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.
Highlights
Preeclampsia (PE) is a serious vascular complication of pregnancy, which may lead to a life-threatening multi-organ dysfunction and a convulsive condition, eclampsia [1]
In the C3 promoter, exons, and flanking introns, a total of 43 single nucleotide polymorphism (SNP) were identified in severe PE women, non-PE controls, or both (Figure 2). rs200046246 is located in a predicted transcription factor-binding site
Six SNPs were independently associated to severe PE. rs190390034 (−39 from exon 2) had the strongest association with a predisposing effect with minor allele T [χ2 = 7.72, p-value = 0.005; OR = 7.627] (Figure 2)
Summary
Preeclampsia (PE) is a serious vascular complication of pregnancy, which may lead to a life-threatening multi-organ dysfunction and a convulsive condition, eclampsia [1]. PE affects 3–5% of pregnancies in all ethnic groups. Preeclampsia has been the subject of numerous genetic studies and several associating single nucleotide polymorphisms (SNPs) have been identified. Among the genes where associating SNPs have been described are genes linked to hypertension and vascular and metabolic disease [2,3,4], all diseases whose risk is increased in the later life of PE patients [5]. Genes encoding for proteins involved in the immunological processes have been found to harbor SNPs that predispose patients to PE [6, 7]
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