title: Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00198068.
authors: Autoimmunity and Inflammation Program, Hospital for Special Surgery, Cornell Weill Medical College, New York, New York, USA. salmonj@hss.edu
authors: Jane E
authors: JE
authors: Salmon
authors: Cara
authors: C
authors: Heuser
authors: Michael
authors: M
authors: Triebwasser
authors: M Kathryn
authors: MK
authors: Liszewski
authors: David
authors: D
authors: Kavanagh
authors: Lubka
authors: L
authors: Roumenina
authors: D Ware
authors: DW
authors: Branch
authors: Tim
authors: T
authors: Goodship
authors: Veronique
authors: V
authors: Fremeaux-Bacchi
authors: John P
authors: JP
authors: Atkinson
mesh_terms: D000328:Adult; D000818:Animals; D001327:Autoimmune Diseases / Q000150:complications / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D015331:Cohort Studies; D003167:Complement Activation / Q000276:immunology; D003179:Complement C3b / Q000378:metabolism; D015935:Complement C4b / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics; D017244:Complement Factor I / Q000235:genetics; D003165:Complement System Proteins / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D051916:Membrane Cofactor Protein / Q000235:genetics; D051379:Mice; D009154:Mutation / Q000235:genetics*; D011225:Pre-Eclampsia / Q000235:genetics* / Q000276:immunology*; D011247:Pregnancy; D011256:Pregnancy Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; C497857:CD46 protein, human; D051916:Membrane Cofactor Protein; D003179:Complement C3b; D015935:Complement C4b; D017242:Complement Factor H; D003165:Complement System Proteins; D017244:Complement Factor I