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Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort.

ABSTRACT: 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.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.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.ClinicalTrials.gov NCT00198068.

SUBMITTER: Salmon JE

PROVIDER: S-EPMC3062534 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort.

Salmon Jane E JE Heuser Cara C Triebwasser Michael M Liszewski M Kathryn MK Kavanagh David D Roumenina Lubka L Branch D Ware DW Goodship Tim T Fremeaux-Bacchi Veronique V Atkinson John P JP

PLoS medicine 20110322 3

<h4>Background</h4>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.<h4>Methods and findings</h4>We use PROMISSE, a prospective study of 250 pregnant patients with SLE a ...[more]

PMID: 21445332

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Project description:BackgroundGestational hypertension (GH) and preeclampsia (PE) are severe adverse gestational complications. Previous studies supported potential link between elevated liver enzyme levels and GH and PE. However, given the transient physiological reduction of liver enzyme levels in pregnancy, little is known whether the associations of the high-normal liver enzyme levels in early pregnancy with GH and PE exist in pregnant women.MethodsPregnant women in this study came from a sub-cohort of Shanghai Preconception Cohort, who were with four liver enzyme levels examined at 9-13 gestational weeks and without established liver diseases, hypertension and preeclampsia. After exclusion of pregnant women with clinically-abnormal liver enzyme levels in the current pregnancy, associations of liver enzyme levels, including alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT), with GH and PE status were assessed by multivariable log-binomial regression. Population attributable fraction was measured to estimate the fractions of GH and PE that were attributable to the high-normal liver enzyme levels.ResultsAmong 5,685 pregnant women 160 (2.8%) and 244 (4.3%) developed GH and PE, respectively. After adjustment for potential covariates, higher ALP, ALT and GGT levels were significantly associated with the risk of GH (adjusted risk ratio (aRR):1.21 [95% confidence interval, 1.05-1.38]; 1.21 [1.05-1.38]; and 1.23 [1.09-1.39]), as well as the risk of PE(1.21 [1.13-1.29]; 1.15 [1.03-1.28]; 1.28 [1.16-1.41]), respectively. The cumulative population attributable fraction of carrying one or more high-normal liver enzyme levels (at 80th percentile or over) was 31.4% for GH and 23.2% for PE, respectively.ConclusionHigher ALT, ALP and GGT levels within the normal range in early pregnancy are associated with increased risk of GH and PE. The documented associations provide new insight to the role of hepatobiliary function in GH and PE pathogenesis.

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Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort.

Publications

Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort.

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