Maternal TLR4 and NOD2 gene variants, pro-inflammatory phenotype and susceptibility to early-onset preeclampsia and HELLP syndrome
Maternal TLR4 and NOD2 gene variants, pro-inflammatory phenotype and susceptibility to early-onset preeclampsia and HELLP syndrome
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.
Methods and findings: 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.
e1865
van Rijn, Bas B.
c958dfb5-2010-46de-a350-4903295ac340
Franx, Arie
2376857f-07db-4821-9512-a7b55036b6f0
Steegers, Eric A.P.
6061f35a-1c75-4f9f-ac9f-ed369f475ce9
de Groot, Christianne J.M.
37585ad7-b921-402a-9685-db11dd9e3ade
Bertina, Rogier M.
b36e135d-3c8a-4748-899c-ee2ba6378626
Pasterkamp, Gerard
f2983717-2c4a-46cc-82fd-af35c117b0a6
Voorbij, Hieronymus A.M.
7a96a258-4ef6-479e-b96f-4c66a8ab61cf
Bruinse, Hein W.
9cf35612-505e-4035-a2b8-c63a0ec15421
Roest, Mark
370165b6-0adb-44f8-a502-5b97e89745b5
2 April 2008
van Rijn, Bas B.
c958dfb5-2010-46de-a350-4903295ac340
Franx, Arie
2376857f-07db-4821-9512-a7b55036b6f0
Steegers, Eric A.P.
6061f35a-1c75-4f9f-ac9f-ed369f475ce9
de Groot, Christianne J.M.
37585ad7-b921-402a-9685-db11dd9e3ade
Bertina, Rogier M.
b36e135d-3c8a-4748-899c-ee2ba6378626
Pasterkamp, Gerard
f2983717-2c4a-46cc-82fd-af35c117b0a6
Voorbij, Hieronymus A.M.
7a96a258-4ef6-479e-b96f-4c66a8ab61cf
Bruinse, Hein W.
9cf35612-505e-4035-a2b8-c63a0ec15421
Roest, Mark
370165b6-0adb-44f8-a502-5b97e89745b5
van Rijn, Bas B., Franx, Arie, Steegers, Eric A.P., de Groot, Christianne J.M., Bertina, Rogier M., Pasterkamp, Gerard, Voorbij, Hieronymus A.M., Bruinse, Hein W. and Roest, Mark
(2008)
Maternal TLR4 and NOD2 gene variants, pro-inflammatory phenotype and susceptibility to early-onset preeclampsia and HELLP syndrome.
PLoS ONE, 3 (4), .
(doi:10.1371/journal.pone.0001865).
(PMID:18382655)
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.
Methods and findings: 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.
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Published date: 2 April 2008
Organisations:
Human Development & Health
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Local EPrints ID: 352047
URI: http://eprints.soton.ac.uk/id/eprint/352047
ISSN: 1932-6203
PURE UUID: 3a35aa65-4653-47b8-9b9a-9143722504cb
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Date deposited: 01 May 2013 12:25
Last modified: 14 Mar 2024 13:46
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Author:
Bas B. van Rijn
Author:
Arie Franx
Author:
Eric A.P. Steegers
Author:
Christianne J.M. de Groot
Author:
Rogier M. Bertina
Author:
Gerard Pasterkamp
Author:
Hieronymus A.M. Voorbij
Author:
Hein W. Bruinse
Author:
Mark Roest
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