👤 Art Schuermans

Elevated lipoprotein(a) [Lp(a)] levels are an established risk factor for atherosclerotic cardiovascular disease, but the association between Lp(a) and venous thromboembolism (VTE) remains unclear. Sex and hormonal status may modify the relationship between Lp(a) and VTE. The present study included participants from the UK Biobank with available baseline Lp(a) data. Individuals with a history of VTE or cancer, as well as those using anticoagulants, were excluded. Multivariable-adjusted Cox models were used to assess the association between Lp(a) levels ≥ 125 nmol/L and incident VTE in premenopausal women, postmenopausal women, and men. Subgroup analyses stratified premenopausal women by oral contraceptive (OCP) use and postmenopausal women by menopausal hormone therapy (MHT) use. Among 55 302 premenopausal women, 129 045 postmenopausal women, and 189 013 men, the proportions with Lp(a) ≥ 125 nmol/L were 14.0%, 19.0%, and 15.0%, respectively. Over a median (interquartile range) follow-up of 13.6 (12.9-14.4) years, 8186 VTE events occurred (cumulative incidence 2.2%). Lp(a) ≥ 125 nmol/L was associated with incident VTE in premenopausal women [adjusted hazard ratio (aHR) 1.32; 95% confidence interval (CI) 1.04-1.66; P = 0.02] but not in postmenopausal women (aHR 1.03; 95% CI 0.94-1.13; P = 0.47; Pinteraction = 0.03) or men (aHR 1.00; 95% CI 0.92-1.08; P = 0.94). OCP use did not modify the Lp(a)-VTE association among premenopausal women (Pinteraction = 0.61). However, among postmenopausal MHT users, Lp(a) ≥ 125 nmol/L was associated with higher VTE risk (aHR 1.48; 95% CI 1.03-2.12; P = 0.03; Pinteraction = 0.04). Elevated Lp(a) was associated with VTE in premenopausal women and in postmenopausal MHT users, suggesting that hormonal context may influence Lp(a)- associated thrombotic risk. Show less

Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. However, the current understanding of its underlying biological pathways remains limited. 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. We demonstrate genetic associations of 18 circulating proteins with preeclampsia (SULT1A1 [sulfotransferase 1A1], SH2B3 [SH2B adapter protein 3], SERPINE2 [serpin family E member 2], RGS18 [regulator of G-protein signaling 18], PZP [pregnancy zone protein], NOTUM [notum, palmitoleoyl-protein carboxylesterase], METAP1 [methionyl aminopeptidase 1], MANEA [mannosidase endo-alpha], jun-D [JunD proto-oncogene], GDF15 [growth differentiation factor 15], FGL1 [fibrinogen like 1], FGF5 [fibroblast growth factor 5], FES [FES proto-oncogene], APOBR [apolipoprotein B receptor], ANP [natriuretic peptide A], ALDH-E2 [aldehyde dehydrogenase 2 family member], ADAMTS13 [ADAM metallopeptidase with thrombospondin type 1 motif 13], and 3MG [N-methylpurine DNA glycosylase]), 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. 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. Show less