (2022).
Ozyurt, G., Ekmen, D., Durmuş, M. & Ucar, Y. Assessment of the safety of dietary fish oil supplements in terms of content and quality. Environ Sci Pollut Res Int 29, 25006–25019 (2022).
Raygan, F. et al. A comparison between the effects of flaxseed oil and fish oil supplementation on cardiovascular health in type 2 diabetic patients with coronary heart disease: A randomized, double-blinded, placebo-controlled trial. Phytother Res 33, 1943–1951 (2019).
Mohan, D. et al. Associations of Fish Consumption With Risk of Cardiovascular Disease and Mortality Among Individuals With or Without Vascular Disease From 58 Countries. JAMA Intern Med 181, 631–649 (2021).
Bernasconi, A. A., Wiest, M. M., Lavie, C. J., Milani, R. V. & Laukkanen, J. A. Effect of Omega-3 Dosage on Cardiovascular Outcomes: An Updated Meta-Analysis and Meta-Regression of Interventional Trials. Mayo Clin Proc 96, 304–313 (2021).
Liu, H. et al. Effects of marine-derived and plant-derived omega-3 polyunsaturated fatty acids on erythrocyte fatty acid composition in type 2 diabetic patients. Lipids Health Dis 21, 20 (2022).
Konishi, T., Takahashi, Y., Shiina, Y., Oike, H. & Oishi, K. Time-of-day effects of consumption of fish oil-enriched sausages on serum lipid parameters and fatty acid composition in normolipidemic adults: A randomized, double-blind, placebo-controlled, and parallel-group pilot study. Nutrition 90, 111247 (2021).
Block, R. C. et al. Aspirin and omega-3 fatty acid status interact in the prevention of cardiovascular diseases in Framingham Heart Study. Prostaglandins Leukot Essent Fatty Acids 169, 102283 (2021).
Li, Z.-H. et al. Associations of habitual fish oil supplementation with cardiovascular outcomes and all cause mortality: evidence from a large population based cohort study. BMJ 368, m456 (2020).

No competing interests reported.

Download PDF

Reviewers invited by journal
11 Sep, 2024
Editor assigned by journal
11 Sep, 2024
Editor invited by journal
22 Aug, 2024
Submission checks completed at journal
20 Aug, 2024
First submitted to journal
09 Jul, 2024

You are reading this latest preprint version

Oily Fish Intake and Cardiovascular Diseases: A Mendelian Randomization Study

Status:

Version 1

Abstract

Figures

Introduction

Methods and Study design

Data sources

IVs selection and evaluation

Mediation MR analysis

Sensitivity analysis

Results

The causal effect of cardiovascular disease

Sensitivity analysis of Mendelian randomization

Discussion

Conclusions

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1