Proteome- and Transcriptome-Wide Genetic Analysis Identifies Biological Pathways and Candidate Drug Targets for Preeclampsia.

BACKGROUND: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. However, the current understanding of its underlying biological pathways remains limited. METHODS: In this study, we performed a cross-platform proteome- and transcriptome-wide genetic analysis aimed at evaluating the causal relevance of >2000 circulating proteins with preeclampsia, supported by data on the expression of over 15 000 genes across 36 tissues leveraging large-scale preeclampsia genetic association data from women of European ancestry. RESULTS: We demonstrate genetic associations of 18 circulating proteins with preeclampsia (SULT1A1, SH2B3, SERPINE2, RGS18, PZP, NOTUM, METAP1, MANEA, jun-D, GDF15 [growth/differentiation factor 15], FGL1, FGF5, FES, APOBR, ANP, ALDH-E2, ADAMTS13, and 3MG), among which 11 were either directly or indirectly supported by gene expression data, 9 were supported by Bayesian colocalization analyses, and 5 (SERPINE2, PZP, FGF5, FES, and ANP) were supported by all lines of evidence examined. Protein interaction mapping identified potential shared biological pathways through natriuretic peptide signaling, blood pressure regulation, immune tolerance, and thrombin activity regulation. CONCLUSIONS: This investigation identified multiple targetable proteins linked to cardiovascular, inflammatory, and coagulation pathways, with SERPINE2, PZP, FGF5, FES, and ANP identified as pivotal proteins with likely causal roles in the development of preeclampsia. The identification of these potential targets may guide the development of targeted therapies for preeclampsia.

Mechanical circulatory support in patients with congenital heart disease: a European Registry for Patients with Mechanical Circulatory Support (EUROMACS) study.

OBJECTIVES: This study aims to explore characteristics and clinical outcomes of patients with congenital heart disease (CHD) in the European Registry for Patients with Mechanical Circulatory Support (EUROMACS). METHODS: This is a retrospective study of EUROMACS participants receiving MCS as bridge-to-transplant, possible bridge-to-transplant, or rescue therapy/bridge-to-recovery from 2011 to 2023 (n = 5340). Adult and paediatric cohorts were analysed separately. The primary outcome was mortality on MCS; secondary outcomes included recovery, transplant and complications including bleeding, cerebrovascular events, and sepsis. RESULTS: Among adult patients, mortality at 1-year was 33.3% among the CHD cohort vs 22.1% in the non-CHD cohort. Adult CHD patients had higher hazards of mortality within the first year after MCS implantation [hazard ratios 1.98, 95% confidence interval (CI) 1.35-2.91, P < 0.001] and bleeding events (subdistribution hazard ratios 2.10, 95% CI 1.40-3.16, P < 0.001) compared with non-CHD patients. Both associations remained significant after accounting for multiple mediators. Among paediatric patients, mortality at 1 year was 22.1% in the CHD cohort vs 17.3% in the non-CHD cohort (hazard ratios 1.39, 95% CI 0.83-2.32, P = 0.213). CONCLUSIONS: Adult and paediatric patients with CHD on MCS have higher adverse event risk compared with non-CHD MCS patients, though children did not have greater risk of mortality. As the number of CHD patients requiring advanced heart failure management continues to grow, these findings can enhance informed decision-making. CLINICAL TRIAL REGISTRATION NUMBER: Registry name: EUROMACS.

Genetically proxied low-density lipoprotein cholesterol lowering via PCSK9-inhibitor drug targets and risk of congenital malformations.

AIMS: Current guidelines advise against the use of lipid-lowering drugs during pregnancy. This is based only on previous observational evidence demonstrating an association between statin use and congenital malformations, which is increasingly controversial. In the absence of clinical trial data, we aimed to use drug-target Mendelian randomization to model the potential impact of fetal LDL-lowering, overall and through PCSK9 drug targets, on congenital malformations. METHODS AND RESULTS: Instrumental variants influencing LDL levels overall and through PCSK9-inhibitor drug targets were extracted from genome-wide association study (GWAS) summary data for LDL on 1 320 016 individuals. Instrumental variants influencing circulating PCSK9 levels (pQTLs) and liver PCSK9 gene expression levels (eQTLs) were extracted, respectively, from a GWAS on 10 186 individuals and from the genotype-tissue expression project. Gene-outcome association data was extracted from the 7th release of GWAS summary data on the FinnGen cohort (n = 342 499) for eight categories of congenital malformations affecting multiple systems. Genetically proxied LDL-lowering through PCSK9 was associated with higher odds of malformations affecting multiple systems [OR 2.70, 95% confidence interval (CI) 1.30-5.63, P = 0.018], the skin (OR 2.23, 95% CI 1.33-3.75, P = 0.007), and the vertebral, anorectal, cardiovascular, tracheo-esophageal, renal, and limb association (VACTERL) (OR 1.51, 95% CI 1.16-1.96, P = 0.007). An association was also found with obstructive defects of the renal pelvis and ureter, but this association was suggestive of horizontal pleiotropy. Lower PCSK9 pQTLs were associated with the same congenital malformations. CONCLUSION: These data provide genetic evidence supporting current manufacturer advice to avoid the use of PCSK9 inhibitors during pregnancy.

Using genetic techniques to mimic the effects of PCSK9-inhibitors, a group of lipid-lowering medications, this study provides evidence to support recommendations to avoid the use of these medications in pregnancy due to potential risk of multiple malformations in the newborn.This study provides genetic evidence to support potential associations of PCSK9-inhibitor medications with newborn malformations affecting multiple organ systems, the skin, and a cluster of structural defects simultaneously affecting the spine, anus/rectum, heart, throat, kidneys, arms and legs.There was also weaker evidence of an association of PCSK9-inhibitor medications with newborn malformations resulting in blockages of the kidneys and urine system, though the evidence was less certain for these than for the other malformations.

Birth weight influences cardiac structure, function, and disease risk: evidence of a causal association.

BACKGROUND AND AIMS: Low birth weight is a common pregnancy complication, which has been associated with higher risk of cardiometabolic disease in later life. Prior Mendelian randomization (MR) studies exploring this question do not distinguish the mechanistic contributions of variants that directly influence birth weight through the foetal genome (direct foetal effects), vs. variants influencing birth weight indirectly by causing an adverse intrauterine environment (indirect maternal effects). In this study, MR was used to assess whether birth weight, independent of intrauterine influences, is associated with cardiovascular disease risk and measures of adverse cardiac structure and function. METHODS: Uncorrelated (r2 < .001), genome-wide significant (P < 5 × 10-8) single nucleotide polymorphisms were extracted from genome-wide association studies summary statistics for birth weight overall, and after isolating direct foetal effects only. Inverse-variance weighted MR was utilized for analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischaemic stroke, and 16 measures of cardiac structure and function. Multiple comparisons were accounted for by Benjamini-Hochberg correction. RESULTS: Lower genetically-predicted birth weight, isolating direct foetal effects only, was associated with an increased risk of coronary artery disease (odds ratio 1.21, 95% confidence interval 1.06-1.37; P = .031), smaller chamber volumes, and lower stroke volume, but higher contractility. CONCLUSIONS: The results of this study support a causal role of low birth weight in cardiovascular disease, even after accounting for the influence of the intrauterine environment. This suggests that individuals with a low birth weight may benefit from early targeted cardiovascular disease prevention strategies, independent of whether this was linked to an adverse intrauterine environment during gestation.

Effects of intensive induction and consolidation chemotherapy with idarubicin and high dose cytarabine on minimal residual disease levels in newly diagnosed adult precursor-B acute lymphoblastic leukemia.

An intensive induction regimen, consisting of idarubicin and high dose cytarabine, was assessed in 19 adult patients, median age 44 years, with newly diagnosed precursor-B acute lymphoblastic leukemia (ALL). Patients achieving a complete response (CR) were given an attenuated consolidation course. The primary endpoints were induction death rate and incidence of serious non-hematological toxicity. Grades 3-4 diarrhoea occurred in 47% of patients during induction. Two patients (11%) died during induction therapy, and 2 were withdrawn due to resistant disease or prolonged marrow hypoplasia. Fifteen patients achieved CR (79%), but levels of minimal residual disease (MRD) after induction were comparable with those previously observed using a modified pediatric protocol. Overall survival at 5 years was 36.8% while leukemia-free survival was 44.1%. An intensive AML protocol used in adults with ALL resulted in substantial toxicity and provided similar levels of cytoreduction to conventional ALL protocols, without improving long-term outcomes.