@article{be9d2d9fde8d490988fdc8f3fe9751bf,
title = "Dysfunction of complement receptors CR3 (CD11b/18) and CR4 (CD11c/18) in pre-eclampsia: a genetic and functional study",
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.",
keywords = "complement receptors, complement system, genetic association, pre-eclampsia, pregnancy, β2-integrins",
author = "Finnpec and Lokki, {A. I.} and L. Teiril{\"a} and M. Triebwasser and E. Daly and A. Bhattacharjee and L. Uotila and {Llort Asens}, M. and Kurki, {M. I.} and M. Perola and K. Auro and Salmon, {J. E.} and M. Daly and Atkinson, {J. P.} and H. Laivuori and S. Fagerholm and S. Meri and Hannele Laivuori and Seppo Heinonen and Juha Kere and Katja Kivinen and Anneli Pouta and Eero Kajantie",
note = "Funding Information: This study was supported by: the Alfred Kordelin, Oskar {\"O}flund and Maud Kuistila foundations (to AIL); the Jane and Aatos Erkko Foundation (to HL); The Academy of Finland (121196 and 278941, to HL); the Sigrid Jus{\'e}lius Foundation and National Institutes of Health grants U54 HL112303 (JPA) and R01 GM099111-20A1 (to JPA); the Finnish Medical Foundation (to HL); the University of Helsinki Funds (to HL); the Special State Subsidy for Health Research (EVO funding, to HL and SM); and the Sakari and P{\"a}ivikki Sohlberg Foundation (to HL). The Novo Nordisk Foundation, the Signe and Ane Gyllenberg Foundation, and the Foundation for Pediatric Research contributed to the FINNPEC study. The funders did not influence the design or data analysis of the study or contribute to the article. We thank the members of The Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) Core Investigator Group (principal investigator Hannele Laivuori): Seppo Heinonen, Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital; Eero Kajantie, Department of Public Health Solutions, Public Health Promotion Unit, National Institute for Health and Welfare, Helsinki, Finland; Hospital for Children and Adolescents, University of Helsinki and Helsinki University Hospital, and Helsinki, Finland; PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Juha Kere, Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden, Folkh{\"a}lsan Research Center, Helsinki, Finland, Stem Cells and Metabolism Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland; Katja Kivinen, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; and Anneli Pouta, Department of Government Services, National Institute for Health and Welfare, Helsinki. Funding Information: This study was supported by: the Alfred Kordelin, Oskar {\"O}flund and Maud Kuistila foundations (to AIL); the Jane and Aatos Erkko Foundation (to HL); The Academy of Finland (121196 and 278941, to HL); the Sigrid Jus{\'e}lius Foundation and National Institutes of Health grants U54 HL112303 (JPA) and R01 GM099111‐20A1 (to JPA); the Finnish Medical Foundation (to HL); the University of Helsinki Funds (to HL); the Special State Subsidy for Health Research (EVO funding, to HL and SM); and the Sakari and P{\"a}ivikki Sohlberg Foundation (to HL). The Novo Nordisk Foundation, the Signe and Ane Gyllenberg Foundation, and the Foundation for Pediatric Research contributed to the FINNPEC study. The funders did not influence the design or data analysis of the study or contribute to the article. Funding Information: AIL reports personal fees from Alexion, outside the submitted work. JES reports personal fees from ReAlta Life Sciences, grants from UCB and personal fees from UCB, outside the submitted work. The remaining authors have no disclosure of interests. Completed disclosure of interests forms are available to view online as supporting information. Publisher Copyright: {\textcopyright} 2021 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.",
year = "2021",
month = jul,
doi = "10.1111/1471-0528.16660",
language = "English",
volume = "128",
pages = "1282--1291",
journal = "BJOG: An International Journal of Obstetrics and Gynaecology",
issn = "1470-0328",
number = "8",
}