Elevated plasma concentration of complement factor C5 is associated with risk of future venous thromboembolism.

Abstract The role of complement in the pathogenesis of venous thromboembolism (VTE) is unclear. We aimed to (i) investigate whether plasma complement component C5 levels are influenced by genetic variants or chronic inflammation, and (ii) investigate the association between plasma C5 and risk of future VTE in a nested case-control study with 415 VTE patients and 848 age- and sex-matched controls derived from the Tromso study. Plasma C5 levels were measured at inclusion. Odds ratios (ORs) with 95% confidence intervals (95% CI) for provoked and unprovoked VTE across tertiles of C5 concentrations were estimated using logistic regression. C-reactive protein (CRP) was adjusted for as a proxy for general inflammation. Whole exome sequencing and protein quantitative trait loci analyses were performed to assess genetic influence on C5 concentrations. There was no association between genome-wide or C5-related gene variants and C5 levels. The association between plasma C5 levels and VTE risk displayed a threshold effect, wheresubjects with C5 levels above the lowest tertile had increased VTE risk.Subjects in tertile 3 (highest C5 levels)had an age and sex-adjusted OR of 1.45 (95% CI 1.07-1.96) compared to tertile 1(lowest).This was more pronounced for unprovoked VTE (OR 1.70, 95%CI 1.11-2.60).Adjustments for body mass index and CRP had minor impact on risk estimates. The ORs increased substantially with shorter time between blood sampling and VTE event. In conclusion,plasma C5 was associated with risk of future VTE. C5 levels werenot genetically regulated and only slightly influenced by chronic inflammation.