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

A Inkeri Lokki; Zhen Ren; Michael Triebwasser; Emma Daly; FINNPEC; Markus Perola; Kirsi Auro; Richard Burwick; Jane E Salmon; Mark Daly; Hannele Laivuori; John P Atkinson; Anuja Java; Seppo Meri

doi:10.1111/1471-0528.17529

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

BJOG. 2023 Nov;130(12):1473-1482. doi: 10.1111/1471-0528.17529. Epub 2023 May 8.

Authors

A Inkeri Lokki^{1

2}, Zhen Ren³, Michael Triebwasser⁴, Emma Daly⁵; FINNPEC⁶; Markus Perola⁷, Kirsi Auro⁷, Richard Burwick^{8

9}, Jane E Salmon¹⁰, Mark Daly^{11

12}, Hannele Laivuori^{6

12

13

14}, John P Atkinson¹⁵, Anuja Java¹⁶, Seppo Meri^{1

17}

Collaborators

FINNPEC:
Seppo Heinonen, Eero Kajantie, Juha Kere, Katja Kivinen, Anneli Pouta

Affiliations

¹ Immunobiology Research Program, Bacteriology and Immunology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
² Heart and Lung Centre, Helsinki University Hospital, Helsinki, Finland.
³ Division of Clinical Immunology and Allergy, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
⁴ Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
⁵ Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁶ Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁷ Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
⁸ Maternal Fetal Medicine, San Gabriel Valley Perinatal Medical Group, Pomona Valley Hospital Medical Center, Pomona, California, USA.
⁹ Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
¹⁰ Hospital for Special Surgery, Weill Medical College of Cornell University, New York, New York, USA.
¹¹ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹² Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
¹³ Department of Obstetrics and Gynaecology, Tampere University Hospital, Tampere University, Tampere, Finland.
¹⁴ Centre for Child, Adolescent, and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
¹⁵ Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁶ Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁷ HUSLAB Diagnostic Centre, Helsinki University Hospital, Helsinki, Finland.

Abstract

Objective: The objective of the study was to investigate the role of genetic variants in complement proteins in pre-eclampsia.

Design: In a case-control study involving 609 cases and 2092 controls, five rare variants in complement factor H (CFH) were identified in women with severe and complicated pre-eclampsia. No variants were identified in controls.

Setting: Pre-eclampsia is a leading cause of maternal and fetal morbidity and mortality. Immune maladaptation, in particular, complement activation that disrupts maternal-fetal tolerance leading to placental dysfunction and endothelial injury, has been proposed as a pathogenetic mechanism, but this remains unproven.

Population: We genotyped 609 pre-eclampsia cases and 2092 controls from FINNPEC and the national FINRISK cohorts.

Methods: Complement-based functional and structural assays were conducted in vitro to define the significance of these five missense variants and each compared with wild type.

Main outcome measures: Secretion, expression and ability to regulate complement activation were assessed for factor H proteins harbouring the mutations.

Results: We identified five heterozygous rare variants in complement factor H (L3V, R127H, R166Q, C1077S and N1176K) in seven women with severe pre-eclampsia. These variants were not identified in controls. Variants C1077S and N1176K were novel. Antigenic, functional and structural analyses established that four (R127H, R166Q, C1077S and N1176K) were deleterious. Variants R127H and C1077S were synthesised, but not secreted. Variants R166Q and N1176K were secreted normally but showed reduced binding to C3b and consequently defective complement regulatory activity. No defect was identified for L3V.

Conclusions: These results suggest that complement dysregulation due to mutations in complement factor H is among the pathophysiological mechanisms underlying severe pre-eclampsia.

Keywords: complement system; factor H; genetics; pre-eclampsia: basic science.

MeSH terms

Case-Control Studies
Complement Factor H* / genetics
Complement Factor H* / metabolism
Female
Genotype
Humans
Placenta / metabolism
Pre-Eclampsia* / genetics
Pregnancy

Substances

Complement Factor H

Abstract

MeSH terms

Substances

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