Genetic Associations of Circulating Cardiovascular Proteins With Gestational Hypertension and Preeclampsia
Authors: Schuermans Art , Truong Buu , Ardissino Maddalena , Bhukar Rohan , Slob Eric A. W. , Nakao Tetsushi , Dron Jacqueline S. , Small Aeron M. , Cho So Mi Jemma , Yu Zhi , Hornsby Whitney , Antoine Tajmara , Lannery Kim , Postupaka Darina , Gray Kathryn J. , Yan Qi , Butterworth Adam S. , Burgess Stephen , Wood Malissa J. , Scott Nandita S. , Harrington Colleen M. , Sarma Amy A. , Lau Emily S. , Roh Jason D. , Januzzi James L. , Natarajan Pradeep , Honigberg Michael C. 
Published: January 2024

Importance

Hypertensive disorders of pregnancy (HDPs), including gestational hypertension and preeclampsia, are important contributors to maternal morbidity and mortality worldwide. In addition, women with HDPs face an elevated long-term risk of cardiovascular disease.

Objective

To identify proteins in the circulation associated with HDPs.

Design, Setting, and Participants

Two-sample mendelian randomization (MR) tested the associations of genetic instruments for cardiovascular disease–related proteins with gestational hypertension and preeclampsia. In downstream analyses, a systematic review of observational data was conducted to evaluate the identified proteins’ dynamics across gestation in hypertensive vs normotensive pregnancies, and phenome-wide MR analyses were performed to identify potential non-HDP–related effects associated with the prioritized proteins. Genetic association data for cardiovascular disease–related proteins were obtained from the Systematic and Combined Analysis of Olink Proteins (SCALLOP) consortium. Genetic association data for the HDPs were obtained from recent European-ancestry genome-wide association study meta-analyses for gestational hypertension and preeclampsia. Study data were analyzed October 2022 to October 2023.

Exposures

Genetic instruments for 90 candidate proteins implicated in cardiovascular diseases, constructed using cis-protein quantitative trait loci (cis-pQTLs).

Main Outcomes and Measures

Gestational hypertension and preeclampsia.

Results

Genetic association data for cardiovascular disease–related proteins were obtained from 21 758 participants from the SCALLOP consortium. Genetic association data for the HDPs were obtained from 393 238 female individuals (8636 cases and 384 602 controls) for gestational hypertension and 606 903 female individuals (16 032 cases and 590 871 controls) for preeclampsia. Seventy-five of 90 proteins (83.3%) had at least 1 valid cis-pQTL. Of those, 10 proteins (13.3%) were significantly associated with HDPs. Four were robust to sensitivity analyses for gestational hypertension (cluster of differentiation 40, eosinophil cationic protein [ECP], galectin 3, N-terminal pro–brain natriuretic peptide [NT-proBNP]), and 2 were robust for preeclampsia (cystatin B, heat shock protein 27 [HSP27]). Consistent with the MR findings, observational data revealed that lower NT-proBNP (0.76- to 0.88-fold difference vs no HDPs) and higher HSP27 (2.40-fold difference vs no HDPs) levels during the first trimester of pregnancy were associated with increased risk of HDPs, as were higher levels of ECP (1.60-fold difference vs no HDPs). Phenome-wide MR analyses identified 37 unique non-HDP–related protein-disease associations, suggesting potential on-target effects associated with interventions lowering HDP risk through the identified proteins.

Conclusions and Relevance

Study findings suggest genetic associations of 4 cardiovascular disease–related proteins with gestational hypertension and 2 associated with preeclampsia. Future studies are required to test the efficacy of targeting the corresponding pathways to reduce HDP risk.