Complement C5/C5a in the diagnosis and treatment of Graves' ophthalmopathy: A Mendelian randomized study.

Objectives: Graves' ophthalmopathy is a complex organ-specific autoimmune disease with an unclear pathogenesis. Complement component 5/5a (C5/C5a), a key element of the component system, may play a significant role in the disease's pathological process. This study aims to investigate the causal relationship between C5/C5a and Graves' ophthalmopathy using Mendelian randomization (MR) to provide new theoretical insights for its diagnosis and treatment.

Methods: Utilizing summary data from genome-wide association study (GWAS), C5/C5a was designated as the exposure factor and Graves' ophthalmopathy as the outcome. The causal relationship between C5/C5a and Graves' ophthalmopathy was analyzed, and colocalization analysis was performed to determine the posterior probability of hypothesis (PPH) and verify the genetic association between C5 and Graves' ophthalmopathy.

Results: The Wald ratio model showed a significant positive correlation between C5 and Graves' ophthalmopathy (OR=4.109, 95% CI 1.990 to 8.486, P<0.001). Similarly, the inverse variance weighted (IVW) model showed a positive correlation between C5a and Graves' ophthalmopathy (OR=2.901, 95% CI 1.225 to 6.869, P=0.015). Colocalization analysis showed that C5 and Graves' ophthalmopathy share a single nucleotide polymorphism (SNP), rs7036980, within the specified genetic window, with a PPH4 value of 0.81 (a value >0.80 indicates high probability).

Conclusions: Elevated levels of C5/C5a significantly increase the risk of developing Graves' ophthalmopathy. Targeting complement C5 with inhibitors may effectively reduce the risk of Graves' ophthalmopathy.