Identification of complement factor H variants that predispose to pre-eclampsia: A genetic and functional study

Area of Science:

• Genetics
• Immunology
• Obstetrics

Background:

• Pre-eclampsia is a major cause of maternal and fetal mortality.
• Complement activation is a proposed, yet unproven, mechanism in pre-eclampsia pathogenesis.
• Immune maladaptation and placental dysfunction are implicated in pre-eclampsia.

Purpose of the Study:

• To investigate the role of genetic variants in complement proteins, specifically complement factor H (CFH), in pre-eclampsia.
• To determine if rare CFH variants are associated with severe pre-eclampsia.

Main Methods:

• A case-control study genotyped 609 pre-eclampsia cases and 2092 controls.
• Five rare missense variants in CFH were identified in cases.
• In vitro functional and structural assays assessed the impact of these variants on CFH protein function, secretion, and complement regulation.

Main Results:

• Seven women with severe pre-eclampsia carried five heterozygous rare CFH variants (L3V, R127H, R166Q, C1077S, N1176K); none were found in controls.
• Four variants (R127H, R166Q, C1077S, N1176K) were found to be deleterious, affecting protein secretion or complement regulatory activity.
• Specifically, R127H and C1077S variants were not secreted, while R166Q and N1176K showed reduced C3b binding and defective complement regulation.

Conclusions:

• Genetic variants in complement factor H (CFH) are associated with severe pre-eclampsia.
• Complement dysregulation resulting from CFH mutations is a potential pathophysiological mechanism underlying severe pre-eclampsia.
• These findings highlight the role of the complement system in pre-eclampsia.