Effect of Life Course Adiposity on Bell's Palsy Mediated by Glucose Levels

Abstract

Introduction and aims: Previous observational studies have reported an association between obesity and Bell's palsy (BP), but the causality and the underlying mediating pathways remain unclear. We aimed to investigate the causal effects of adiposity across the life course on BP and to identify potential mediators in this relationship.

Methods: Utilizing summary statistics from genome-wide association studies predominantly of European ancestry, we conducted univariable and multivariable Mendelian randomization (MR) to estimate overall and independent effects of 5 adiposity-related traits (birth weight, childhood body mass index [BMI], adult BMI, adult body fat percentage, and adult waist circumference) on BP. Two-step MR was employed to assess the mediating role of metabolic and inflammatory traits. Sensitivity analyses were performed to evaluate robustness.

Results: Univariable MR revealed that genetically predicted adult BMI (OR: 1.29, 95% CI: 1.11-1.49, P = .001), body fat percentage (OR: 1.33, 95% CI: 1.08-1.65, P = .008), and waist circumference (OR: 1.29, 95% CI: 1.08-1.55, P = .005) were significantly associated with increased risk of BP. Multivariable MR confirmed an independent causal effect of adult BMI after adjusting for birth weight and childhood BMI. Two-step MR further identified glucose levels as a partial mediator, accounting for 23.8% (95% CI: 4.9%-42.6%) of the total effect. Findings were consistent across sensitivity analyses.

Conclusion: Higher genetically predicted adult BMI could increase the risk of BP, partly mediated by impaired glucose regulation.

Keywords: Bell’s palsy; Glucose; Mediation analysis; Mendelian randomization; Obesity.

Fig. 1

Schematic causal graphs in the MR study. A, Univariable MR analyses to estimate overall effects between life course adiposity (birth weight; childhood body mass index, BMI; adult BMI; body fat percentage; waist circumference) and Bell’s palsy; B, Multivariable MR analyses to estimate direct effects of adult BMI on Bell’s palsy; C, Applying the 2-step MR framework to estimate mediation proportion of potential mediators in the associations of adult BMI with Bell’s palsy. The coloured arrows in red and green on these graphs illustrate the causal effect of adult BMI on the outcome being estimated in MR analyses.

Fig. 2

Forest plot depicting MR results for the association of genetically proxied life course adiposity with Bell’s palsy. N. SNPs, number of SNPs used in MR; OR, odds ratio; CI, confidence intervals; IVW, inverse variance weighted; WM, weighted median; BMI, body mass index.

Fig. 3

Multivariable MR estimating the association of birth weight, childhood body mass index, and adult body mass index with Bell’s palsy. Red plots represent the multivariable MR analyses of the effects of birth weight (BW) on Bell’s palsy (BP) after adjusting for childhood body mass index (BMI) and adult BMI; Green plots represent the multivariable MR analyses of the effects of childhood BMI on BP after adjusting for BW and adult BMI; Yellow plots represent the multivariable MR analyses of the effects of adult BMI on BP after adjusting for BW and childhood BMI. N. SNPs, number of SNPs used in MR; OR, odds ratio; CI, confidence intervals; IVW, inverse variance weighted.

Fig. 4

Selection process for mediators of the causal association between adult body mass index and Bell’s palsy. Four processes were applied to screen for mediators in the causal association between adult body mass index (BMI) and Bell’s palsy (BP), on the basis of the following criteria: the mediator should be causally associated with BP; the adult BMI should be causally associated with the mediator, but not vice versa; the BMI-mediator association and the mediator-BP association should be in the same direction; and the mediator should have a direct causal effect on the BP independent of adult BMI. Finally, 1 mediator (glucose levels) qualified for all criteria was included in the mediation analyses.

Fig. 5

The glucose levels mediate the association between higher adult body mass index and Bell’s palsy. Initially, univariable MR was used to estimate the causal effect of genetically determined body mass index (BMI) on the glucose levels (β1), while reverse causality was tested to confirm the absence of bidirectional effects that might compromise the mediation model’s validity. Subsequently, the mediator’s causal effect on Bell’s palsy, adjusted for BMI (β2), was estimated using multivariable MR. The mediation proportion (β1 × β2 / Total effect β) and 95% confidence intervals for each mediator in the association between BMI and Bell’s palsy were calculated using the delta method.