High Levels of Complement Activating Enzyme MASP-2 Are Associated With the Risk of Future Incident Venous Thromboembolism

• Published in: Arteriosclerosis, Thrombosis, and Vascular Biology
• Main Authors: Damoah, Christabel Esi, Snir, Omri, Hindberg, Kristian, Garred, Peter, Ludviksen, Judith K., Brækkan, Sigrid K., Morelli, Vânia M., Mollnes, Tom Eirik, Hansen, John Bjarne
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2022
• Subjects: case-control studies; complement; deep vein thrombosis; humans; mannose-binding lectin; MASP; venous thromboembolism; Tromsø
• Online Access: https://curis.ku.dk/portal/da/publications/high-levels-of-complement-activating-enzyme-masp2-are-associated-with-the-risk-of-future-incident-venous-thromboembolism(8d66a171-e03a-4622-9580-87fe2e9c1285).html; https://doi.org/10.1161/ATVBAHA.122.317746; https://curis.ku.dk/ws/files/327674787/ATVBAHA.122.317746.pdf

Background: Experimental studies have shown that the complement activating enzyme MASP-2 (mannose-binding lectin associated serine protease 2) exhibits a thrombin-like activity and that inhibition of MASP-2 protects against thrombosis. In this study, we investigated whether plasma MASP-2 levels were associated with risk of future venous thromboembolism (VTE) and whether genetic variants linked to MASP-2 levels were associated with VTE risk. Methods: We conducted a population-based nested case-control study involving 410 VTE patients and 842 age- and sex-matched controls derived from the Norwegian Tromsø Study. Logistic regression was used to estimate odds ratios (ORs) of VTE across MASP-2 quartiles. Whole-exome sequencing and protein quantitative trait loci analyses were performed to assess genetic variants associated with MASP-2 levels. A 2-sample Mendelian randomization study, also including data from the INVENT consortium (International Network of Venous Thrombosis), was performed to assess causality. Results: Subjects with plasma MASP-2 in the highest quartile had a 48% higher OR of VTE (OR, 1.48 [95% CI, 1.06-2.06]) and 83% higher OR of deep vein thrombosis (OR, 1.83 [95% CI, 1.23-2.73]) compared with those with MASP-2 levels in the lowest quartile. The protein quantitative trait loci analysis revealed that 3 previously described gene variants, rs12711521 (minor allele frequency, 0.153), rs72550870 (minor allele frequency, 0.045; missense variants in the MASP2 gene), and rs2275527 (minor allele frequency, 0.220; exon variant in the adjacent MTOR gene) explained 39% of the variation of MASP-2 plasma concentration. The OR of VTE per 1 SD increase in genetically predicted MASP-2 was 1.03 ([95% CI, 1.01-1.05] P=0.0011). Conclusions: Our findings suggest that high plasma MASP-2 levels are causally associated with risk of future VTE.