A I Lokki1,2, L Teirilä1,3, M Triebwasser4, E Daly5, A Bhattacharjee6,7, L Uotila8, M Llort Asens9, M I Kurki10,11, M Perola12, K Auro13, J E Salmon14, M Daly15,16, J P Atkinson4, H Laivuori2,16,17, S Fagerholm9, S Meri1,3. 1. Translational Immunology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. 2. Department of Obstetrics and Gynecology, Faculty of Medicine and Health Technology, Tampere University Hospital, Tampere University, Tampere, Finland. 3. Bacteriology and immunology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 4. Department of Medicine, Division of Rheumatology, Washington University School of Medicine, Saint Louis, MO, USA. 5. Hospital and Harvard Medical School, Boston, MA, USA. 6. Herantis Pharma Plc, Espoo, Finland. 7. Neuroscience Center, HiLife, University of Helsinki, Helsinki, Finland. 8. Research Services, University of Helsinki, Helsinki, Finland. 9. Molecular and Integrative Biosciences Research Program, Faculty of Bio- and Environmental Sciences, University of Helsinki, Helsinki, Finland. 10. Neurosurgery of Neuro Center, Kuopio University Hospital, Finland. 11. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 12. Department of Health, National Institute for Health and Welfare, Helsinki, Finland. 13. Department of Government Services, National Institute for Health and Welfare, Helsinki, Finland. 14. Hospital for Special Surgery-Weill Cornell Medicine, Department of Medicine, New York, NY, USA. 15. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. 16. Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland. 17. Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Abstract
OBJECTIVE: To study genetic variants and their function within genes coding for complement receptors in pre-eclampsia. DESIGN: A case-control study. SETTING: Pre-eclampsia is a common vascular disease of pregnancy. The clearance of placenta-derived material is one of the functions of the complement system in pregnancy. POPULATION: We genotyped 500 women with pre-eclamptic pregnancies and 190 pregnant women without pre-eclampsia, as controls, from the FINNPEC cohort, and 122 women with pre-eclamptic pregnancies and 1905 controls from the national FINRISK cohort. METHODS: The functional consequences of genotypes discovered by targeted exomic sequencing were explored by analysing the binding of the main ligand iC3b to mutated CR3 or CR4, which were transiently expressed on the surface of COS-1 cells. MAIN OUTCOME MEASURES: Allele frequencies were compared between pre-eclamptic pregnancies and controls in genetic studies. The functional consequences of selected variants were measured by binding assays. RESULTS: The most significantly pre-eclampsia-linked CR3 variant M441K (P = 4.27E-4, OR = 1.401, 95% CI = 1.167-1.682) displayed a trend of increased adhesion to iC3b (P = 0.051). The CR4 variant A251T was found to enhance the adhesion of CR4 to iC3b, whereas W48R resulted in a decrease of the binding of CR4 to iC3b. CONCLUSIONS: Results suggest that changes in complement-facilitated phagocytosis are associated with pre-eclampsia. Further studies are needed to ascertain whether aberrant CR3 and CR4 activity leads to altered pro- and anti-inflammatory cytokine responses in individuals carrying the associated variants, and the role of these receptors in pre-eclampsia pathogenesis. TWEETABLE ABSTRACT: Genetic variants of complement receptors CR3 and CR4 have functional consequences that are associated with pre-eclampsia.
OBJECTIVE: To study genetic variants and their function within genes coding for complement receptors in pre-eclampsia. DESIGN: A case-control study. SETTING: Pre-eclampsia is a common vascular disease of pregnancy. The clearance of placenta-derived material is one of the functions of the complement system in pregnancy. POPULATION: We genotyped 500 women with pre-eclamptic pregnancies and 190 pregnant women without pre-eclampsia, as controls, from the FINNPEC cohort, and 122 women with pre-eclamptic pregnancies and 1905 controls from the national FINRISK cohort. METHODS: The functional consequences of genotypes discovered by targeted exomic sequencing were explored by analysing the binding of the main ligand iC3b to mutated CR3 or CR4, which were transiently expressed on the surface of COS-1 cells. MAIN OUTCOME MEASURES: Allele frequencies were compared between pre-eclamptic pregnancies and controls in genetic studies. The functional consequences of selected variants were measured by binding assays. RESULTS: The most significantly pre-eclampsia-linked CR3 variant M441K (P = 4.27E-4, OR = 1.401, 95% CI = 1.167-1.682) displayed a trend of increased adhesion to iC3b (P = 0.051). The CR4 variant A251T was found to enhance the adhesion of CR4 to iC3b, whereas W48R resulted in a decrease of the binding of CR4 to iC3b. CONCLUSIONS: Results suggest that changes in complement-facilitated phagocytosis are associated with pre-eclampsia. Further studies are needed to ascertain whether aberrant CR3 and CR4 activity leads to altered pro- and anti-inflammatory cytokine responses in individuals carrying the associated variants, and the role of these receptors in pre-eclampsia pathogenesis. TWEETABLE ABSTRACT: Genetic variants of complement receptors CR3 and CR4 have functional consequences that are associated with pre-eclampsia.
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