Dysfunction of complement receptors CR3 (CD11b/18) and CR4 (CD11c/18) in pre-eclampsia : a genetic and functional study

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Lokki , A I , Teirilä , L L , Triebwasser , M , Daly , E , Bhattacharjee , A , Uotila , L , Llort Asens , M , Kurki , M , Perola , M , Auro , K , Salmon , J E , Daly , M , Atkinson , J P , Laivuori , H , Fagerholm , S , Meri , S , FINNPEC & Heinonen , S 2021 , ' Dysfunction of complement receptors CR3 (CD11b/18) and CR4 (CD11c/18) in pre-eclampsia : a genetic and functional study ' , BJOG : An International Journal of Obstetrics & Gynaecology , vol. 128 , no. 8 , pp. 1282-1291 . https://doi.org/10.1111/1471-0528.16660

Title: Dysfunction of complement receptors CR3 (CD11b/18) and CR4 (CD11c/18) in pre-eclampsia : a genetic and functional study
Author: Lokki, Anna Inkeri; Teirilä, Laura L; Triebwasser, M.; Daly, E.; Bhattacharjee, Atreyi; Uotila, Lasse; Llort Asens, Marc; Kurki, M.; Perola, M.; Auro, K.; Salmon, J. E.; Daly, Mark; Atkinson, J. P.; Laivuori, Hannele; Fagerholm, Susanna; Meri, Seppo; FINNPEC; Heinonen, Seppo
Contributor organization: HUS Heart and Lung Center
TRIMM - Translational Immunology Research Program
HUSLAB
Clinicum
Department of Bacteriology and Immunology
Neuroscience Center
Helsinki Institute of Life Science HiLIFE
Department of Diagnostics and Therapeutics
Faculty of Biological and Environmental Sciences
Molecular and Integrative Biosciences Research Programme
Institute for Molecular Medicine Finland
HUS Gynecology and Obstetrics
Genomics of Neurological and Neuropsychiatric Disorders
Pregnancy and Genes
Department of Medical and Clinical Genetics
Faculty Common Matters
Integrins in immunity
Seppo Meri / Principal Investigator
Department of Obstetrics and Gynecology
Date: 2021-07
Language: eng
Number of pages: 10
Belongs to series: BJOG : An International Journal of Obstetrics & Gynaecology
ISSN: 1470-0328
DOI: https://doi.org/10.1111/1471-0528.16660
URI: http://hdl.handle.net/10138/333338
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.
Subject: &#946
2&#8208
integrins
complement receptors
complement system
genetic association
pre&#8208
eclampsia
pregnancy
3123 Gynaecology and paediatrics
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: acceptedVersion


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