As things stand at present, this is the first two-sample MR study to investigate the potential causal correlation of PA and CVDs. We found genetically predicted PA is significantly associated with the risk of CVDs including heart failure, atrial fibrillation, hypertension, coronary artery disease, myocardial infarction and stroke. In the reverse MR, we also found genetically predicted hypertension is significantly associated with the risk of PA.
PA is a common form of arterial hypertension, but it is rarely diagnosed or treated even in patients with hypertension. Our study suggested a bidirectional causal association between PA and hypertension from the genetic level, highlighting the necessity of routine screening, diagnosis and treatment of PA even in people with normal blood pressure. In addition, PA has several harmful consequences on the heart and arterial wall. Many observational studies have shown an increased risk of cardiovascular events in people with PA compared to those with essential hypertension. For example, a meta-analysis revealed that subjects with PA (4,546 individuals) had a higher risk of coronary artery disease (risk ratio = 1.67) and stroke (risk ratio = 2.03) than those with essential hypertension (52,284 individuals)[35]. Furthermore, another meta-analysis of 31 studies showed PA patients were at more than twice the risk of stroke as patients with essential hypertension[1]. However, the causal association between PA and CVDs remains uncertain because of the relatively small sample size and potential confounders of these observational studies. Using MR analysis can overcome the interference of reverse causal association and confounding factors in observational studies. Our study suggested that genetic prediction of PA is significantly correlated with the risk of atrial fibrillation, heart failure, hypertension, coronary artery disease, stroke and myocardial infarction, further emphasizing that PA needs to be aware and educated.
The adrenal disease characterized by excessive secretion of aldosterone is called hyperaldosteronism and can be divided into primary (also called Conn’s syndrome or PA) and secondary forms[36, 37]. Pathologically, on the one hand, aldosterone promotes stimulating inflammatory cell infiltration, oxidative stress, and endothelial damage. On the other hand, it also activates sympatho excitation and the renin angiotensin aldosterone system. Finally, the toxic effects of high aldosterone secretion will further cause the occurrence and development of cardiovascular dysfunction, leading to an increased incidence of adverse events[38, 39]. Accordingly, our data confirmed the role of PA in the development of cardiovascular events at the genetic level. From a reverse perspective, when some CVDs occur, the expression of the mineralocorticoid receptor is upregulated, or the disease is accompanied by increased aldosterone secretion, such as atrial fibrillation and myocardial infarction[16, 38, 40, 41]. In this regard, patients with acute myocardial infarction need timely use of aldosterone receptor blockers to inhibit short-term sharp increase in aldosterone secretion, and to improve heart failure and long-term prognosis[16]. In our reverse MR analyses, we found hypertension could potentially affect risk of PA although the sample size of GWAS of PA we used was relatively small. However, we found no evidence for the role of other CVDs on PA. The exact complex mechanisms of the association between CVDs and PA remain unclear, and more researches are needed to explore the underlying mechanisms.
It must be admitted that there are some limitations to this study. First of all, our study was restricted to European ancestry ethnicity, so whether our findings can be generalized to other ethnicities is uncertain. Second, significant heterogeneity of atrial fibrillation, stroke and myocardial infarction were obtained from individual variants through Cochran's Q value in the reverse MR analysis, although the leave-one-out analysis showed that the results did not significantly change after removing each SNP. Third, the sample size of the GWAS of PA is relatively small[22] which might bias our MR results. The calculated R2 of the IVs of PA reached above 1% and the F-statistic of the IVs reached above 10 which suggested the robustness of the IVs. In addition, the powers of the MRs were 100% which further demonstrated the robustness of the results. However, in the reverse MRs, the powers were less than 80% which might be due to the relatively small sample size of PA GWAS. Future studies with larger samples, whether prospective cohort studies or genetic studies, are needed to clarify the association between PA and CVDs.
In conclusion, our results indicated genetically predicted PA was positively associated with heart failure, atrial fibrillation, hypertension, coronary artery disease, myocardial infarction and stroke. But the reverse directional results showed no causal relationships, except for hypertension. Our data suggest the clinicians need to pay more attention to the early diagnosis and early treatment of PA, in case of irreversible cardiovascular damage.