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

A. I. Lokki, L. Teirilä, M. Triebwasser, E. Daly, A. Bhattacharjee, L. Uotila, M. Llort Asens, M. I. Kurki, M. Perola, K. Auro, J. E. Salmon, M. Daly, J. P. Atkinson, H. Laivuori, S. Fagerholm, S. Meri, FINNPEC

    Research output: Contribution to journalArticleScientificpeer-review

    2 Citations (Scopus)
    5 Downloads (Pure)

    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.

    Original languageEnglish
    Pages (from-to)1282-1291
    Number of pages10
    JournalBJOG: AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY
    Volume128
    Issue number8
    DOIs
    Publication statusPublished - Jul 2021
    Publication typeA1 Journal article-refereed

    Keywords

    • complement receptors
    • complement system
    • genetic association
    • pre-eclampsia
    • pregnancy
    • β2-integrins

    Publication forum classification

    • Publication forum level 2

    ASJC Scopus subject areas

    • Obstetrics and Gynaecology

    Fingerprint

    Dive into the research topics of 'Dysfunction of complement receptors CR3 (CD11b/18) and CR4 (CD11c/18) in pre-eclampsia: a genetic and functional study'. Together they form a unique fingerprint.

    Cite this