PLoS Medicine: Mutations in Complement Regulatory Proteins Predispose to Preeclampsia: A Genetic Analysis of the PROMISSE Cohort

Mutations in Complement Regulatory Proteins Predispose to Preeclampsia: A Genetic Analysis of the PROMISSE Cohort


Jane E. Salmon1*, Cara Heuser2, Michael Triebwasser3, M. Kathryn Liszewski3, David Kavanagh4, Lubka Roumenina5, D. Ware Branch2, Tim Goodship4, Veronique Fremeaux-Bacchi5, John P. Atkinson3

1 Autoimmunity and Inflammation Program, Hospital for Special Surgery, Cornell Weill Medical College, New York, New York, United States of America, 2 Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, United States of America, 3 Department of Medicine/Division of Rheumatology, Washington University School of Medicine, St. Louis, Missouri, United States of America, 4 Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom, 5 Assistance Publique-Hopitaux de Paris, Hôpital Européen Georges-Pompidou, Service d'Immunologie Biologique, Paris, France

Abstract Top
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.

Study Registration
ClinicalTrials.gov NCT00198068

Please see later in the article for the Editors' Summary

Citation: Salmon JE, Heuser C, Triebwasser M, Liszewski MK, Kavanagh D, et al. (2011) Mutations in Complement Regulatory Proteins Predispose to Preeclampsia: A Genetic Analysis of the PROMISSE Cohort. PLoS Med 8(3): e1001013. doi:10.1371/journal.pmed.1001013

Academic Editor: Nicholas M. Fisk, University of Queensland, Australia


Received: September 19, 2010; Accepted: February 14, 2011; Published: March 22, 2011

Copyright: © 2011 Salmon et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This research was supported in part by NIH grants AR49772 (JES), NIH 5 RO1 AI037618 (JPA), NIH F30HL103072 NHLBI (MT), NIH 5 T32 AI007172-30 (MT), the Mary Kirkland Center for Lupus Resarch (JES), UK Medical Research Council grant G0701325 (TG), and grants from Assistance Publique-Hopitaux de Paris, Program Hospitalier de Recherche Clinique AOM 08198 (VFB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: JES holds stock in Taligen Therapeutics. JPA is on the Scientific Advisory Board and holds stock in Taligen Therapeutics. TG has acted as a Scientific Advisor for Taligen Therapeutics. All other authors have no conflict of interest.

Abbreviations: aHUS, atypical hemolytic uremic syndrome; APL Ab, antiphospholipid antibody; APS, antiphospholipid syndrome; C5aR, C5a receptor; CCP, complement control protein; CFH, complement factor H; CFI, complement factor I; CHO, Chinese hamster ovary; HWE, Hardy-Weinberg equilibrium; MCP (or CD46), membrane cofactor protein; PROMISSE, Predictors of pRegnancy Outcome: bioMarkers In antiphospholipid antibody Syndrome and Systemic lupus Erythematosus); sFlt-1, soluble fms-like tyrosine kinase 1; SLE, systemic lupus erythematosus; sVEGFR-1, soluble VEGF receptor-1; VEGF, vascular endothelial growth factor; WTCCC, Wellcome Trust Case Control Consortium

* E-mail: salmonj@hss.edu

full-text:
PLoS Medicine: Mutations in Complement Regulatory Proteins Predispose to Preeclampsia: A Genetic Analysis of the PROMISSE Cohort