Bell’s palsy is one type of peripheral facial nerve palsy, and is more common in young adults than in other age groups (Holland and Bernstein, 2014; Vakharia and Vakharia, 2016). Patients usually do not experience any prodromal symptoms, but find a series of facial paralysis symptoms directly when they wake up in the morning (Holland and Bernstein, 2014; Vakharia and Vakharia, 2016). At present, the causes and risk factors for Bell’s palsy are not well understood. Previous studies reported that viral infections, blood vessel disorders, immunodeficiency, genetic defects and physical stress were involved in the pathogenesis of Bell’s palsy (Amit, 1987; Browning, 2010; Tseng et al., 2017; Grewal, 2018; Yamamoto et al., 2022). However, a firmed conclusion can not be drawn, and more research about this topic are ongoing.

An increasing number of evidence had reported that several chronic diseases might be associated with the development and progression of Bell’s palsy. Stamatiou et al. concluded recently that the risk of Bell’s palsy was significantly increased in patients with type 2 diabetes mellitus (T2DM), while T2DM may contribute to severe facial nerve degeneration (Stamatiou et al., 2022). Savadi-Oskouei et al. in their study reported that hypertension was related to the increased risk of Bell’s palsy among those patients aged above 40 years (Savadi-Oskouei et al., 2008). Psillas et al. suggested that the mean severity of Bell’s palsy was more significant in patients with hypercholesterolemia, T2DM or hypertension, in comparison to control group (Psillas et al., 2021). Meanwhile, patients suffering from Bell’s palsy and concomitant comorbidities had a poorer prognosis compared to patients without comorbidities (Psillas et al., 2021). Kim et al. using a national health screening cohort revealed that obesity was associated with the risk of Bell’s palsy in the population over 40 years old (Kim et al., 2020). However, all these findings were obtained from previous observational studies, which can not avoid the effects of confounding factors and can not distinguish the chronological order of research factors.

Mendelian randomization studies adopt genetic variants to replace traits, and the latters usually refer to exposures or outcomes in observational studies. Thus, Mendelian randomization studies explain the potential effect of one exposure on one outcome by studing the relationship between the corresponding two genetic variants. The characteristics of this genetic method determine that it may make up for the above shortcomings of observational studies and provide more reliable findings (Emdin et al., 2017; Sanderson, 2021). However, there was no Mendelian randomization studies focusing on the association of T2DM, hypertension and obesity with Bell’s palsy at present.

Taken together, the study adopted a well-designed Mendelian randomization study to explore the genetic effects of several chronic diseases, such as T2DM, hypertension and obesity, on the risk of Bell’s palsy, and also to reveal the potential effects of several blood lipids, lipoproteins and apolipoproteins on the risk of the disease.

As shown in Table 1, a total of 13–453 suitable SNPs were selected to predict T2DM, hypertension, BMI, several blood lipids, apolipoproteins and lipoproteins. All SNPs (including their F-statistics) were listed in Supplementary Table S1.

To our knowledge, this was the first Mendelian randomization study focusing on the association of hypertension with Bell’s palsy. Based on the results from the study, we reported that hypertension might increase the risk of Bell’s palsy by about 130% at the genetic level. As mentioned above, a great number of traits, such as viral infections, blood vessel disorders, immunodeficiency, genetic defects and physical stress, contributed to the occurrence of Bell’s palsy (Amit, 1987; Browning, 2010; Tseng et al., 2017; Grewal, 2018; Yamamoto et al., 2022), and should be regarded as confounding factors in the study. So, all the instrumental variables related to these confounding factors were manually excluded using PhenoScanner Pheno Scanner V2 prior to conducting Mendelian randomisation analyses. All the instrumental variables were also consistent with the principles of relevance and independence. Therefore, we believed that a causal correlation between hypertension and Bell’s palsy was relatively well established.

A number of observational studies had explored the relationship between hypertension and Bell’s palsy. Savadi-Oskouei et al. and Psillas et al. separately reported that hypertension may be related to the increased risk of Bell’s palsy in different populations (Savadi-Oskouei et al., 2008; Psillas et al., 2021). Two earlier studies also showed that hypertension might be an potential predisposing and prognostic factor in Bell’s palsy, though a firm conclusion can not be drawn (Abraham-Inpijn et al., 1982; Abraham-Inpijn et al., 1987). These were consistent with the results of the present study.

The mechanisms by which hypertension promoted the development of Bell’s palsy were unclear and no previous studies had been published. As hypertension was an important vasculogenic factor and nerve ischaemia was a potential cause of Bell’s palsy (Grewal, 2018; Humphrey, 2021), we speculated that hypertension may cause nerve damage by affecting the blood supply to the associated facial nerve, which in turn induced Bell’s palsy.

This study also found, for the first time, an unexpected result of an inverse causal relationship between LDL cholesterol and Bell’s palsy. For each standard deviation increase in LDL cholesterol levels, the risk of the disease was reduced by approximately 20%. This result seemed to contradict the current understanding of LDL cholesterol, which was now widely regarded as a risk factor for atherosclerosis and coronary heart disease (Navarese et al., 2018). However, some scholars still had opposite views on the role of LDL cholesterol (Ravnskov et al., 2018). Perhaps the role of this cholesterol was more complex than one might think. In addition, this result did not exist in isolation. The present study also showed that increased level of apolipoprotein B was almost associated with a reduced risk of Bell’s palsy, although this correlation was not statistically significant after excluding one outlier. Whereas apolipoprotein B was the main structural protein of LDL cholesterol, measurement of apolipoprotein B gave a direct indication of LDL cholesterol level (Sniderman et al., 2021). Therefore, the causal relationship between LDL cholesterol and Bell’s palsy must be revalidated and the underlying mechanisms should be further explored.

In addition, the present study did not find any association of T2DM and obesity with Bell’s palsy risk. However, a number of published observational studies suggested that T2DM and obesity contributed to the development of Bell’s palsy, which was inconsistent with the present study (Kim et al., 2020; Psillas et al., 2021; Stamatiou et al., 2022). One reasonable explanation was that although there was no genetic relationship, some uncertain traits may act as an intermediary and link these two diseases (i.e., T2DM and obesity) and Bell’s palsy. For example, the trait that most readily came to mind was the inflammatory response. Both obesity and T2DM were accompanied by systemic metabolic inflammation, while inflammation was one of the important pathophysiological changes in Bell’s palsy (Kınar et al., 2021). It was possible that obesity and T2DM promoted the development of Bell’s palsy through inflammatory pathways, rather than genetic variants.

As we all know, observational studies had a range of congenital deficiencies, which made them difficult to avoid the interference of reverse causality and confounding factors (Bowden and Holmes, 2019). Mendelian randomization studies adopted specific genetic variants (i.e., SNPs or instrumental variables) to replace traits (i.e., exposures or outcomes). The design overcame the deficiencies and led to more reliable conclusions. This was the main advantage of this study.

As a two-sample Mendelian randomisation study, the summary data for the outcome were all from FinnGen, while the summary data for the exposures were mainly from UKB, whose population included only a very small proportion of Finnish individuals. According to previous studies, the European population can be divided into two subgroups, namely, Finns and non-Finnish Europeans (Liu and Fu, 2015; Lek et al., 2016; Gilbert et al., 2022). In this sense, the exposures and outcomes in this study can be considered to be from two different populations, which would affect the estimation of causal effects. Although most previously published two-sample Mendelian randomisation studies had not distinguished between these two European subgroups, this did represent a potential limitation of the study. For this reason, this study initially compared allele frequencies of the exposures and outcome for all instrumental variables and did not find substantial differences between them. In addition, we also provided these allele frequencies in Supplementary Table S1 to make these information public. We hoped that future research may overcome this limitation and validate the reliability of our findings in different European subgroups.

In conclusion, this study confirmed that hypertension may be a risk factor for Bell’s palsy at the genetic level. Also, this study provided some insufficient evidence to prove that LDL cholesterol might reduce the risk of Bell’s palsy. In addition, no genetic association of other lipids, apolipoproteins and lipoproteins with Bell’s palsy was found. The results of this study (especially for LDL cholesterol) need to be validated by further studies.