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Published on: January 26, 2024
Effects of Genetically-Proxied Antihypertensive Drug Targets on Preeclampsia and Birth Weight
Maddalena Ardissino1,2, Alec P Morley3,4, Eleanor M F Richards5
1MRC Laboratory of Medical Sciences, Imperial College London, London, UK.
Insights
Beta blockers (BB) do not appear to reduce preeclampsia (PE) risk and may lower fetal growth, primarily through fetal mechanisms. Calcium channel blockers (CCB) are linked to reduced PE risk with neutral fetal growth effects.
Area of Science:
- Pharmacogenomics
- Obstetrics
- Cardiovascular Genetics
Background:
- Preeclampsia (PE) is a major cause of maternal and perinatal complications, with hypertension treatment during pregnancy often involving beta blockers (BB) and calcium channel blockers (CCB).
- The specific impact of BB and CCB on PE risk and fetal development, whether via maternal or direct fetal pathways, remains unclear.
Purpose of the Study:
- To investigate the effects of genetically proxied inhibition of beta-adrenergic and L-type calcium-channel targets on preeclampsia risk, birth weight, and gestational age using drug-target Mendelian randomization (MR).
- To differentiate between maternal and fetal genetic contributions to these outcomes.
Main Methods:
- Constructed genetic instruments for drug targets (ADRB1 for BB, various for CCB) and a general systolic blood pressure (SBP) instrument.
- Employed two-sample MR to analyze associations with preeclampsia, birth weight (maternal and fetal components), and gestational age in large European ancestry cohorts.
- Utilized Bayesian colocalization to assess shared causal variants and conducted sensitivity analyses for heterogeneity and pleiotropy.
Main Results:
- Genetically lower SBP was associated with reduced PE risk and increased birth weight and gestational age.
- Beta blocker (BB) target inhibition showed no significant reduction in PE risk but was linked to lower birth weight, with strong evidence for direct fetal genetic effects.
- Calcium channel blocker (CCB) targets collectively showed an association with lower PE risk, without consistent evidence of fetal growth impairment.
Conclusions:
- Drug-target MR suggests BB pathways are unlikely to reduce preeclampsia risk and may negatively impact fetal growth via direct fetal mechanisms.
- CCB pathways are associated with a reduced risk of preeclampsia and largely neutral effects on fetal growth, supporting their evaluation in PE prevention trials.
Background:
Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality, and a major contributor to low birth weight. Beta blockers (BB) and calcium channel blockers (CCB) are the most commonly recommended agents to treat hypertension in pregnancy. Yet it remains unknown whether these agents alter the risk of preeclampsia (PE), and if so, whether effects arise through maternal physiology or through direct fetal mechanisms.
Objectives:
To use drug-target Mendelian randomization (MR) to estimate the effects of genetically-proxied inhibition of beta-adrenergic and L-type calcium-channel targets on PE risk, birth weight, partitioned into maternal and fetal genetic components, and gestational age (GA).
Methods:
We constructed instruments from genome-wide significant, LD-independent variants within prespecified windows around systolic blood pressure (SBP) modulating drug targets in addition to a genome-wide SBP instrument (European ancestry). Outcomes comprised of PE (16,349 cases / 595,135 controls), maternal and fetal genetic effects on birth weight (n≈210,267 and n≈298,142), and GA (n≈151,987). Two-sample MR estimated effects per 5mmHg decrease in SBP. Bayesian colocalization assessed shared causal variants. Multiple testing was controlled with Benjamini-Hochberg correction.
Results:
Genetically lower SBP was associated with reduced PE risk and modest increases in birth weight and GA. BB (ADRB1) target inhibition showed no convincing reduction in PE risk but was associated with lower birth weight, with associations predominantly through direct fetal genetic effects and strong colocalization at ADRB1 with fetal birth-weight signals. In contrast, CCB targets collectively associated with lower PE risk without consistent evidence of fetal growth impairment; colocalization support for individual CCB loci was limited. Sensitivity analyses (heterogeneity, pleiotropy) did not materially alter these patterns where instrument counts permitted.
Conclusions:
Drug-target MR suggests that BB pathways are unlikely to meaningfully reduce PE and are linked to reduced fetal growth - chiefly via direct fetal mechanisms. In contrast, CCB pathways are associated with lower PE risk and largely neutral fetal growth effects. These findings support prioritizing CCBs for evaluation in comparative trials of PE prevention.
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