👤 Michelle L O'Donoghue

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

Physical inactivity post-stroke increases risk of recurrent stroke. Adaptive physical activity (PA) interventions are recommended, and alternative designs, such as sequential multiple assignment randomized trials (SMARTs) can be used. This SMART investigates the feasibility of a mobile health (mHealth) PA intervention post-stroke. People post-stroke are randomized to 12-week online exercise (EX) or lifestyle PA (LPA). Six-week daily step count data are used to classify participants as responders or nonresponses. Nonresponders are re-randomized to switch or augment their mHealth intervention, responders continue unchanged. Primary outcomes include recruitment, retention and adherence rates. Secondary outcomes include PA, sedentary behavior, fatigue, quality of life, psychological distress, and activities of daily living. General linear models estimate trends regarding first-stage interventions, nonresponse strategies, and adaptive interventions are examined using weighted and replicated regressions. Fifty participants are included. Recruitment, retention, and adherence rates are 85%, 84%, and 82%. Positive trends are seen for nonresponse strategies, switching interventions, on step count, fatigue, and quality of life. Starting with EX and switching to LPA show potential benefits for fatigue, quality of life and return to normal living. Potential benefits of these interventions are preliminary and require validation in a full-scale trial. This SMART offers novel evidence supporting the design of adaptive mHealth PA interventions post-stroke, confirming the feasibility of a definitive SMART. Show less

Lipoprotein(a) (Lp[a]) is thought to be the major carrier of oxidized phospholipids (OxPL). OxPL are believed to be a potent driver of inflammation and atherosclerosis. Olpasiran, a small interfering RNA, blocks Lp(a) production by inducing degradation of apolipoprotein(a) messenger RNA. Olpasiran's effects on OxPL and systemic markers of inflammation are not well described. To assess the effects of olpasiran on OxPL, high-sensitivity interleukin 6 (hs-IL-6), and hs-C-reactive protein (hs-CRP) in the OCEAN(a)-DOSE randomized clinical trial. OCEAN(a)-DOSE was an international, multicenter, placebo-controlled, phase 2, dose-finding randomized clinical trial conducted between July 2020 and November 2022. A total of 281 patients with atherosclerotic cardiovascular disease and Lp(a) levels greater than 150 nmol/L were included. Participants were randomized to receive 1 of 4 active subcutaneous doses of olpasiran vs placebo: (1) 10 mg, administered every 12 weeks (Q12W); (2) 75 mg, Q12W; (3) 225 mg, Q12W; or (4) 225 mg, administered every 24 weeks (Q24W). OxPL on apolipoprotein B (OxPL-apoB), hs-CRP, and hs-IL-6 were assessed at baseline, week 36, and week 48 in 272 patients. The primary outcome was placebo-adjusted change in OxPL-apoB from baseline to week 36. Among 272 participants, median (IQR) age was 62 years (56-69), and 86 participants (31.6%) were female. Baseline median (IQR) Lp(a) concentration was 260.3 nmol/L (198.1-352.4) and median (IQR) OxPL-apoB concentration was 26.5 nmol/L (19.7-33.9). The placebo-adjusted mean percentage change in OxPL-apoB from baseline to week 36 was -51.6% (95% CI, -64.9% to -38.2%) for the 10-mg Q12W dose, -89.7% (95% CI, -103.0% to -76.4%) for the 75-mg Q12W dose, -92.3% (95% CI, -105.6% to -78.9%) for the 225-mg Q12W dose, and -93.7% (95% CI, -107.1% to -80.3%) for the Q24W dose (P < .001 for all). These effects were maintained to week 48 (-50.8%, -100.2%, -104.7%, and -85.8%, respectively; P < .001 for all). There was a strong correlation between percentage reduction in Lp(a) and OxPL-apoB for patients treated with olpasiran (r = 0.79; P < .001). Olpasiran did not significantly impact hs-CRP or hs-IL-6 compared with placebo to weeks 36 or 48 (P > .05). In the OCEAN(a)-DOSE multicenter randomized clinical trial, olpasiran led to a significant and sustained reduction in OxPL-apoB but no significant effects on hs-CRP or hs-IL-6. Show less

The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction. Show less

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity. Show less

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases. Show less