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Lookup NU author(s): Professor David KavanaghORCiD, Professor Tim Goodship, Dr Veronique Fremaux-Bacchi
Background: Pregnancy in women with systemic lupus erythematosus (SLE) or antiphospholipid antibodies (APL Ab)-autoimmune conditions characterized by complement-mediated injury-is associated with increased risk of preeclampsia and miscarriage. Our previous studies in mice indicate that complement activation targeted to the placenta drives angiogenic imbalance and placental insufficiency. Methods and Findings: We use PROMISSE, a prospective study of 250 pregnant patients with SLE and/or APL Ab, to test the hypothesis in humans that impaired capacity to limit complement activation predisposes to preeclampsia. We sequenced genes encoding three complement regulatory proteins-membrane cofactor protein (MCP), complement factor I (CFI), and complement factor H (CFH)-in 40 patients who had preeclampsia and found heterozygous mutations in seven (18%). Five of these patients had risk variants in MCP or CFI that were previously identified in atypical hemolytic uremic syndrome, a disease characterized by endothelial damage. One had a novel mutation in MCP that impairs regulation of C4b. These findings constitute, to our knowledge, the first genetic defects associated with preeclampsia in SLE and/or APL Ab. We confirmed the association of hypomorphic variants of MCP and CFI in a cohort of non-autoimmune preeclampsia patients in which five of 59 were heterozygous for mutations. Conclusion: The presence of risk variants in complement regulatory proteins in patients with SLE and/or APL Ab who develop preeclampsia, as well as in preeclampsia patients lacking autoimmune disease, links complement activation to disease pathogenesis and suggests new targets for treatment of this important public health problem.
Author(s): Salmon JE, Heuser C, Triebwasser M, Liszewski MK, Kavanagh D, Roumenina L, Branch DW, Goodship T, Fremeaux-Bacchi V, Atkinson JP
Publication type: Article
Publication status: Published
Journal: PLoS Medicine
Year: 2011
Volume: 8
Issue: 3
Print publication date: 22/03/2011
Date deposited: 07/11/2011
ISSN (print): 1549-1277
ISSN (electronic): 1549-1676
Publisher: Public Library of Science
URL: http://dx.doi.org/10.1371/journal.pmed.1001013
DOI: 10.1371/journal.pmed.1001013
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