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Comment
. 2024 Mar 1;9(3):209-220.
doi: 10.1001/jamacardio.2023.4994.

Genetic Associations of Circulating Cardiovascular Proteins With Gestational Hypertension and Preeclampsia

Art Schuermans  1   2   3 , Buu Truong  1   2 , Maddalena Ardissino  4   5 , Rohan Bhukar  1   2 , Eric A W Slob  6   7   8 , Tetsushi Nakao  1   2   9   10 , Jacqueline S Dron  1   2 , Aeron M Small  1   10   11 , So Mi Jemma Cho  1   2   12 , Zhi Yu  1   2 , Whitney Hornsby  1   2 , Tajmara Antoine  1   2 , Kim Lannery  1   2 , Darina Postupaka  1   2 , Kathryn J Gray  13 , Qi Yan  14 , Adam S Butterworth  4   15   16   17   18 , Stephen Burgess  6 , Malissa J Wood  11   19   20 , Nandita S Scott  11   19 , Colleen M Harrington  11   19 , Amy A Sarma  11   19 , Emily S Lau  2   11   19 , Jason D Roh  11   19 , James L Januzzi Jr  11   19   21 , Pradeep Natarajan  1   2   11   19 , Michael C Honigberg  1   2   11   19
Affiliations
Comment

Genetic Associations of Circulating Cardiovascular Proteins With Gestational Hypertension and Preeclampsia

Art Schuermans et al. JAMA Cardiol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Nakao reported receiving grants from Japan Society for the Promotion of Science Overseas Fellowship and the National Heart, Lung, and Blood Institute outside the submitted work. Dr Gray reported receiving personal fees from BillionToOne, Roche, and Aetion outside the submitted work. Dr Butterworth reported receiving grants from AstraZeneca, Bayer, Biogen, BioMarin, and Sanofi outside the submitted work. Dr Scott reported receiving personal fees from HOPE registry and grants from the REBIRTH study during the conduct of the study. Dr Sarma reported receiving grants from CRICO and the American Heart Association and consulting fees from Pfizer during the conduct of the study. Dr Lau reported receiving grants from the National Institutes of Health/National Heart, Lung, and Blood Institute and the American Heart Association and advisory board fees from Astellas Pharma outside the submitted work. Dr Natarajan reported receiving grants from Allelica, Amgen, Apple, Boston Scientific, Genentech/Roche, and Novartis; personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Eli Lilly & Co, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, and Novartis; advisory board fees from Esperion Therapeutics, TenSixteen Bio, and MyOme; and equity from Preciseli, TenSixteen Bio, and MyOme outside the submitted work. Dr Honigberg reported receiving advisory board fees from Miga Health; personal fees from Comanche Biopharma; and grants from the National Heart, Lung, and Blood Institute, the American Heart Association, and Genentech outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Associations of Genetically Predicted Protein Levels With Hypertensive Disorders of Pregnancy (HDPs) in Primary Analyses
cis-Mendelian randomization analyses were performed using cis-variants at P < 1 × 10−4 clumped at R2 <0.4. Associations are expressed per SD increase in genetically predicted protein levels. Biomarkers reaching statistical significance (false discovery rate–adjusted P < .05) are displayed in blue (if β <0) or orange (if β >0). CCL4 indicates C-C motif chemokine 4; CD40, cluster of differentiation 40; CSTB, cystatin B; ECP, eosinophil cationic protein; Gal-3, galectin 3; HSP27, heat shock protein 27; KIM-1, kidney injury molecule 1; MMP-12, matrix metalloproteinase 12; NT-proBNP, N-terminal pro–brain natriuretic peptide; ST2, suppression of tumorigenicity 2.
Figure 2.
Figure 2.. Genetic Associations of Protein Levels With Hypertensive Disorders of Pregnancy (HDPs) Robust to Sensitivity Analyses
Forest plots show associations that were significant in primary analyses (orange squares) with directionally consistent sensitivity analyses (blue squares). Associations are expressed per SD increase in genetically predicted protein levels. Main analyses included cis-protein quantitative trait loci with P < 1 × 10−4 at R2 <0.4 and used inverse-variance–weighted (IVW) adjusting for between-variant correlation. From top to bottom, sensitivity analyses used IVW with principal component analysis ([IVW-PCA] 99% of variance); mendelian randomization–Egger (MR-Egger); IVW adjusting for between-variant correlation using different linkage disequilibrium R2 thresholds (0.001, 0.01, 0.1, 0.2, 0.6, and 0.8); and IVW adjusting for between-variant correlation using different P-value thresholds (1 × 10−6 and 5 × 10−8). CD40 indicates cluster of differentiation 40; CSTB, cystatin B; ECP, eosinophil cationic protein; Gal-3, galectin 3; HSP27, heat shock protein 27; NT-proBNP, N-terminal pro–brain natriuretic peptide.
Figure 3.
Figure 3.. Observational Associations Between Hypertensive Disorders of Pregnancy (HDPs) and N-Terminal Pro–Brain Natriuretic Peptide (NT-proBNP), Galectin 3 (Gal-3), and Heat Shock Protein 27 (HSP27) Across Gestation
Scatterplots illustrate the association between protein levels and gestational age at blood sampling. Protein levels were compared by log10-transforming the ratio of mean protein concentration in the HDP vs non-HDP group. Lines depict linear regression estimates (and corresponding 95% confidence bands) for HDP subgroups (preeclampsia or gestational hypertension) weighted by each study’s sample size, generated using ggplot2 in R. Studies with data labeled as mixed did not distinguish between preeclampsia and gestational hypertension. Each 1-week increase in gestational age was associated with a 0.039-point increase (95% CI, 0.032-0.046; P = 4.4 × 10−10) in NT-proBNP abundance (log-fold change in women with vs without HDP) for preeclampsia; a 0.007-point increase (95% CI, −0 to 0.015; P = .06) in NT-proBNP abundance for gestational hypertension; a 0-point increase (95% CI, −0.003 to 0.004; P = .94) in Gal-3 abundance for preeclampsia; and a 0.019-point decrease (β = −0.019; 95% CI, −0.035 to −0.005; P = .03) in HSP27 abundance for preeclampsia.
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