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

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 preeclampsia. 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.

Effects of Pre-Pregnancy Overweight/Obesity on the Pattern of Association of Hypertension Susceptibility Genes with Preeclampsia

“…It should be noted that our data on significant correlations between genetic predisposition to hypertension/BP and PE in preBMI ≥ 25 pregnant women are consistent with the results of previous studies on this issue [26][27][28]. According to the multi-ethnic maternal PE GWAS data from Gray et al, the disorder-associated locus rs9478812 PLEKHG1 [28] has previously been implicated in GWAS of BP and BMI [72,73].…”

“…in the susceptibility to PE, etc. [8,[19][20][21][22][23][24][25], genetic studies revealing the role of specific GWAS candidate genes of the cardiovascular disease in the formation of PE when interacting with BMI are extremely limited [14,[26][27][28]. It has been hypothesized that pre-pregnancy overweight/obesity might influence the association between GWAS gene polymorphisms of hypertension and PE.…”

Heart Disease and Stroke Statistics—2022 Update: A Report From the American Heart Association

“…The role of GRS composed of preeclampsia risk factor variants in preeclampsia is supported by a study of 498 preeclampsia cases; a hypertension GRS and a BMI GRS were associated with increased risk of preeclampsia (OR, 1.11 [95% CI, 1.01–1.21] and 1.10 [95% CI, 1.00–1.20], respectively). 36…”

Pregnancy and Reproductive Risk Factors for Cardiovascular Disease in Women

“…82,83 Recent data demonstrate that women with HDPs have elevated polygenic risk of hypertension and obesity (Table 2), implying that HDPs signify latent genetic cardiometabolic risk. [84][85][86] In addition, the fetal FLT1 gene, whose product (soluble fms-like tyrosine kinase receptor 1) is a causal preeclampsia biomarker, has been associated with development of maternal preeclampsia. 86…”