Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia

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Lokki , A I , Kaartokallio , T , Holmberg , V , Onkamo , P , Koskinen , L L E , Saavalainen , P , Heinonen , S , Kajantie , E , Kere , J , Kivinen , K , Pouta , A , Villa , P M , Hiltunen , L , Laivuori , H & Meri , S 2017 , ' Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia ' , Frontiers in Immunology , vol. 8 , 589 . https://doi.org/10.3389/fimmu.2017.00589

Title: Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia
Author: Lokki, A. Inkeri; Kaartokallio, Tea; Holmberg, Ville; Onkamo, Paivi; Koskinen, Lotta L. E.; Saavalainen, Paivi; Heinonen, Seppo; Kajantie, Eero; Kere, Juha; Kivinen, Katja; Pouta, Anneli; Villa, Pia M.; Hiltunen, Leena; Laivuori, Hannele; Meri, Seppo
Contributor: University of Helsinki, Research Programs Unit
University of Helsinki, Pregnancy and Genes
University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Biosciences
University of Helsinki, Research Programs Unit
University of Helsinki, Research Programs Unit
University of Helsinki, Department of Obstetrics and Gynecology
University of Helsinki, Children's Hospital
University of Helsinki, Research Programs Unit
University of Helsinki, Department of Obstetrics and Gynecology
University of Helsinki, HUS Gynecology and Obstetrics
University of Helsinki, Seppo Meri / Principal Investigator
Date: 2017-05-29
Language: eng
Number of pages: 10
Belongs to series: Frontiers in Immunology
ISSN: 1664-3224
URI: http://hdl.handle.net/10138/193777
Abstract: Preeclampsia (PE) is a common vascular disease of pregnancy with genetic predisposition. Dysregulation of the complement system has been implicated, but molecular mechanisms are incompletely understood. In this study, we determined the potential linkage of severe PE to the most central complement gene, C3. Three cohorts of Finnish patients and controls were recruited for a genetic case-control study. Participants were genotyped using Sequenom genotyping and Sanger sequencing. Initially, we studied 259 Finnish patients with severe PE and 426 controls from the Southern Finland PE and the Finnish population-based PE cohorts. We used a custom-made single nucleotide polymorphism (SNP) genotyping assay consisting of 98 SNPs in 18 genes that encode components of the complement system. Following the primary screening, C3 was selected as the candidate gene and consequently Sanger sequenced. Fourteen SNPs from C3 were also genotyped by a Sequenom panel in 960 patients with severe PE and 705 controls, including already sequenced individuals. Three of the 43 SNPs observed within C3 were associated with severe PE: rs2287845 (p = 0.038, OR = 1.158), rs366510 (p = 0.039, OR = 1.158), and rs2287848 (p = 0.041, OR = 1.155). We also discovered 16 SNP haplotypes with extreme linkage disequilibrium in the middle of the gene with a protective (p = 0.044, OR = 0.628) or a predisposing (p = 0.011, OR = 2.110) effect to severe PE depending on the allele combination. Genetic variants associated with PE are located in key domains of C3 and could thereby influence the function of C3. This is, as far as we are aware, the first candidate gene in the complement system with an association to a clinically relevant PE subphenotype, severe PE. The result highlights a potential role for the complement system in the pathogenesis of PE and may help in defining prognostic and therapeutic subgroups of preeclamptic women.
Subject: preeclampsia
complement
C3
association study
gene regulation
genetic risk
pregnancy complication
innate immunity
POPULATION GENOTYPE DATA
RNA SECONDARY STRUCTURE
COMPONENT C3
PREGNANCY
POLYMORPHISMS
ACTIVATION
HYPERTENSION
VARIANTS
PATHWAY
SYSTEM
3111 Biomedicine
1184 Genetics, developmental biology, physiology
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