Circulation: Genomic and Precision Medicine最新文献

Background: Coronary artery disease (CAD) is a major contributor to cardiovascular morbidity (including myocardial infarction and heart failure) and mortality. Although the burden of CAD (number and degree of coronary artery stenosis) has been observationally linked to these outcomes, the causal contribution and independence from traditional cardiovascular risk factors have been poorly defined.

Methods: We developed a polygenic risk score for angiographic CAD burden using data from the VA Million Veteran Program (n=41 507) and validated this score using data from the Penn Medicine Biobank (n=41 660 with genotyping, N=3771 with angiogram data). We then used publicly available GWAS data and a mediation framework using Mendelian Randomization to investigate whether angiographic CAD burden contributes to adverse cardiovascular outcomes independent of traditional risk factors.

Results: We first demonstrated that increasing levels of the polygenic risk score were strongly associated with increased prevalence of nonobstructive and obstructive CAD on coronary angiography (odds ratio, 1.26 [95% CI, 1.14-1.39]; odds ratio, 2.23 [95% CI, 1.94-2.55], respectively) and was associated with other forms of cardiometabolic disease including peripheral artery disease and atherosclerotic risk factors including hyperlipidemia, hypercholesterolemia and hypertension. Through Mendelian randomization analyses, we found that lipid measures (apolipoprotein B, high-density lipoprotein, low-density lipoprotein, total cholesterol, triglycerides) and type 2 diabetes significantly influenced myocardial infarction risk through their effects on angiographic CAD burden. Furthermore, low-density lipoprotein and total cholesterol demonstrated significant indirect effects on heart failure through angiographic CAD burden, suggesting these lipids primarily influence heart failure through their impact on coronary atherosclerosis.

Conclusions: Our findings indicate that angiographic burden of coronary atherosclerosis mediates a substantial proportion of the relationship between traditional cardiovascular risk factors and adverse outcomes. These results support prioritizing primary prevention efforts targeting modifiable risk factors to prevent the development and progression of coronary plaques before clinical disease manifestation.

Background: Atrial septal defects (ASDs) are a prevalent type of congenital heart disease. Previous GWAS (Genome-Wide Association Studies) have identified common variants associated with ASDs, though their mechanisms remain unknown. We aimed to expand insights into the architecture of common variants associated with ASD risk and elucidate functional mechanisms.

Methods: We conducted a GWAS using isolated ASD cases and healthy controls and replicated findings in an independent cohort. We examined epigenetic marks within this ASD locus in human induced pluripotent stem cell-derived cardiomyocytes and fetal human hearts. We characterized the consequences of deletions introduced by CRISPR-Cas9 mutagenesis of human induced pluripotent stem cells to assess the effect on downstream gene expression. In addition, we investigated the 3-dimensional genome architecture of the locus using chromosome conformation capture sequencing.

Results: We identified a novel ASD locus on chromosome 3p12.3 encompassing the ROBO2 gene, which encodes the Roundabout guidance receptor 2 for Slit ligands. This locus includes 15 common single nucleotide polymorphisms, an enhancer, and a CTCF-binding site. Deletions of varying lengths within the ASD-associated locus in human induced pluripotent stem cell-derived cardiomyocytes reduced ROBO2 expression and dysregulated the expression of extracellular matrix genes. Chromosome conformation capture sequencing indicated that this region physically interacts with the ROBO2 promoter and demonstrates that the CTCF-binding site is essential for this contact.

Conclusions: Novel common single nucleotide polymorphisms in regulatory elements controlling ROBO2 transcription contribute to risk for ASDs. These data infer key roles for the Roundabout guidance receptor 2 and Slit ligands in embryogenic development and maturation of the atrial septa.

Background: PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition is a potent cholesterol-lowering strategy. This study examined the effects of PCSK9 monoclonal antibodies (mAbs) and high-intensity statins beyond low-density lipoprotein cholesterol reduction, which are not fully defined, particularly in patients with acute myocardial infarction (MI).

Methods: Combined proteomics and lipidomics analyses was conducted on plasma from 265 patients with acute MI from the PACMAN-AMI (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction) randomized, placebo-controlled PCSK9 mAb trial and 34 patients without MI with hyperlipidemia from the Vienna Lipid Clinic registry, also receiving PCSK9 mAbs.

Results: Discovery proteomics revealed changes in apolipoproteins and increased PCOLCE (procollagen C-endopeptidase enhancer 1) levels in both the PCSK9 mAb and placebo groups after MI. UK Biobank data confirmed PCOLCE and PCSK9 upregulation as associated with statin use. Hepatoma cell experiments demonstrated a dose-dependent PCOLCE induction on statin treatment. Compared with placebo (statins only), PCSK9 mAb therapy resulted in greater reductions in APOB, APOE, APO C₂, and APO C₃, as shown by targeted proteomics. Mediation analysis indicated that these changes were largely explained by low-density lipoprotein cholesterol lowering. Lipidomics identified more pronounced reductions in cholesteryl esters, ceramides, sphingomyelins, phosphatidylcholines, triglycerides, and diglycerides in PCSK9 mAb-treated patients with MI. Results were largely consistent in patients without MI. However, levels of LPA (apolipoprotein[a]), the characteristic protein component of lipoprotein(a), remained unchanged in PCSK9 mAb-treated patients with MI, since a rise of LPA was observed in the placebo group post-MI.

Conclusions: Most apolipoprotein changes after PCSK9 mAb therapy after MI were mediated by low-density lipoprotein cholesterol lowering. Statin use is associated with increased circulating PCOLCE, with hepatoma cell experiments supporting a predominant hepatic origin. Combining PCSK9 mAbs with high-intensity statins mitigates post-MI increases in lipoprotein(a).

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03067844.

Background: Genetic variation affects clinical outcomes, prognosis, and family planning decisions in individuals with congenital heart disease (CHD). While genetic testing recommendations for infants and children with CHD have expanded, similar broad guidelines are lacking for patients with adult CHD (ACHD). Here, we investigated the current state of genetic testing in patients with ACHD and their perceptions toward testing, which has not been previously reported.

Methods: A single-center prospective cohort survey of patients with ACHD aged ≥18 years was evaluated in a large ACHD clinic over a 12-month period.

Results: Among 336 survey respondents (median age, 29 years; 52% male), CHD lesions were wide ranging, albeit largely represented by conotruncal (35%) or left ventricular outflow tract (35%) lesions. Most patients did not have children (64%) or a family history of CHD (79%). Thirteen percent had evidence of prior genetic testing despite 41% to 98% meeting criteria by current pediatric recommendations. Most desired genetic testing (68%) though interest varied by sex, education level, and family status. Individual and family health factors were reported as the most influential considerations for genetic testing.

Conclusions: Few patients with ACHD have had genetic testing despite most being eligible based on current pediatric guidelines, likely related to birth era. Patients were interested in genetic testing though demographic factors and family status affected interest. The lack of broad recommendations for genetic testing in the ACHD population likely represents a significant barrier to increased utilization of genetic tests.

Background: Circulating proteins represent robust drug targets with therapeutic potential. Many discoveries have focused on European-ancestry populations, disregarding minuscule yet substantial proteomic differences that may contribute to disease and alter drug generalizability in other ancestry groups.

Methods: Using 2-sample Mendelian randomization and colocalization, we analyzed the effects of 1562 circulating proteins on 145 cardiometabolic-centric outcomes to identify robust protein-phenotype associations in African-ancestry populations and reveal African-ancestry associations with heterogeneous effects. We further replicated these findings using the proteomic data available from the UK Biobank Pharma Proteomics Project and tested the effect of protein quantity in association with select phenotypes. Population branch statistics were also constructed to examine whether protein-genetic instruments under natural selection could lead to significant protein-outcome associations specific to the African ancestry.

Results: We identified 115 robust protein target-outcome associations in African-ancestry populations. Among these, 51 demonstrated heterogeneous effects between African- and European-ancestry populations. We further replicated 4 cross-platform African-ancestry associations in the UK Biobank Pharma Proteomics Project and also revealed 4 significant, direct associations between protein levels and phenotypes. Ultimately, based on our prioritization criteria, we found that CD36 (glycoprotein IIIb), APOC1 (apolipoprotein C1), GSTA1 (glutathione S-transferase alpha 1), and FOLH1 (folate hydrolase 1) were shown to influence lipids and heart diseases, and were uniquely represented in African-ancestry populations. In addition, using population branch statistics, we showed that 47.5% of the 115 significant protein-outcome associations were possibly driven by cis-acting protein quantitative trait loci under natural selection.

Conclusions: Multiple lines of evidence were used to interrogate proteomic determinants of cardiometabolic diseases and traits in African-ancestry populations. We highlighted actionable circulating protein targets that could represent potential drug targets for cardiovascular diseases specific to populations with African ancestry.

Background: Cardiac involvement is the main determinant of adverse outcomes in Fabry disease. The study aimed to investigate cardiovascular outcomes in patients with Fabry disease.

Methods: This was a multicenter, retrospective, longitudinal study of consecutively referred adult patients with Fabry disease. The primary end point was the occurrence of major adverse cardiovascular events defined as a composite of cardiovascular death, major arrhythmic events, bradyarrhythmias requiring pacemaker implantation, and stroke.

Results: A total of 680 patients (age, 42.3±15.9 years; 41.0% male; 68.7% on disease-specific therapy) were included. During a median follow-up of 7.1 (interquartile range, 3.9-11.6) years, 92 patients (13.5%) experienced a major adverse cardiovascular event. At 10 years, freedom from major adverse cardiovascular event was 85.1% (95% CI, 81.3-88.2) and was lower in males compared with females (76.1% [95% CI, 68.9-81.9] versus 91.3% [95% CI, 87.0-94.2]; log-rank χ²=26.9; P<0.001). On multivariable analysis, age (hazard ratio, 1.04 [95% CI, 1.01-1.06] per 1 year; P<0.001), estimated glomerular filtration rate (hazard ratio, 0.99 [95% CI, 0.98-0.99] per 1 mL/min per 1.73 m²; P<0.001), QRS interval (hazard ratio, 1.02 [95% CI, 1.01-1.03] per 1 ms; P=0.002), and left ventricular mass index (hazard ratio, 1.01 [95% CI, 1.00-1.01] per 1 g/m²; P=0.032) were independent predictors of major adverse cardiovascular events during follow-up.

Conclusions: This study shows that the prevention and treatment of cardiovascular disease remain an unmet need for patients with Fabry disease.

Background: Spontaneous coronary artery dissection (SCAD) is an uncommon cause of myocardial infarction that disproportionately affects women, particularly during pregnancy and the peripartum period. Limited understanding of its underlying pathophysiology hinders the development of effective preventive and therapeutic strategies.

Methods: This study investigated associations between genetically predicted circulating proteins and tissue-specific RNA levels with genetically predicted SCAD risk using Mendelian randomization and Bayesian colocalization. Genetic scores for >1500 circulating proteins were derived from the UK Biobank (N=34 557) and deCODE (N=35 559). Scores for 13 848 gene transcripts in arterial and fibroblast tissues were generated from Genotype-Tissue Expression data. Associations between these scores and SCAD were assessed in a genome-wide association study meta-analysis of 1917 individuals with SCAD and 9292 controls. Findings were validated in vitro using mass spectrometry-based proteomic analysis of extracellular vesicles from 50 patients with SCAD and 50 healthy controls.

Results: Genetic associations of 4 circulating proteins with SCAD (AFAP1 [actin filament-associated protein 1], ECM1 [extracellular matrix protein 1], SPON1 [spondin 1], and STAT6 [signal transducer and activator of transcription 6]) were identified. Two were supported by gene expression data (AFAP1 and ECM1), and one by tissue-specific Bayesian colocalization analyses (ECM1). Protein interaction mapping identified potential shared pathways through the JAK-STAT (Janus kinases and signal transducers and activators of transcription) signaling pathway and inflammatory regulation. Mass spectrometry-based proteomic analysis demonstrated that ECM1 was significantly upregulated in SCAD cases versus controls.

Conclusions: Integrative analysis of proteomic, transcriptomic, and experimental data revealed 4 circulating proteins genetically associated with SCAD risk, with ECM1 emerging as a key protein with a likely causal role in SCAD pathogenesis. These findings highlight biological pathways for mechanistic studies and protein targets for potential therapeutic interventions.

Background: NPs (natriuretic peptides) are bioactive hormones crucial for regulating blood pressure, glucose homeostasis, and lipid metabolism. Despite the high heritability of circulating NP levels, the genetic determinants of NP regulation, particularly across ancestries and sexes, remain poorly understood. The objective of the current study was to identify genetic variants associated with NT-proBNP (N-terminal pro-B-type NP) levels in a multiancestry study population.

Methods: Whole genome sequencing and array-based data from 81 213 individuals without heart failure were analyzed from the Trans-Omics for Precision Medicine cohorts, UK Biobank, All of Us Research Program, and REGARDS (Reasons for Geographic and Racial Differences in Stroke) study to identify common, rare, and structural variants associated with NT-proBNP levels. The main outcome of the study was rank-based inverse normal and standardized NT-proBNP levels. Genetic associations with NT-proBNP were examined, followed by gene prioritization, transcriptome-wide association studies, colocalization, and rare variant analyses.

Results: Nine novel loci and 3 previously reported loci were identified to be associated with NT-proBNP levels. Novel structural variants were detected across 12 loci. Similar effect sizes were observed for both common and rare variants. Key genes such as BAG3 (10q26.11) and SLC39A8 (4q24) were identified through gene prioritization, with prior animal models supporting their therapeutic relevance. Rare variant analysis identified 6 masks with significant associations, specifically non-coding masks, suggesting regulatory modulation of NT-proBNP.

Conclusions: This study identifies novel common, rare, and structural variants associated with NT-proBNP levels, highlighting the contribution of both coding and regulatory non-coding variation. These findings advance our understanding of the genetic architecture of NT-proBNP and may inform future cardiometabolic therapeutic strategies.