Dysfunction of complement receptors CR3 (CD11b/18) and CR4 (CD11c/18) in pre-eclampsia: a genetic and functional
A I Lokki1,2, L Teirilä1,3, M Triebwasser4
1Translational Immunology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
Insights
Genetic variants in complement receptors 3 and 4 are linked to pre-eclampsia. These genetic changes impact receptor function, potentially affecting pregnancy outcomes and immune responses.
Area of Science:
- Immunology
- Genetics
- Obstetrics
Background:
- Pre-eclampsia is a common pregnancy vascular disease.
- The complement system aids in clearing placental material during pregnancy.
- Complement receptors CR3 and CR4 play roles in immune function.
Purpose of the Study:
- To investigate genetic variants in complement receptors CR3 and CR4.
- To determine the functional consequences of these genetic variants in pre-eclampsia.
Main Methods:
- A case-control study involving over 2,500 women (FINNPEC and FINRISK cohorts).
- Targeted exomic sequencing to identify genetic variants.
- Functional analysis of mutated receptors (CR3, CR4) by measuring iC3b binding to transiently expressed proteins.
Main Results:
- A significant association was found between the CR3 variant M441K and pre-eclampsia (P = 4.27E-4, OR = 1.401).
- This CR3 variant showed a trend towards increased iC3b adhesion (P = 0.051).
- CR4 variants A251T and W48R demonstrated enhanced and decreased binding to iC3b, respectively.
Conclusions:
- Genetic variations in CR3 and CR4 have functional implications associated with pre-eclampsia.
- Aberrant CR3 and CR4 activity may influence cytokine responses and play a role in pre-eclampsia pathogenesis.
- Further research is needed to confirm these findings and their clinical significance.
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.
