This study employs UVMR and MVMR analyses to reveal a positive genetic causal relationship between MS and the risk of AD. Upon conducting a MVMR analysis that incorporated a range of potential confounders—such as BMI, CRP levels, telomere length, serum 25(OH)D levels, vitamin deficiencies, the age of smoking initiation, smoking status, current tobacco smoking, presence of smokers in household, past tobacco smoking, and the frequency of alcohol intake—it was determined that the causal link is modulated by smoking status, serum 25(OH)D levels, and CRP levels as independent factors. These findings offer new perspectives for understanding the potential connections between MS and AD, potentially guiding future prevention and treatment strategies for AD.
MS is an autoimmune disease with a high recurrence and fatality rate [3], while patients with AD often have one or more autoimmune diseases [22]. The association between AD and MS has been controversial. Some observational studies suggest a higher prevalence of MS in patients with AD [9, 23]. A large Swedish case-control study identified an increased prevalence of MS exclusively in female patients with AD, highlighting sex differences in comorbidities [10]. Conversely, another large study found no association, potentially due to variations in study design, sample selection, or population characteristics [24]. The majority of existing studies are cross-sectional, retrospective, or case-control in nature, which limits their ability to establish causality. To address this limitation, we employed MR analysis to investigate the genetic causal relationship between MS and AD. Additionally, we conducted MVMR analysis to mitigate the effects of pleiotropy at the GWAS database level. After adjusting for BMI, telomere length, vitamin deficiency, and smoking-related factors, MS remained positively associated with AD. However, adjustments for CRP, serum 25(OH)D levels, and smoking status did not reveal a significant effect of MS on the risk of AD, suggesting a non-negligible interaction between these factors in the risk of MS on AD occurrence. Studies have demonstrated that the incidence of autoimmune comorbidities is significantly higher in patients with a history of smoking compared to non-smoking patients MS [24]. Previous studies have indicated that CRP [25, 26], serum 25(OH)D) levels [27, 28], and smoking status [29, 30] are all influential factors in the association between MS and AD. Our study supports the notion that these factors may play a role in this causal relationship, and the precise effects of these variables require further investigation in subsequent studies.
The pathogenesis of AD and MS is complex, involving genetic, immunologic, and environmental factors, with both conditions characterized by chronic recurrent exacerbations. A meta-analysis of genome-wide association studies has revealed substantial genetic overlap between susceptibility loci for AD and various autoimmune diseases [31]. Additionally, commonalities exist in the immune regulation implicated in both MS and AD. T helper cell (Th) 1 and Th17 cells, along with the inflammatory factors they secrete, play crucial roles in the progression of MS. These cells migrate to CNS, triggering an immune response. Th1 cells and interferon-γ (IFN-γ) they secrete cause demyelination of CNS neurons and neuronal degeneration [32]. Interleukin (IL)-17A secreted by Th17 cells disrupts the blood-brain barrier, allowing more Th17 cells to migrate into the brain parenchyma, producing additional IL-17A and resulting in severe neurological deficits [33, 34]. Th17 cells are increased in the peripheral blood, cerebrospinal fluid, and brain lesions of MS patients, with their counts increasing further during relapses [35]. Similarly, AD is associated with Th1 and Th17 cells. Th1 cytokines, such as IFN-γ, are expressed in the skin lesions of AD patients [36]. In the chronic phase of AD, Th1 cells predominate, producing IFN-γ and tumor necrosis factor-α(TNF-α), leading to chronic inflammatory lesions in eczema [37, 38]. Recent studies have found that Th17 cytokines, such as IL-17 and IL-22, are expressed in the skin lesions of patients with AD [39–41]. Elevated levels of IL-17 promote the differentiation of B-cells into IgE-producing plasma cells [42], leading to eosinophil- mediated and neutrophil-mediated inflammation [43]. The expression of Th17 cells and IL-17 is increased in the peripheral blood of AD patients and correlates with disease severity. Immunohistochemistry has shown that Th17 cells also infiltrate the papillary dermis of AD lesion skin [44]. Therefore, the overexpression of key factors such as IFN-γ and IL-17, along with the proliferation of T-cell subsets Th1 and Th17, play significant roles in both AD and MS. These findings provide a biological basis for the potential association between AD and MS.
The MR analysis employed in this study leverages genetic variants as IVs to simulate random allocation in a controlled trial setting, thereby assessing the causal relationship between MS and AD. This approach circumvents the biases introduced by confounding factors and reverse causality inherent in observational studies. The use of European population data minimizes bias due to population heterogeneity, and the multivariate nature of our analysis further validates our findings.
However, this study has limitations. The analysis is based on GWAS data from European populations, which may limit the generalizability of the results. Future research should validate these findings in diverse racial and geographical populations. Additionally, differences in age and gender distribution between MS and AD may affect the interpretation of the causal relationship, suggesting a need for age and gender subgroup analyses in future studies. Lastly, while MR analysis is a robust tool, its findings should be corroborated by large-sample, multicenter, randomized controlled trials.