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

By Kathryn J. Gray, Vesela P Kovacheva, Hooman Mirzakhani, Andrew C Bjonnes, Berta Almoguera, Melissa L Wilson, Sue Ann Ingles, Charles J Lockwood, Hakon Hakonarson, Thomas F McElrath, Jeffrey C Murray, Errol R Norwitz, S. Ananth Karumanchi, Brian T Bateman, Brendan J Keating, Richa Saxena

Posted 05 Mar 2020
bioRxiv DOI: 10.1101/2020.03.04.976472

Objective: To assess whether women with a genetic predisposition to medical conditions known to increase preeclampsia risk have an increased risk of preeclampsia in pregnancy. Design: Case-control study. Setting and population: Preeclampsia cases (n=498) and controls (n=1864) of European ancestry from 5 US sites genotyped on a cardiovascular gene-centric array. Methods: Significant single nucleotide polymorphisms (SNPs) from 21 traits in 7 disease categories (cardiovascular, inflammatory/autoimmune, insulin resistance, liver, obesity, renal, 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 preeclampsia were compared across quartiles of the genetic instrument and evaluated for significance using a test for trend. Main Outcome Measures: preeclampsia. 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 preeclampsia (DBP: overall OR 1.11 (1.01-1.21), p=0.025; BMI: OR 1.10 (1.00-1.20), p=0.042), while risk alleles associated with elevated alkaline phosphatase (ALP) were protective (OR 0.89 (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 (<34 weeks) preeclampsia cases (OR 1.30 (1.08-1.56), p=0.005). For all other traits, the genetic instrument was not robustly associated with preeclampsia risk. Conclusions: These results suggest that the underlying genetic architecture of preeclampsia is shared with other disorders, specifically hypertension and obesity.

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