Our investigation explored the causal dynamics between obesity indices and MG through two-sample MR analysis. The results of the study support an increase in hip circumference and whole body fat mass significantly increased the risk of MG. hip circumference also has a notable impact on the susceptibility to LOMG. These relationships were affirmed to persist, even after adjustments for type 1 diabetes influences by multivariate analyses. In a reverse analysis, EOMG was found to contribute to an increase in arm fat-free mass, leg fat-free mass, and predicted leg mass. To the best of our knowledge, this is the first investigation into the bidirectional influences of obesity and body composition on MG. Clarifying this complex interplay may pave the way for pioneering health management strategies for MG, introducing novel intervention methods and potentially reducing the prevalence of MG.
Emerging evidence underscores a substantial link between obesity and a heightened risk for MG. An epidemiologic investigation into hospitalized pregnant women across the United States, spanning 2005 to 2015, revealed an elevated occurrence of obesity in individuals diagnosed with MG[21]. Notably, the prevalence of obesity exhibits variability among MG subtypes. Research conducted by Elisabet et al, analyzing 40 MG patients, identified an increased incidence of obesity (BMI > 30), especially in subjects with LOMG[9]. Moreover, a previous study employed dual-energy X-ray absorptiometry to determine that arm and leg fat mass was significantly higher in the MG cohort, irrespective of corticosteroid administration[22].
Our MR analysis not only corroborates but also broadens the scope of previous observational studies. The prior research may have primarily concentrated on systemic or ocular acetylcholine receptor antibody-positive MG, overlooking individual differences between EOMG and LIMG. This extension is significant, as it addresses a gap in the research landscape by focusing on these less-studied MG subtypes.
Obesity is recognized as a significant risk factor for immune diseases, mediated through mechanisms including the shift in macrophage phenotypes from anti-inflammatory M2 to pro-inflammatory M1, adiponectin reduction, leptin elevation, and compromised vitamin D metabolism. Adipose tissue, previously defined as an immuno-endocrine organ, plays crucial roles in immunoregulation and metabolism[23; 24]. adipose tissue is a complex entity comprising adipocytes, endothelial cells, fibroblasts, and a variety of immune cells such as T and B cells, macrophages, and dendritic cells[25]. Macrophages are differentiated into M1 and M2 types which reflect pro-inflammatory and anti-inflammatory states respectively. Substantial evidence indicates that obesity induces dysfunction in adipocytes and facilitates a phenotypic transition of macrophages from M2 to M1, sustaining a state of chronic inflammation[24; 26]. In addition, this imbalance in adipose tissue function leads to the release of pro-inflammatory mediators, including leptin, which induces helper T cell 1 (Th1)-driven immune responses, attenuates the activity of regulatory cells, and promotes the production of inflammatory cytokines such as IL-6, IL-12, and TNF-α[27].
Obesity-associated metabolic dysfunctions, such as insulin resistance and diabetes, facilitate the accumulation of advanced glycation end-products (AGEs), leading to inflammation and a surge in reactive oxygen species (ROS). This cascade disrupts cellular metabolic processes and compromises the integrity of the neuromuscular junction, increasing susceptibility to MG.
Furthermore, concurrent investigations have revealed a prevalent deficiency in vitamin D metabolite concentrations within obese populations. Vitamin D plays a key role in orchestrating the immune response, in particular by increasing regulatory T (Treg) cell populations and inhibiting the differentiation of Th17 and Th1 cells[28].
Obesity promotes autoantibody synthesis through an elevation in the apoptosis inhibitor of macrophage (AIM) concentrations[29].AIM is a macrophage-derived factor located in immune complexes containing IgM and antigens[30]. At the same time, chemokines secreted by adipocytes in subcutaneous adipose tissue contribute to autoantibody production.
Obesity-related endocrine dysfunction, particularly elevated levels of estrogen and decreased levels of progesterone may subtly impair the integrity of the neuromuscular junction. Several studies have highlighted the critical role of estrogen in the pathogenesis of MG. In particular, estrogen is critical in priming AchR-specific Th cells in animal models of MG, culminating in the production of anti-AChR antibodies[31].
Our investigation shows that the correlation between hip circumference and risk differs between MG subtypes, with LOMG having an increased risk compared to EOMG. We speculate that hip circumference may affect different immune mechanisms, and further observational studies are needed to clarify.
Conversely, MG also increases susceptibility to obesity, attributable to multifaceted factors. The debilitating effects of MG, characterized by marked muscle weakness and fatigue, limit patients' daily activity levels and reduce physical activity leading to progressive weight and body fat accumulation. In addition, MG treatment protocols, particularly corticosteroids and immunosuppressants, exacerbate this scenario by stimulating appetite, altering metabolic pathways, promoting insulin resistance and diabetes, and exacerbating weight gain and obesity[32]. Braz et al shows that prolonged use of high-dose corticosteroids in MG patients correlates with increased body fat accumulation[33]. This effect is intensified by the psychological stress and stress responses triggered by MG, including anxiety and depression, which can lead to unhealthy eating patterns, especially the overconsumption of high-calorie foods. Moreover, MG adversely impacts muscle tissue health and quantity, resulting in a lower basal metabolic rate and, subsequently, a decrease in resting calorie expenditure.
Our research suggests that EOMG has a higher risk of obesity than LOMG, possibly due to different underlying factors. Specifically, LOMG patients have a higher incidence of diabetes complications and corticosteroid side effects than their EOMG counterparts, resulting in a more limited use of corticosteroids[34]. Francesca Pasquali et al discover that The percentage of patients taking corticosteroids for more than 10 years was four times higher in EOMG than in LOMG[35].
This investigation exhibits multiple significant advantages. Firstly, it substantially reduces confounding variables and biases linked to reverse causation. Therefore, it sharpens the accuracy in discerning the link between obesity and MG. The incorporation of aggregated data from comprehensive genetic studies targeting European cohorts diminishes the risk of demographic skew.
Despite its strengths, our study confronts several limitations. First, horizontal pleiotropy may influence autoimmune disease through pathways not previously considered. Although our MR-Egger analysis found no evidence of horizontal pleiotropy and identified strong correlations adjusted in the multivariate MR framework to minimize pleiotropic effects, we cannot categorically exclude the possibility of other causal mechanisms. Second, the amalgamation of data from various sources enhances statistical power yet interpretations of weak associations demand careful consideration, especially due to the infrequency of conditions like myasthenia gravis. Lastly, while these findings pertain to European populations, their applicability to other ethnic groups warrants further investigation to ascertain the universality of these associations.