University of Oulu

Lokki AI, Kaartokallio T, Holmberg V, Onkamo P, Koskinen LLE, Saavalainen P, Heinonen S, Kajantie E, Kere J, Kivinen K, Pouta A, Villa PM, Hiltunen L, Laivuori H and Meri S (2017) Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia. Front. Immunol. 8:589. doi: 10.3389/fimmu.2017.00589

Analysis of complement C3 gene reveals susceptibility to severe preeclampsia

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Author: Lokki, A. Inkeri1,2,3; Kaartokallio, Tea2; Holmberg, Ville2,4;
Organizations: 1Immunobiology, Research Programs Unit, University of Helsinki, Helsinki, Finland
2Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
3Bacteriology and Immunology, University of Helsinki, Helsinki, Finland
4Clinic of Infectious Diseases, HYKS Inflammation Center, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
5Department of Biosciences, University of Helsinki, Helsinki, Finland
6Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
7Chronic Disease Prevention Unit, Department of Health, National Institute for Health and Welfare, Helsinki, Finland
8Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
9PEDEGO Research Unit, MRC Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
10Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
11Folkhälsan Institute of Genetics, Helsinki, Finland
12Molecular Neurology, Research Programs Unit, University of Helsinki, Helsinki, Finland
13Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK
14Department of Government Services, National Institute for Health and Welfare, Helsinki, Finland
15Finnish Red Cross Blood Service, Helsinki, Finland
16Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.2 MB)
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Language: English
Published: Frontiers Research Foundation, 2017
Publish Date: 2018-02-15


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.

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Series: Frontiers in immunology
ISSN: 1664-3224
ISSN-E: 1664-3224
ISSN-L: 1664-3224
Volume: 8
Article number: 589
DOI: 10.3389/fimmu.2017.00589
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
Funding: This study was supported by Maud Kuistila memorial foundation (AIL), Oskar Öflund’s Foundation (AIL), Alfred Kordelin Foundation (AIL), Jane and Aatos Erkko Foundation (HL), The Academy of Finland (121196, 134957, and 278941, HL), Päivikki and Sakari Sohlberg Foundation (HL), Sigrid Jusélius Foundation (SM), Doctoral Programme in Biomedicine, Clinical Graduate Program (TK), Research Foundation of the University of Helsinki (TK) and Biomedicum Helsinki Foundation (TK). Finska Läkaresällskapet, Emil Aaltonen Foundation, Finnish Medical Foundation, University of Helsinki Funds, Special State Subsidy for Health Research (EVO funding), Novo Nordisk Foundation, Signe and Ane Gyllenberg Foundation, and Foundation for Pediatric Research contributed to the FINNPEC study. JK is a recipient of The Royal Society Wolfson Research Excellence award. Funders had no influence in methodology or data interpretation of our work.
Copyright information: © 2017 Lokki, Kaartokallio, Holmberg, Onkamo, Koskinen, Saavalainen, Heinonen, Kajantie, Kere, Kivinen, Pouta, Villa, Hiltunen, Laivuori and Meri. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.