High Levels of Complement Activating Enzyme MASP-2 Are Associated With the Risk of Future Incident Venous Thromboembolism
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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.
Original language | English |
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Journal | Arteriosclerosis, Thrombosis, and Vascular Biology |
Volume | 42 |
Issue number | 9 |
Pages (from-to) | 1186-1197 |
ISSN | 1079-5642 |
DOIs | |
Publication status | Published - 2022 |
Bibliographical note
Funding Information:
This work was supported by a former grant from Stiftelsen Kristian Gerhard Jebsen. The Thrombosis Research Center was supported by an independent grant from Stiftelsen Kristian Gerhard Jebsen (2014–2020).
- case-control studies, complement, deep vein thrombosis, humans, mannose-binding lectin, MASP, venous thromboembolism
Research areas
ID: 327674783