In this MR study, we first explored the causal association between plasma uridine and AF by using different publicly available GWAS datasets. We provided evidence from a genetic perspective that increased plasma uridine levels reduced the risk of AF. Furthermore, we duplicated the results using a series of complementary MR methods. When using the FinnGen consortium as the outcome datasets, it showed high heterogeneity among IVs, and the associations of uridine with AF were directionally coherent though lacking statistical significance. So, we selected the IVW method in the multiplicative random-effects model, which can estimate relatively reliably when conditions of high heterogeneity exist among SNPs, as our primary analysis approach. The meta-analyses combined three datasets to get an integrated MR estimate, further enhanced the causal inference. Our findings provided new possibilities for the preventive strategies of atrial fibrillation.
Uridine, a pyrimidine nucleoside, is more abundant in plasma than other nucleosides in humans[34]. Thus, it plays a critical role in the synthesis of various metabolites in vivo, such as endogenous pyrimidine, glycogen, biomembrane and the like[35]. The previous study suggested that uridine can control heart rhythm disorders owing to its participation in myocardial glycogen resynthesis and production of ATP for ion transport systems in pathological conditions[36]. At present, fibrosis has been well established and exerts a crucial effect in the development of AF[37]. Specifically, mitochondrial reactive oxygen species (ROS) were activated under various pathological and stress conditions, which further activated p38 and ERK1/2 to accelerate the fibrotic genes’ transcription[38]. The recent research conducted by Liu et al. found that uridine supplementation promoted tissue recovery in cardiac injury models and decreased fibrotic as well as reduced inflammatory cytokine levels[3]. Over the past few years, oxidative stress and inflammation have been investigated as playing crucial roles in the onset and development of AF[37]. Additionally, previous studies have also demonstrated that uridine treatment can significantly decrease the levels of oxidative stress and inflammation in vitro[39]. The positive effects of uridine in reducing oxidative stress and inflammation might be involved with the activation of the mitoKATP channel and thus preserve the structure and function of mitochondria[39, 40], which finally leads to less fibrosis in the myocardium. However, the essence of the protective effect of uridine in AF is still uncertain and needs further preclinical studies to be deeply explored.
Our findings coincided with a prospective cohort study based on the Atherosclerosis Risk in Communities (ARIC) study, which reported that higher plasma uridine levels were associated with a decreased risk of AF (hazard ratio, 0.85; 95% CI, 0.79, 0.92; p = 1.3 ⋅ 10− 4)[41]. In addition, another previous observational cohort study based on the Framingham Heart Study provided similar results for uridine and risk of AF (hazard ratio, 0.84; 95% CI, 0.70,1.00; p = 0.052), though with nonsignificant[42]. As we all known, observational studies can be influenced by potential confounders, making reverse causation difficult to determine and distorting true casual associations. To figure out whether uridine plays a protective role in reducing the risk of AF, more prospective clinical trials based on large populations may shed light on this but expend a relative amount of time. This MR analysis based on datasets from GWASs of mountains of European population sought to demonstrate this issue.
One of the primary strengths of this study is that it is based on the MR analysis framework, which provides casual associations more reliably. Also, our MR estimates strengthened the reliability of the casual inference between plasma uridine levels and AF with less confounding bias. Additionally, no horizontal pleiotropy was discovered for any of the outcomes examined utilizing MR-Egger regression (one of the sensitivity analyses), MR steiger test and PhenoScanner V2. There should thus be few possibilities for pleiotropic effects in this investigation. These findings provide the foundation for further research to assess the therapeutic significance of increased plasma uridine levels for better preventing AF.
However, there were certain limitations worth recognizing in this study. First, the numbers of uridine-associated SNPs are too few to perform the MR Pleiotropy Residual Sum and Outlier methods, which were deemed a global test to detect pleiotropy of the IVs and calculate a MR estimate after removing pleiotropic outliers[43]. It is still worth noting that a potential pleiotropy bias might exist in this study. Second, the I2 statistic calculated based on the FinnGen consortium is 76%, suggesting high heterogeneity among the 3 SNPs. This might be due to the fact that the numbers of selected IVs were too few, larger GWAS datasets of uridine are need to detect more uridine-associated SNPs. Third, given that this study was based on summary-level data, the potential nonlinear associations between plasma uridine and AF were not examined. Fourth, the MR estimate results based on the FinnGen consortium are significantly different from the others, which could be attributed to the fact that the AF cases in the FinnGen consortium contain some atrial flutter patients. Moreover, because the AF HRC collaboration includes individuals of non-European ancestry (nearly 9%), demographic stratification may increase bias. Owing to this MR study was limited to participants who were mostly of European heritage, it is difficult to generalize to populations of other descents. Investigating the causal relationships among various populations would be of great interest. Future research is necessary to expand on our findings.