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Preeclampsia (PE) generally manifests in the second half of pregnancy with hypertension and proteinuria. The understanding of the origin and mechanism behind PE is incomplete, although there is clearly an immune component to this disorder. The placenta constitutes a complicated immune interface between fetal and maternal cells, where regulation and tolerance are key. Stress factors from placental dysfunction in PE are released to the maternal circulation evoking the maternal response. Several complement factors play a role within this intricate landscape, including C1q in vascular remodeling and Factor H (FH) as the key regulator of alternative pathway complement activation. We hypothesize that decreased levels of C1q or FH, or disturbance of their function by autoantibodies, may be associated with PE. Autoantibodies against C1q and FH and the concentrations of C1q and FH were measured by ELISA in maternal sera from women with preeclamptic and normal pregnancies. Samples originated from cohorts collected in the Netherlands (n=63 PE; n=174 control pregnancies, n=51 nonpregnant), Finland (n=181 PE; n=63 control pregnancies) and Norway (n=59 PE; n=27 control pregnancies). Serum C1q and FH concentrations were higher in control pregnancy than in nonpregnant women. No significant differences were observed for serum C1q between preeclamptic and control pregnancy in any of the three cohorts. Serum levels of FH were lower in preeclamptic pregnancies compared to control pregnancies in two of the cohorts, this effect was driven by the early onset PE cases. Neither anti-C1q autoantibodies nor anti-FH autoantibodies levels differed between women with PE and normal pregnancies. In conclusion, levels of anti-C1q and anti-FH autoantibodies are not increased in PE. C1q and FH are increased in pregnancy, but importantly, a decrease in FH concentration is associated with PE. publishedVersion

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Supplemental data for JCEM.

Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10-11) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.

Elucidating the genetic architecture of preeclampsia is a major goal in obstetric medicine. We have performed a genome-wide association study (GWAS) for preeclampsia in unrelated Australian individuals of Caucasian ancestry using the Illumina OmniExpress-12 BeadChip to successfully genotype 648,175 SNPs in 538 preeclampsia cases and 540 normal pregnancy controls. Two SNP associations (rs7579169, p = 3.58×10−7, OR = 1.57; rs12711941, p = 4.26×10−7, OR = 1.56) satisfied our genome-wide significance threshold (modified Bonferroni p0.92). We attempted to provide evidence of a putative regulatory role for these SNPs using bioinformatic analyses and found that they all reside within regions of low sequence conservation and/or low complexity, suggesting functional importance is low. We also explored the mRNA expression in decidua of genes ±500 kb of INHBB and found a nominally significant correlation between a transcript encoded by the EPB41L5 gene, ∼250 kb centromeric to INHBB, and preeclampsia (p = 0.03). We were unable to replicate the associations shown by the significant GWAS SNPs in case-control cohorts from Norway and Finland, leading us to conclude that it is more likely that these SNPs are in LD with as yet unidentified causal variant(s). © 2012 Johnson 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.

Objective To assess the association between maternal cytomegalovirus (CMV) antibodies in mid-pregnancy and preeclampsia. Design Nested case–control study. Setting Pregnancies registered in the Norwegian Mother and Child Cohort Study (MoBa): a large population-based pregnancy cohort (1999–2006). Sample A cohort of 1500 women with pre-eclampsia and 1000 healthy pregnant women. Methods Plasma samples and pregnancy-related information were provided by the MoBa. Antibody status (CMV IgG and CMV IgM) and levels (CMV IgG) at 17–18 weeks of gestation were determined by enzyme-linked immunosorbent assay (ELISA). Main outcome measure A diagnosis of pre-eclampsia, as defined in the Medical Birth Registry of Norway. Results There was no evidence of an effect of CMV IgG seropositivity on the likelihood of developing pre-eclampsia, and CMV IgG antibody levels among women who were seropositive did not differ between groups. Adjusted for maternal age, parity and smoking, the odds ratio for pre-eclampsia in women seropositive for CMV IgG was 0.89 (95% CI 0.74–1.05; P = 0.17). The proportions of women who were seropositive for IgM did not differ between women with pre-eclampsia and women who were healthy (P = 0.98). Among nulliparous women, the proportion of women who were seropositive for CMV IgG was slightly lower among women with pre-eclampsia (53.5%) than among healthy women (59.8%) (P = 0.03). Subgroup analyses were performed for women with early or late onset pre-eclampsia, with preterm delivery and/or with neonates that were small for gestational age, but antibody status did not differ between pre-eclampsia subtypes and controls. Conclusions The presence of maternal antibodies to CMV was not associated with pre-eclampsia in our study. The results suggest that CMV infection is unlikely to be a major cause of preeclampsia. This is the peer reviewed version of the following article: Cytomegalovirus antibody status at 17 - 18 weeks of gestation and preeclampsia: a case-control study of pregnant women in Norway, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/j.1471-0528.2012.03420.x/epdf. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia., Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.

Studie av mekanismer for betennelse i morkaken Betennelse (inflammasjon) er en immunrespons som kroppen setter i gang for å beskytte seg mot infeksjoner og vevsskade. Alle mennesker er født med "mønster-gjenkjennende" pattern recognition reseptorer (PRRer) som en del av immunforsvaret. Disse reseptorene er avgjørende for igangsettelse av betennelsesreaksjoner, blant annet gjennom produksjon av signalmolekyler kalt cytokiner. En betennelsesreaksjon er som regel både nødvendig og gunstig for kroppen, men hvis responsen blir for kraftig eller langvarig kan den føre til stor skade og sykdom. Et normalt svangerskap er assosiert med en mild betennelsestilstand, mens hos kvinner som utvikler svangerskapsforgiftning (preeklampsi) vil nivået av betennelsesmarkører, som cytokiner og C-reaktivt protein (CRP), være forhøyet. Man tror svangerskapsforgiftning begynner tidlig i svangerskapet med en ufullstendig utvikling av morkaken. En mangelfull utvikling av morkaken vil gi redusert blodtilførsel fra mor til morkake, og kan resultere i «stressede» celler og betennelse i morkaken. En slik stresset morkake produserer faresignaler som kan aktivere PRRer på f.eks trofoblaster - fosterceller som utgjør den største delen av morkaken. Aktivering av PRRer på trofoblaster kan igangsette overdreven immunrespons i morkaken, som igjen vil kunne bidra til betennelsen man observerer ved svangerskapsforgiftning, men kunnskapen om de underliggende sykdomsmekanismene er mangelfull. Formålet med denne avhandlingen var å bidra til økt kunnskap om betennelse igangsatt av PRRer i morkaken ved friske svangerskap og svangerskapsforgiftning. Vi studerte PRR-aktivering av trofoblaster isolert fra morkaker tidlig i svangerskapet, og sammenliknet resultatene med syv trofoblast-cellelinjer (modifiserte celler med forlenget levetid). De isolerte trofoblastene uttrykte et bredt repertoar av fungerende PRRer, men kun én av syv cellelinjer viste seg å ha et liknende uttrykk av funksjonelle PRRer. Det brede uttrykket av PRRer vi påviste i de isolerte trofoblastene tyder på at disse cellene spiller en viktig rolle ved betennelse i morkaken. Videre viser våre resultater at det er viktig å velge riktig trofoblast-cellelinje når man skal studere disse betennelsesreaksjonene og tilgangen til isolerte trofoblaster er begrenset. For å avklare om kjente PRR-aktiverende faresignaler som kolesterol, urinsyre og HMGB1 spiller en rolle ved utvikling av svangerskapsforgiftning, ble morkakevev og blodprøver fra kvinner med og uten svangerskapsforgiftning undersøkt. Vi avdekket høyere nivåer av kolesterol og urinsyre, men ikke HMGB1, i blodprøver fra kvinner med svangerskapsforgiftning sammenlignet med friske gravide kvinner. I morkaken fant vi at HMGB1 og PRRen som gjenkjenner HMGB1, TLR4, var høyest uttrykt i morkaker fra kvinner med svangerskapsforgiftning. HMGB1 aktivering av TLR4 økte produksjonen av cytokinet interleukin (IL)-8, og vi målte forhøyet IL-8 nivå både i morkakevev og blodprøver fra kvinner med svangerskapsforgiftning. PRRen NLRP3, som aktiveres av kolesterol og urinsyre, var spesielt høyt uttrykt av trofoblaster i morkaken, og vi målte et høyere uttrykk av det NLRP3 responsive cytokinet IL-1 i trofoblaster ved svangerskapsforgiftning. Videre viste vi at de aktuelle PRR mekanismene lar seg aktivere av kolesterol og HMGB1 i morkakevev og en trofoblast-cellelinje. Studiene av PRR mekanismene TLR4 og NLRP3 påviste forhøyede nivåer av kolesterol, urinsyre og/eller HMGB1 som mulige underliggende årsaker til betennelse i morkaken og utvikling av svangerskapsforgiftning. Resultatene i denne avhandlingen indikerer at trofoblaster i morkaken og bestemte PRR mekanismer er involvert i betennelsen som observeres i både normale svangerskap og ved svangerskapsforgiftning. Det langsiktige målet med arbeidet er å kunne identifisere kvinner med økt risiko for svangerskapsforgiftning, samt kartlegge nye muligheter for behandling av sykdommen.