Circulation: Genomic and Precision Medicine最新文献

Background: Most polygenic risk scores (PRS) have been developed in European populations, frequently leading to limited transferability across diverse ancestry populations. This study aimed to develop and evaluate PRS for blood pressure (BP) traits in continental African populations and investigate how African genetic diversity influences PRS performance.

Methods: We generated PRS for systolic BP, diastolic BP, pulse pressure, and hypertension. We used a pan-African cohort as the target population and compared single-ancestry and multi-ancestry PRS methods. We compared the performance of African ancestry-derived PRS against multi-ancestry PRS on the entire data set and within South, East, and West African subpopulations.

Results: Multi-ancestry PRS demonstrated significantly higher predictive accuracy compared with single-ancestry PRS models. PRS predictive accuracy varied across different African regions, with the highest performance observed in East Africa. In the combined population, the difference in mean BP values between the first multi-ancestry PRS quartile and the top quartile was 6.53 (95% CI, 5.3-7.74), 3.81 (95% CI, 3.9-4.52), and 3.59 (95% CI, 2.4-4.32) mm Hg for systolic BP, diastolic BP, and pulse pressure, respectively. Individuals in the highest PRS risk quartile had odds of hypertension that were 1.47 (95% CI, 1.7-1.69) times greater than those in the lowest risk quartile.

Conclusions: These findings highlight the importance of integrating diverse ancestries in PRS development and accounting for subpopulation genetic variation to improve the predictive accuracy of BP PRS in African populations.

Background: The genetic risk of intracranial aneurysm (IA) development has been ascribed to the genetic risk of smoking exposure and hypertension. The relationship of IA to other cardiovascular traits and the contribution of IA risk loci to aberrant gene programs within cerebrovascular cell types remains unclear.

Methods: We performed a genome-wide association study in the Million Veteran Program and Finnish cohort study testing association of roughly 25 million DNA variants with unruptured IA (4694 cases and 877 091 controls) in individuals of European, African, and Hispanic ancestries. Meta-analysis with publicly available summary statistics generated a final cohort of 15 438 cases and 1 183 973 controls. We constructed a cerebrovascular single-nuclear RNA sequencing data set and integrated IA summary statistics to prioritize candidate causal cell types. We constructed a polygenic risk score to identify patients at risk of developing IA.

Results: We identified 5 novel associations with IA, increasing the number of known susceptibility loci to 22. At these susceptibility loci, we prioritized 17 candidate causal genes. We found a significant positive genetic correlation of IA with coronary artery disease and abdominal aortic aneurysm. Integration of an IA gene set with cerebrovascular single-nuclear RNA sequencing data revealed a significant association with pericytes and smooth muscle cells. Finally, a polygenic risk score was significantly associated with IA across European (odds ratio, 1.87 [95% CI, 1.61-2.17]; P=8.8×10^-17), African (odds ratio, 1.62 [95% CI, 1.19-2.15]; P=1.2×10^-3), and Hispanic (odds ratio, 2.28 [95% CI, 1.47-3.38]; P=1.0×10^-4) ancestries.

Conclusions: Here, we identify 5 novel loci associated with IA. Integration of summary statistics with cerebrovascular single-nuclear RNA sequencing reveals an association of cell types involved in matrix production. We validated a polygenic risk score that predicts IA, controlling for demographic variables including smoking status and blood pressure. Our findings suggest that a deficit in matrix production may drive IA pathogenesis independent of hypertension and smoking.

Background: This study aimed to evaluate the prevalence of pathogenic/likely pathogenic cardiomyopathy variant carriers in a multiancestry US population and examine the risk of adverse clinical outcomes.

Methods: This retrospective cohort study included multiancestry US adults aged ≥18 years with sequencing data from the All of Us Research Program. Pathogenic/likely pathogenic variants in cardiomyopathy genes were identified using the ClinVar database. The primary outcome was heart failure. Secondary outcomes included cardiomyopathy and arrhythmia. Outcomes were identified from electronic health records. Interval-censored Cox models, taking age on the timescale, were used to assess the risk of outcomes in pathogenic/likely pathogenic variant carriers with noncarriers as the reference group.

Results: Among 167 435 individuals (median age, 55.2 [39.5-66.3] years; 61.7% female; 40.7% non-European ancestry) included, the prevalence of pathogenic/likely pathogenic cardiomyopathy variant carriers was 0.7% in the overall population and 0.8%, 0.8%, 0.5%, and 1.2% among European, African, East Asian, and South Asian ancestry individuals, respectively. Over their lifetime, there were 12 867 heart failure events (205 in carriers and 12 662 in noncarriers), with an incidence rate of 3.05 (95% CI, 2.66-3.49) per 1000 person-years in carriers and 1.37 (95% CI, 1.35-1.40) in noncarriers (adjusted hazard ratio, 2.30 [95% CI, 2.04-2.60]). Cardiomyopathy occurred in 5164 (161 in carriers and 5003 in noncarriers), with an incidence rate of 2.38 (95% CI, 2.04-2.78) per 1000 person-years among carriers and 0.54 (95% CI, 0.53-0.56) in noncarriers (adjusted hazard ratio, 4.31 [95% CI, 3.73-4.97]). There were 19 405 arrhythmia events (263 in carriers and 19 142 in noncarriers), with an incidence rate of 3.93 (95% CI, 3.48-4.44) per 1000 person-years among carriers and 2.09 (95% CI, 2.06-2.12) in noncarriers (adjusted hazard ratio, 2.12 [95% CI, 1.78-2.53]).

Conclusions: Pathogenic/likely pathogenic cardiomyopathy variant carriers have an increased risk of heart failure, cardiomyopathy, and arrhythmias. Despite the modest overall prevalence, the associated risks suggest potential benefits of targeted genetic screening for early detection and management.

Background: Nonischemic cardiomyopathies are frequently caused by genetic mutations in about 100 different genes. The cardiomyopathy-associated gene DES encodes the intermediate filament protein desmin, which is important for the structural integrity of the cardiomyocytes.

Methods: Using a next-generation sequencing approach, we performed cascade screening of a previously identified heterozygous DES missense mutation (c.380G>C, p.R127P) segregating in a large 6-generation Kuwaiti family, where several members died from sudden cardiac death or developed different cardiomyopathies, partially in combination with conduction disease and atrial fibrillation. DES-p.R127P affects a highly conserved position and is absent or super rare in different genetic human population databases. In silico predictions support the pathogenicity of DES-p.R127P. To investigate the detrimental impact of desmin-p.R127P, we performed cell transfection experiments using different cell lines and cardiomyocytes derived from induced pluripotent stem cells in combination with confocal microscopy.

Results: These experiments demonstrated a severe desmin filament assembly defect leading to aberrant cytoplasmic desmin aggregates, even when co-expressed with wild-type desmin. Atomic force microscopy analysis supported the filament assembly defect of mutant recombinant desmin-p.R127P. To investigate the physicochemical impact of the amino acid at this position, we generated a set of 20 different variants and analyzed their filament formation in cell culture. Most of these variants disturbed the filament assembly comparable to p.R127P.

Conclusions: In summary, we present and characterize a likely pathogenic missense mutation DES-p.R127P, which causes high cardiac mortality and morbidity in the described family. Our study has relevance for the interpretation and classification of further DES variants and might be helpful for the genetic counseling of patients and their relatives in future cases.

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.

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.