Circulation: Genomic and Precision Medicine最新文献

Background: Patients with pulmonary hypertension (PH) are classified based on disease pathogenesis and hemodynamic drivers. Classification informs treatment. The heart failure biomarker NT-proBNP (N-terminal pro-B-type natriuretic peptide) is used to help inform risk but is not specific to PH or sub-classification groups. There are currently no other biomarkers in clinical use to help guide diagnosis or risk.

Methods: We profiled a retrospective cohort of 1150 patients from 3 expert centers with PH and 334 non-PH symptomatic controls (disease controls) from the United Kingdom to measure circulating levels of 650 microRNAs (miRNAs) in serum. NT-proBNP (ELISA) and 326 well-detected miRNAs (polymerase chain reaction) were prioritized by feature selection using multiple machine learning models. From the selected miRNAs, generalized linear models were used to describe miRNA signatures to differentiate PH and pulmonary arterial hypertension from the disease controls, and pulmonary arterial hypertension, PH due to left heart disease, PH due to lung disease, and chronic thromboembolic pulmonary hypertension from other forms of PH. These signatures were validated on a UK test cohort and independently validated in the prospective CIPHER study (A Prospective, Multicenter, Noninterventional Study for the Identification of Biomarker Signatures for the Early Detection of Pulmonary Hypertension) comprising 349 patients with PH and 93 disease controls.

Results: NT-proBNP achieved a balanced accuracy of 0.74 and 0.75 at identifying PH and pulmonary arterial hypertension from disease controls with a threshold of 254 and 362 pg/mL, respectively but was unable to sub-categorize PH subgroups. In the UK cohort, miRNA signatures performed similarly to NT-proBNP in distinguishing PH (area under the curve of 0.7 versus 0.78), and pulmonary arterial hypertension (area under the curve of 0.73 versus 0.79) from disease controls. MicroRNA signatures outperformed NT-proBNP in distinguishing PH classification groups. External testing in the CIPHER cohort demonstrated that miRNA signatures, in conjunction with NT-proBNP, age, and sex, performed better than either NT-proBNP or miRNAs alone in sub-classifying PH.

Conclusions: We suggest a threshold for NT-proBNP to identify patients with a high probability of PH, and the subsequent use of circulating miRNA signatures to help differentiate PH subgroups.

Background: Therapies targeting the LPL (lipoprotein lipase) pathway are under development for cardiometabolic disease. Insights into their efficacy-both alone and in combination with existing lipid-lowering therapies-modes of action, and safety of these agents are essential to inform clinical development. Using Mendelian randomization, we aimed to (1) evaluate efficacy, (2) explore shared mechanisms, (3) assess additive effects with approved lipid-lowering drugs, and (4) identify secondary indications and potential adverse effects.

Methods: We selected triglyceride-lowering genetic variants located in the genes encoding ANGPTL3 (angiopoietin-like 3), ANGPTL4 (angiopoietin-like 4), APOC3 (apolipoprotein C3), and LPL and conducted drug target Mendelian randomization on primary outcomes including coronary artery disease and type 2 diabetes, and secondary outcomes, including apolipoprotein B, waist-to-hip ratio, body mass index, and 233 metabolic biomarkers. We conducted interaction Mendelian randomization analyses in 488 139 UK Biobank participants to test the effect of combination therapy targeting the LPL and LDLR (low-density lipoprotein receptor) pathways. Finally, we investigated potential secondary indications and adverse effects by leveraging genetic association data on 1204 disease end points.

Results: Genetically predicted triglyceride lowering through the perturbation of LPL pathway activation targets ANGPTL4, APOC3, and LPL was associated with a lower risk of coronary artery disease and type 2 diabetes and lower apolipoprotein B. Genetically predicted triglyceride lowering through ANGPTL4 was associated with a lower waist-to-hip ratio, suggestive of a favorable body fat distribution. There was no evidence of a multiplicative interaction between genetically proxied perturbation of ANGPTL4, APOC3, and LPL and that of HMGCR (HMG-CoA reductase) and PCSK9 (proprotein convertase subtilisin/kexin type 9) on coronary artery disease and type 2 diabetes, consistent with additive effects. Finally, associations of genetically predicted LPL pathway targeting were supportive of the broad safety of these targets.

Conclusions: Our findings provide genetic evidence supporting the efficacy and safety of LPL pathway activation therapies for the prevention of coronary artery disease and type 2 diabetes, alone or in combination with statins or PCSK9 inhibitors.

Background: Whether prolonged and excessive alcohol consumption contributes to dilated cardiomyopathy (DCM) remains uncertain. This study aimed to describe the prevalence of alcohol use in patients with DCM and their first-degree relatives (FDRs) and determine if cumulative alcohol exposure associates with DCM/partial DCM or modifies the association of DCM with DCM-relevant rare variants.

Methods: All probands had DCM; FDRs were classified as with or without DCM or partial DCM. Alcohol exposure was measured with the Alcohol Use Disorder Identification Test-Consumption questionnaire and years of drinking. Rare variants in 36 DCM genes were classified as pathogenic, likely pathogenic, or variants of uncertain significance (pathogenic, likely pathogenic, variant of uncertain significance). Generalized linear mixed models were used to assess the association of DCM/partial DCM with alcohol use among FDRs.

Results: DCM/partial DCM was found in 21.8% of 1373 FDRs of 1148 DCM probands. The prevalence of former or current alcohol use was 68% for probands and 70% for FDRs. About 30% of probands and 37% of FDRs had positive Alcohol Use Disorder Identification Test-Consumption scores, indicating moderate or heavy drinking. Among FDRs, DCM/partial DCM was associated with the presence of pathogenic/likely pathogenic variants in DCM genes (odds ratio, 3.51 [95% CI, 2.33-5.29]) but not with alcohol exposure. Cumulative alcohol exposure was not found to modify the association between DCM/partial DCM and these variants (P=0.55).

Conclusions: Alcohol use was frequent among probands and FDRs. This study did not provide evidence supporting an association of cumulative alcohol exposure with DCM/partial DCM or a modifying effect of alcohol use on the association of DCM with DCM-relevant rare variants.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037632.

In recent years, there has been a considerable influx of publications assessing the penetrance of pathogenic variants associated with monogenic diseases with dominant inheritance. As large and diverse groups have been sequenced, it has become clear that incomplete penetrance is common to most hereditary diseases, as numerous molecular, genetic, or environmental factors can cause clinical diversity among the carriers of the same variant. In this review, we discuss some of these factors and focus on the existing approaches to estimating penetrance, depending on the data available and their application to different data sets. We also list some currently available large-scale data sets with penetrance estimates.

Background: Genetic disorders are prevalent in patients with congenital heart disease (CHD), but genetic evaluations are underutilized and nonstandardized. We sought to quantify a dysmorphology score and develop phenotype-based prediction models for genetic diagnoses in CHD.

Methods: We used a test-negative case-control study of inpatient infants (<1 year) with CHD undergoing standardized genetic evaluations. We quantified a novel dysmorphology score and combined it with other clinical variables used in multivariable logistic regression models to predict genetic diagnoses identified by genetic testing.

Results: Of 1008 patients, 24.1% (243/1008) had genetic diagnoses identified. About half of the cohort were either nondysmorphic or mildly dysmorphic with dysmorphology scores ≤2. There were higher dysmorphology scores according to CHD class (P=0.0007), extracardiac anomaly-positive status (P<0.0001), female sex (P=0.05), and genetic diagnosis identified (P<0.0001). Multivariable logistic regression models quantified this effect further: each +1 increase in the dysmorphology score was associated with a 17% to 20% increased risk of genetic diagnoses (odds ratios, 1.17-1.20, P<0.0001). Extracardiac anomaly-positive status remained a stronger predictor of genetic diagnoses (odds ratios, 2.81-3.39). Nonetheless, about 10% of the cohort were minimally dysmorphic (dysmorphology scores ≤2), had isolated CHD, and were found to have genetic diagnoses, indicating that dysmorphology-based screening can be used to risk-stratify but not exclude genetic diagnoses.

Conclusions: The dysmorphology score is a novel screen for patients with CHD at high risk of having genetic diagnoses identified by genetic testing, including disorders not easily recognized by clinicians. We used these results to develop predicted probability plots for genetic diagnoses in patients with CHD.

Background: Truncating variants (TTNtvs) in the titin (TTN) gene have been associated with cardiomyopathies or arrhythmias (C/A) and autosomal recessive neuromuscular diseases (NM). However, the clinical significance of TTNtvs across the entire coding sequence of TTN has not been comprehensively assessed. The purpose of this study was to examine the burden of TTNtvs in C/A and NM cases compared with controls in the genome aggregation database.

Methods: This was a retrospective study of probands who underwent multigene testing (49 740 C/A panel, 24 514 NM panel) that included TTN from November 2017 to October 2021. Burden testing was performed using controls in the genome aggregation database v3.1.2 database, and the analysis was stratified by exon/band location and exon usage in cardiac or skeletal muscle. Frequency and odds ratio of TTNtv alleles in C/A or NM cases and genome aggregation database controls were measured.

Results: There were 2446 (4.9%) C/A and 482 (2.0%) NM cases with 2446 and 528 TTNtv alleles, respectively. TTNtvs in all bands were significantly enriched in both C/A and NM cases compared with controls. A significant enrichment of TTNtvs in C/A was observed for exon 358 of the M-band (odds ratio, 2.55 [95% CI, 1.85-3.54]) but not the other M-band exons.

Conclusions: In the largest single-site cohort of C/A and NM cases with TTNtvs, an enrichment of TTNtvs across TTN was observed. These findings expand the clinically relevant regions of TTN.

Background: Pathogenic/likely pathogenic (LP) desmin (DES) variants cause heterogeneous cardiomyopathy and skeletal myopathy phenotypes. Limited data suggest a high incidence of major adverse cardiac events (MACEs), including cardiac conduction disease, sustained ventricular arrhythmias (VA), and heart failure (HF) events (HF hospitalization, left ventricular assist device/cardiac transplant, HF-related death) in patients with pathogenic/LP DES variants. However, pleiotropic presentation and small cohort sizes have limited clinical phenotype and outcome characterization. We aimed to describe the natural history, phenotype spectrum, familial penetrance and outcomes in patients with pathogenic/LP DES variants through a systematic review and individual patient data meta-analysis using published reports.

Methods: We searched Medline (PubMed) and Embase for studies that evaluated cardiac phenotypes in patients with pathogenic/LP DES variants. Cardiomyopathy diagnosis or occurrence of MACE was considered evidence of cardiac involvement/penetrance. Lifetime event-free survival from cardiac conduction disease, sustained VA, HF events, and composite MACE was assessed.

Results: Of the 4212 screened publications, 71 met the inclusion criteria. A total of 230 patients were included (52.6% men, 52.2% probands, median age: 31 years [22.0-42.8] at first evaluation, median follow-up: 3 years [0-11.0]). Overall, 124 (53.9%) patients were diagnosed with cardiomyopathy, predominantly dilated cardiomyopathy (14.8%), followed by restrictive cardiomyopathy (13.5%), whereas other forms were less common: arrhythmogenic cardiomyopathy (7.0%), hypertrophic cardiomyopathy (6.1%), arrhythmogenic right ventricular cardiomyopathy (5.2%), and other forms (7.4%). Overall, 132 (57.4%) patients developed MACE, with 96 (41.7%) having cardiac conduction disease, 36 (15.7%) sustained VA, and 43 (18.7%) HF events. Familial penetrance of cardiac disease was 63.6% among relatives with pathogenic/LP DES variants. Male sex was associated with an increased risk of sustained VA (hazard ratio, 2.28; P=0.02) and HF events (hazard ratio, 2.45; P=0.008).

Conclusions: DES cardiomyopathy exhibits heterogeneous phenotypes and a distinct natural history, characterized by high familial penetrance and a substantial MACE burden. Male patients face a higher risk of sustained VA events.