Causal Associations Between Nine Autoimmune Diseases and IdiopathicThrombocytopenic Purpura: A Mendelian Randomization Study

Introduction: Clinical evidence suggests the presence of comorbidity between Autoimmune diseases (ADs) and secondary Idiopathic thrombocytopenic purpura (ITP), whereas the underlying causal relationship remains to be established. This study employed Mendelian Randomization (MR) analysis to investigate potential causal relationships between multiple common ADs and the risk of ITP. Methods: Using criteria of P<5×10-8 , P<5×10-6 , and F-statistic>10, and excluding single nucleotide polymorphisms (SNPs) with confounding, palindromic sequences, and linkage disequilibrium as instrumental variables (IVs). The primary analysis was conducted using the inverse-variance weighted (IVW) method, supplemented by MR-Egger regression, weighted median estimator (WME), simple mode, and weighted mode approaches to assess robustness. Multiple sensitivity analyses were conducted to assess the robustness of the findings. Results: SNPs significantly associated with each autoimmune disease were identified as IVs, including 6 SNPs for systemic lupus erythematosus (SLE), 5 for rheumatoid arthritis (RA), 6 for ankylosing spondylitis (AS), 5 for Sjögren’s syndrome (SS), 7 for polymyositis (PM), 13 for primary sclerosing cholangitis (PSC), 4 for primary biliary cirrhosis (PBC), 16 for psoriatic arthritis (PsA), and 25 for adult-onset Still’s disease (AOSD). IVW analysis indicated no genetic association between SLE, RA, AS, PBC, PsA, or AOSD and ITP. Significant associations were observed for PM (OR=0.807, 95% CI=0.742-0.876, P=3.93×10⁻⁷), PSC (OR=0.831, 95% CI=0.742-0.933, P=0.002), and SS (OR=1.589, 95% CI=1.375-1.835, P=3.05×10⁻¹⁰). WME analysis yielded consistent results for PM, PSC, and SS. Most sensitivity analyses supported the robustness of these findings. discussion: 4 Discussion This research utilized a bidirectional Mendelian Randomization to assess the causal connections between genetic predisposition to ADs and the likelihood of ITP. The findings indicated that PM and PSC were protective factors for ITP, whereas SS was a risk factor. Significant genetic associations with ITP risk were identified for all three, and the consistency of these associations was verified using various sensitivity analysis methods. In contrast, no significant genetic associations with ITP were observed for SLE, RA, AS, DM, PBC, PsA, or AOSD. Representing a chronic autoimmune disorder, SS involves the systemic infiltration of lymphocytes that destroys exocrine glands. Consequently, this structural damage most notable in salivary and lacrimal glands—precipitates classic symptoms like xerostomia and xerophthalmia. In addition to glandular involvement, SS frequently manifests with extraglandular features affecting the lungs, skin, and nervous system[16]. Retrospective studies have reported that the prevalence of ITP among patients with SS ranges from 12.4% to 21.6%, substantially higher than the 0.05%–1% observed in the general population[17-19], consistent with our MR findings. However, not all SS patients progress to ITP, indicating substantial clinical heterogeneity in risk. Previous retrospective analyses have identified potential risk and protective factors for ITP in SS. Yang et al.[17] reported that, compared with SS patients without ITP, those with secondary ITP had significant differences in age, ESSDAI score, fatigue prevalence, serum IgG level, low complement C3 level, leukocyte count, lymphadenopathy, and arthritis, Among these factors, lymphadenopathy may represent a risk factor for secondary ITP in patients with SS. Conversely, arthritis emerges as a protective element; specifically, within the SS cohort, its presence demonstrates an inverse correlation with the incidence of ITP. This clinical observation may be partially explained by the pro-inflammatory functions of platelets. The pro-inflammatory shift and hyper-proliferation of fibroblast-like synoviocytes (FLS) are reportedly triggered by activated platelets. This process involves the liberation of bioactive molecules from α-granules, notably C-C motif chemokine ligand 5, platelet-derived growth factor, and Transforming growth factor-β1, which contribute to disease progression. Proliferating FLS invading bone or cartilage secrete matrix metalloproteinases (MMP-1, MMP-3), leading to joint destruction[20,21]. Platelet depletion experiments further demonstrated that reduced platelet levels markedly attenuate arthritis severity[22]. The above mechanism explains the potential protective role of arthritis from the perspective of platelet consumption. When the immune system is preferentially engaged in synovial inflammation, it may competitively suppress the anti-platelet autoimmune responses that lead to ITP. However, in SS patients who do progress to ITP, the anti-platelet autoimmune response becomes the dominant immunopathological process. Mechanistically, SS patients with ITP often exhibit elevated levels of autoantibodies against platelet membrane glycoproteins (GPIb, GPIIIa, GPIIb/IIIa)[23,24], which may trigger platelet apoptosis via the FcγRIIA signaling pathway, accompanied by loss of mitochondrial membrane potential. Apoptotic platelets frequently undergo desialylation, exposing β-galactose residues that are recognized by hepatocytes asialoglycoprotein receptors, leading to macrophage-mediated clearance[25]. Moreover, anti-platelet antibodies can impair megakaryocyte maturation and platelet production, further exacerbating thrombocytopenia[26]. The spectrum of idiopathic inflammatory myopathies is primarily represented by two distinct clinical entities: DM and PM. Both conditions are pathologically defined by the immune-mediated destruction of skeletal muscle tissue. From a clinical perspective, these patients primarily exhibit symmetric weakness in the proximal musculature that worsens over time. Additionally, systemic involvements are frequently observed, notably interstitial lung disease and cutaneous signs like Gottron's papules[27]. Crucially, current literature—encompassing both observational surveys and traditional bench research—has failed to establish a definitive positive link between DM/PM and ITP. Against this background, the potential negative association between PM and ITP observed in our study provides a new perspective for understanding the relationship between these two conditions. Although both are ADs, their distinct immunoregulatory patterns may help explain the inverse association identified in our MR analyses. PM is characterized pathologically by predominant CD8⁺ T-cell infiltration, whereas the pathogenesis of ITP is more closely related to dysregulated CD4⁺ T-cell subsets[28]. Therefore, in individuals with a genetic predisposition toward a CD8⁺ T-cell–dominated immune response, as seen in PM, the resulting cytokine environment may be unfavorable for CD4⁺ T-cell differentiation and activation, thereby exerting a protective effect against the development of ITP. Defined as a chronic disorder of cholestasis, PSC involves the progressive inflammation and scarring that leads to stenosis of the bile ducts. Over time, this pathological process poses a significant risk of evolving into biliary cirrhosis and end-stage liver disease[29]. Current epidemiological evidence has not directly demonstrated an association between PSC and ITP. The existing literature is limited to a single case report by Sakai et al[30]. However, this reported comorbidity is more likely attributable to coincidence, or perhaps reflects a degree of immune dysregulation in the patient severe enough to trigger two distinct autoimmune pathways simultaneously—thus masking any potential protective effect of PSC. Moreover, neither PSC nor ITP has been listed as a major associated condition in systematic reviews of the other disease[31,32]. The striking lack of overlapping clinical phenotypes among hundreds of thousands of patients provides real-world evidence supporting the possibility that PSC may act as a protective factor against the development of ITP. There is a robust clinical overlap between PSC and inflammatory bowel disease (IBD), most notably ulcerative colitis. Indeed, concurrent IBD is observed in a vast majority (roughly 70–80%) of the PSC cohort. The chronic inflammatory activation state resulting from IBD-mediated increases in intestinal barrier permeability may underlie the potential protective effect of PSC against ITP[33]. Persistent inflammation drives both biliary stenosis and intestinal microbial dysbiosis. These pathological changes result in the retention of significant levels of primary and secondary bile acids, which subsequently function as immunosuppressants. On one hand, while the pro-inflammatory microenvironment driven by activated macrophages may promote ITP progression, accumulated bile acids can inhibit macrophage-mediated inflammation by activating G-protein–coupled bile acid receptor 1 (GPBAR1) and farnesoid X receptor (FXR), suppressing multiple pathways including the NLRP3 inflammasome and NF-κB signaling. Consequently, this process leads to the downregulation of pro-inflammatory cytokines (specifically interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α), while concurrently upregulating IL-10. This shift effectively dampens macrophage-driven inflammation and fosters an anti-inflammatory milieu[34] . On the other hand, the development of ITP is tightly associated with T-cell subset imbalance. Certain secondary bile acids not only function as inhibitors