Multiple sclerosis (MS) is one of the most common chronic neurological disorders targeting the central nervous system (1). Characterized most generally by impaired ambulation and slowed cognitive processing, MS is the principal non-traumatic cause of disability (2). Cardiovascular diseases (CVDs), comprising coronary artery disease (CAD), myocardial infarction (MI), heart failure (HF), atrial fibrillation (AF), and stroke, are the leading causes of mortality and morbidity worldwide (3). CVDs account for 30% of all global deaths and place a substantial economic burden on the society (4).

The associations between MS and CVDs drawn from epidemiological studies have attracted much attention in the recent years (5, 6). A population-based retrospective cohort study based on 12,251 patients with MS and 72,572 controls suggested that MS was associated with an increased risk of acute coronary syndrome [hazard ratio (HR), 1.28; 95% CI, 1.09–1.51] (7). MS was also associated with increased stroke risks (HR, 4.93; 95% CI, 2.85–8.55) in a cohort study followed 5 years (8). Similarly, another retrospective study involving 14,565 patients with MS and 72,825 matched controls found that MS contributed to a higher risk of MI (adjusted HR 1.63; 95% CI 1.43–1.87) (9). However, a Swedish cohort study of 7,767 cases and 76,045 controls indicated that MS was associated with a decreased risk of angina pectoris and AF (10). The higher incidence of cardiovascular comorbidity compared with age-matched healthy controls may influence low-, mid- and long-term clinical outcomes, namely, greater general disability status, worse physical outcomes, higher depression scores, cognitive aging, and low satisfaction with quality of life (11). Besides, cardiovascular comorbidity burden was reported to be associated with MRI-derived disease outcomes (such as white matter hyperintensities, gray matter volumes and hippocampal volumes) in MS patients (12, 13). Meanwhile, higher Framingham risk score was associated with higher risk of relapses, disability, and disease-modifying therapy escalation in patients with MS over a 5-year follow-up (14). Traditional observational studies are susceptible to potential confounders and reverse causality bias, making it difficult to infer the causality (15). Therefore, the potential causal relationship between MS and CVDs remains unclear.

The Mendelian randomization (MR) method uses genetic variants as the proxy of the exposure in order to evaluate the causal effect of that exposure on the outcome (16). Since the genetic variants are randomly passed to the offspring and kept constant after conception, they can circumvent confounding factors and diminish interference of reverse causality between exposures and outcomes (17).

Hence, to examine the potential causality of genetic liability to MS with the risk of CVDs, we performed a two-sample MR analysis, leveraging the most updated genome-wide association study (GWAS) data.

The detailed characteristics of the SNPs associated with MS are displayed in Supplementary Table 1 . The F-statistics of all 68 SNPs was above the threshold of 10, which indicated that they strongly predicted MS in the MR analysis.

The results of the MR analysis estimates for the effect of MS on risk of CVDs are shown in Figure 2 . In the IVW analyses, one unit increase in log odds of MS was suggestively associated with higher risks of CAD (OR, 1. 02; 95% CI, 1.00–1.04; p = 0.03), MI (OR, 1.03; 95% CI, 1.00–1.06; p = 0.01), HF (OR, 1.02; 95% CI, 1.00–1.04; p = 0.02), AS (OR, 1.02; 95% CI, 1.00–1.05; p = 0.02), and AIS (OR, 1.02; 95% CI, 1.00–1.05; p = 0.04) ( Figure 2 ). However, no evidence was found for the causal associations between MS and the risk of AF (OR, 1.00; 95% CI, 0.98–1.01; p = 0.92) or other ischemic stroke subtypes (LAS: OR, 1.00; 95% CI, 0.95–1.06; p = 0.87; CES: OR, 1.02; 95% CI, 0.98–1.07; p = 0.26; SVS: OR, 1.03; 95% CI, 0.98–1.09; p = 0.21) ( Figure 2 ). In addition, scatter plots visually displayed the associations between MS and subtypes of CVDs ( Supplementary Figures 1–9 ).

The Weighted median method, MR-Egger regression, and MR-PRESSO method were performed as sensitivity analyses to reanalyze the suggestive associations observed in primary IVW analyses ( Table 2 ). In the sensitivity analyses, the association patterns remained directionally consistent in most statistical models, and stable association was found in the MR-PRESSO analysis of MI (OR, 1.03; 95% CI, 1.01–1.05; p =0.02) ( Table 2 ). Weak evidence of directional pleiotropy was found in the MR-Egger intercept tests (p >0.05; Table 3 ). However, the Cochrane’s Q test suggested that the main MR analyses suffered from different degrees of heterogeneity ( Table 3 ). Nonetheless, we had more than 80% statistical power to detect the ORs for associations of MS with CAD (89%), MI (96%), HF (88%), AS (98%), and AIS (96%) ( Supplementary Table 2 ).

In the current study, summary-level data from the large consortia and genetic studies were leveraged to investigate the causality of MS with CVDs. We found suggestive genetic evidence for the causal associations of genetic liability to MS with elevated risk of CAD, MI, HF, AS, and AIS, but not with AF or other stroke subtypes (LAS, CES, and SVS).

Results reported by several previous observational epidemiological studies on the associations between MS and CVDs were inconsistent and mixed. A meta-analysis, namely, 12 studies of 471,874 individuals indicated that compared with the general population, the risk of CVDs in patients with MS increased 29% (OR, 1.29; 95% CI, 1.80–2.51) (30). Another recent meta-analysis comprising 19 studies (44 to 66,616 participants) reported that the pooled OR estimate for MI was 1.41 in MS patients compared to the healthy controls (31). Besides, a meta-analysis of 9 observational studies suggested that MS was associated with an increased risk of MI and HF, but not ischemic heart disease or bradycardia (32). A population-based retrospective cohort study involving 12,251 MS patients and 72,572 controls showed that MS was associated with both acute coronary syndrome (HR, 1.28; 95% CI, 1.09–1.51) and cerebrovascular disease (HR, 1.59; 95% CI, 1.32–1.92) risk (7). Similarly, several retrospective cohort studies indicated MS led to a higher risk among MI, stroke, and HF (5, 6), which was in line with our MR results. Meanwhile, several prior studies also suggested that MS was associated with an increased risk of stroke (8, 33, 34). However, some other studies drew the inconsistent conclusion that MS was not a risk factor for some subtypes of CVDs. In a prospective cohort study, after adjusting for year and sex, the incidence of heart disease between MS patients and controls was no longer different [incidence rate ratio (IRR) 1.00; 95% CI, 0.94–1.06] (35). In addition, a population case–cohort study found no association between MS and ischemic heart disease and a 43% lower risk of AF compared with non-MS patients (10). Therefore, the current MR study was timely to draw attention to the assessment of the causality of MS with CVDs. A very recent two-sample MR study reported that MS was causally associated with an increased risk of MI (OR = 1.03), which was in line with our findings (36). However, this study found weak evidence for the causal association between MS and stroke using data from the CARDIoGRAMplusC4D consortium (40,585 stroke cases), while the genetic associations in the current study were obtained from the MEGASTROKE consortium involving 67,162 cases of all-cause stroke. On the one hand, the calculation of risk was according to the log odds of MS, which may partly explain the low values of ORs. On the other hand, there were much more healthy populations included in the outcome datasets in the current study, especially in the HF and the AF datasets.

The current two-sample MR study indicated suggestive causal associations between MS and a range of CVDs. Several underlying mechanisms have been proposed to explain the increased risk of CVDs in patients with MS. The causality found in the MR analysis was most likely due to common risk factors or etiological pathways, such as inflammation (37–39). Meanwhile, chronic pressure was associated with worsening disease in MS patients, which was related to a higher risk of stroke and MI (40, 41). Another speculative possibility was that immobilization and lack of physical activity amongst MS patients also increased the risk of CVDs (42). Besides, the immune-modulating treatments such as interferon β (INF-β) for MS patients were found to be associated with the risk of CVDs (43, 44). Other MS drugs like fingolimod were also reported to contribute to the risk of CVDs (45, 46). Previous studies have found that homocysteine plasma levels may be higher in patients with MS, which was a risk factor for CVDs (47–49). Other observational studies suggested endothelial dysfunction was evident in patients with MS (50, 51), which was a well-established risk factor of CAD (52).

The present study included several notable advantages. First, for the first time, MR analysis was employed to explore the causality of MS with a range of CVDs, which could largely reduce the influence of the environmental confounders and reverse causality. Second, the selected SNPs explained a relatively high proportion of MS. Furthermore, the large sample size of each MR analysis and the robust estimated effects of each instrumental variable (all F-statistics >10) ensure the statistical power in our study. Finally, several sensitivity analyses, such as the Weighted median analysis, MR-Egger regression, MR-PRESSO, and leave-one-out analysis were conducted to confirm the consistency of causal relationships.

However, several limitations should be considered when interpreting our findings. First, the influence of potential pleiotropy still could not be completely ruled out, though weak evidence of horizontal pleiotropy was found in the MR-Egger intercept tests and MR-PRESSO analyses. Second, different degrees of heterogeneity were detected in the Cochrane’s Q tests, indicating our analyses may be affected by pleiotropy. Third, MS patients in the current study were all of European descent, which might limit the generalizability of our findings to other populations. Further studies are needed to verify our findings in the non-European descents. Finally, we reported the relatively modest effect size (low values of ORs), thus the results of the current MR study should be interpreted with caution.

In conclusion, this MR study provided suggestive genetic evidence for the causal associations of MS with increased risks of CAD, MI, HF, AS, and AIS. These findings highlight the significance of active monitoring and prevention of cardiovascular risk to combat cardiovascular comorbidities in MS patients. Further studies are required to illuminate the effectiveness of timely treating MS on reducing the risk of CVDs and investigate the potential mechanisms of these causal links. Considering the modest effect size, the results should be interpreted with caution.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .

FY and TH designed the study and analyzed the data. FY drafted the manuscript. TH, JY, KH and HC interpreted the data and provided feedback on manuscript drafts. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

This work was supported by grants from the Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province, China (Grant No. 2022E10026), the Major Project of Science and Technology Innovation 2025 in Ningbo, China (Grant No. 2021Z134), and the Key Research and Development Project of Zhejiang Province, China (Grant No. 2021C03096).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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