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.
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.
© 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.