title: Maternal TLR4 and NOD2 gene variants, pro-inflammatory phenotype and susceptibility to early-onset preeclampsia and HELLP syndrome.
abstract: BACKGROUND
  Altered maternal inflammatory responses play a role in the development of preeclampsia and the hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. We examined whether allelic variants of the innate immune receptors Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain 2 (NOD2), that impair the inflammatory response to endotoxin, are related to preeclampsia and HELLP syndrome.
  
  
  RESULTS
  We determined five common mutations in TLR4 (D299G and T399I) and NOD2 (R702W, G908R and L1007fs) in 340 primiparous women with a history of early-onset preeclampsia, of whom 177 women developed HELLP syndrome and in 113 women with a history of only uneventful pregnancies as controls. In addition, we assessed plasma levels of pro-inflammatory biomarkers C-reactive protein, interleukin-6, soluble intercellular adhesion molecule-1, fibrinogen and von Willebrand factor in a subset of 214 women included at least six months after delivery. After adjustment for maternal age and chronic hypertension, attenuating allelic variants of TLR4 were more common in women with a history of early-onset preeclampsia than in controls (OR 2.9 [95% CI 1.2-6.7]). Highest frequencies for TLR4 variants were observed in women who developed HELLP syndrome (adjusted OR 4.1 [95% CI 1.7-9.8]). In addition, high levels of interleukin-6 and fibrinogen were associated with a history of early-onset preeclampsia. Combined positivity for any of the TLR4 and NOD2 allelic variants and high levels of interleukin-6 was 6.9-fold more common in women with a history of early-onset preeclampsia (95% CI 2.1-23.2) compared to controls.
  
  
  CONCLUSIONS
  We observed an association of common TLR4 and NOD2 gene variants, and pro-inflammatory phenotype with a history of early-onset preeclampsia and HELLP syndrome. These findings suggest involvement of the maternal innate immune system in severe hypertensive disorders of pregnancy.
authors.affiliation: Division of Perinatology and Gynecology, University Medical Center Utrecht, Utrecht, The Netherlands. brijn2@umcutrecht.nl
authors.forename: Bas B
authors.initials: BB
authors.lastname: van Rijn
authors.forename: Arie
authors.initials: A
authors.lastname: Franx
authors.forename: Eric A P
authors.initials: EA
authors.lastname: Steegers
authors.forename: Christianne J M
authors.initials: CJ
authors.lastname: de Groot
authors.forename: Rogier M
authors.initials: RM
authors.lastname: Bertina
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.forename: Hieronymus A M
authors.initials: HA
authors.lastname: Voorbij
authors.forename: Hein W
authors.initials: HW
authors.lastname: Bruinse
authors.forename: Mark
authors.initials: M
authors.lastname: Roest
mesh_terms: D000328:Adult; D000483:Alleles; D004731:Endotoxins / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D017359:HELLP Syndrome / Q000235:genetics*; D006801:Humans; D007249:Inflammation; D008954:Models, Biological; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D011225:Pre-Eclampsia / Q000235:genetics*; D011247:Pregnancy; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: D004731:Endotoxins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4