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

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.

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.

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).

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.