O16 pQTL analysis of ficolin-3 activity reveals a link between the lectin pathway of complement and hematological disease manifestations in systemic lupus erythematosus

Objective The complement system plays a central role in the pathogenesis of Systemic Lupus Erythematosus (SLE), but most studies have focused on the classical pathway. Ficolin-3 is the main initiator of the lectin pathway of complement in humans, but its role in systemic autoimmune disease has not been conclusively determined. To address these questions, we performed a protein quantitative trait locus (pQTL) analysis to interrogate the contribution of ficolin-3 to SLE risk and disease manifestations. Methods Ficolin-3 activity was measured in serum samples from Swedish SLE patients (n = 786) and controls matched for age and sex (n = 566). Genetic variants in an extended 300 kb genomic region spanning the FCN3 gene encoding ficolin-3 were analyzed for their association with ficolin-3 activity and SLE manifestations in a Swedish multicenter cohort (n = 985). Results 132 single nucleotide variants in the FCN3 gene region were significantly associated with ficolin-3 activity in the pQTL analysis. Significant pQTLs mapped to an extended block of DNA in high linkage disequilibrium upstream of the FCN3 gene, and were associated with low ficolin-3 activity in serum in SLE patients but not in controls. Patients carrying the lead pQTL variant associated with low ficolin-3 activity had a lower frequency of hematological disease (OR 0.67, p = 0.018) and lymphopenia (OR 0.63, p = 0.031) and fewer autoantibodies (p = 0.0019). In contrast, genetic variants in the FCN3 gene were not associated risk to develop SLE. In agreement with the genetic data, patients with ficolin-3 activity in the highest tertile showed an inverse phenotype compared to pQTL carriers and had increased rates of hematological disease (OR 1.4, p = 0.078) and lymphopenia (OR 1.6, p = 0.039), and showed a strong enrichment in an SLE cluster defined by anti-Sm/DNA/nucleosome antibodies (OR 3.0, p <0.001). Conclusion Overall, our results provide genetic and biochemical evidence that implicate the lectin pathway in hematological SLE manifestations. We also identify activation of the lectin pathway through ficolin-3 as a factor that contributes to the autoantibody response in SLE.