Causal Associations Between Nine Autoimmune Diseases and Idiopathic Thrombocytopenic Purpura: A Mendelian Randomization Study.

Abstract

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: This study preliminarily explored the genetic relationship between ADs and ITP, but it is subject to several limitations, such as the limited number of IVs. Larger-scale genome-wide association study (GWAS) datasets will be needed for further validation.

Conclusions: MR analysis suggested that there might be no significant causal associations between SLE, RA, AS, PBC, PsA, or AOSD and ITP, whereas PM, PSC, and SS might potentially show causal associations with ITP.