Risk of pre-eclampsia in patients with a maternal genetic predisposition to common medical conditions: a case-control study

K J Gray; V P Kovacheva; H Mirzakhani; A C Bjonnes; B Almoguera; M L Wilson; S A Ingles; C J Lockwood; H Hakonarson; T F McElrath; J C Murray; E R Norwitz; S A Karumanchi; B T Bateman; B J Keating; R Saxena

doi:10.1111/1471-0528.16441

Risk of pre-eclampsia in patients with a maternal genetic predisposition to common medical conditions: a case-control study

BJOG. 2021 Jan;128(1):55-65. doi: 10.1111/1471-0528.16441. Epub 2020 Sep 14.

Authors

K J Gray^{1

2}, V P Kovacheva³, H Mirzakhani⁴, A C Bjonnes², B Almoguera⁵, M L Wilson⁶, S A Ingles⁶, C J Lockwood⁷, H Hakonarson^{5

8}, T F McElrath¹, J C Murray⁹, E R Norwitz¹⁰, S A Karumanchi^{11

12}, B T Bateman⁴, B J Keating¹³, R Saxena^{2

4}

Affiliations

¹ Division of Maternal-Fetal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
² Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
³ Department of Anesthesiology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁴ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁵ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁶ Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁷ Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
⁸ Department of Pediatrics, Divisions of Human Genetics and Pulmonary Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁹ Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
¹⁰ Department of Obstetrics & Gynecology, Tufts Medical Center, Boston, Massachusetts, USA.
¹¹ Center for Vascular Biology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
¹² Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
¹³ Department of Surgery and Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Abstract

Objective: To assess whether women with a genetic predisposition to medical conditions known to increase pre-eclampsia risk have an increased risk of pre-eclampsia in pregnancy.

Design: Case-control study.

Setting and population: Pre-eclampsia cases (n = 498) and controls (n = 1864) in women of European ancestry from five US sites genotyped on a cardiovascular gene-centric array.

Methods: Significant single-nucleotide polymorphisms (SNPs) from 21 traits in seven disease categories (cardiovascular, inflammatory/autoimmune, insulin resistance, liver, obesity, renal and thrombophilia) with published genome-wide association studies (GWAS) were used to create a genetic instrument for each trait. Multivariable logistic regression was used to test the association of each continuous scaled genetic instrument with pre-eclampsia. Odds of pre-eclampsia were compared across quartiles of the genetic instrument and evaluated for significance.

Main outcome measures: Genetic predisposition to medical conditions and relationship with pre-eclampsia.

Results: An increasing burden of risk alleles for elevated diastolic blood pressure (DBP) and increased body mass index (BMI) were associated with an increased risk of pre-eclampsia (DBP, overall OR 1.11, 95% CI 1.01-1.21, P = 0.025; BMI, OR 1.10, 95% CI 1.00-1.20, P = 0.042), whereas alleles associated with elevated alkaline phosphatase (ALP) were protective (OR 0.89, 95% CI 0.82-0.97, P = 0.008), driven primarily by pleiotropic effects of variants in the FADS gene region. The effect of DBP genetic loci was even greater in early-onset pre-eclampsia cases (at <34 weeks of gestation, OR 1.30, 95% CI 1.08-1.56, P = 0.005). For other traits, there was no evidence of an association.

Conclusions: These results suggest that the underlying genetic architecture of pre-eclampsia may be shared with other disorders, specifically hypertension and obesity.

Tweetable abstract: A genetic predisposition to increased diastolic blood pressure and obesity increases the risk of pre-eclampsia.

Keywords: Cardiovascular risk; genetic epidemiology; genetic predisposition to disease; genetic risk score; pre-eclampsia; pregnancy.

Publication types

Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Body Mass Index
Case-Control Studies
Europe
Female
Genetic Predisposition to Disease*
Genome-Wide Association Study
Humans
Hypertension
Polymorphism, Single Nucleotide
Pre-Eclampsia / genetics*
Pregnancy
Risk Factors
United States
White People
Young Adult

Abstract

Publication types

MeSH terms

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