Circulation: Genomic and Precision Medicine最新文献

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: 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.

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: Anthracyclines induce cardiotoxicity via DNA double-strand breaks and reactive oxygen species formation, resulting in cardiomyocyte dysfunction. The role of DNA damage response/repair (DDR) genes in anthracycline-induced cardiomyopathy remains unstudied.

Methods: We conducted a gene-based and pathway-based analysis to examine the main effect and gene-anthracycline interaction effect between DDR genes and anthracycline-induced cardiomyopathy. A discovery analysis performed with a matched case-control set of anthracycline-exposed non-Hispanic White childhood cancer survivors from Children's Oncology Group-ALTE03N1 (113 cases; 226 controls) was replicated using a cohort of anthracycline-exposed non-Hispanic White childhood cancer survivors from the Childhood Cancer Survivor Study cohort (n=1658; 97 cases). Functional analyses were performed by examining the response to doxorubicin of human-induced pluripotent stem cell-derived cardiomyocytes with CRISPR/Cas9-mediated knockout of prioritized genes.

Results: Successfully replicated DDR genes demonstrating main-effect association included FANCC (P=0.037) and XRCC5 (P=0.001) and demonstrated gene-anthracycline interaction included MGMT (P=0.041). Knockouts of FANCC and MGMT in human-induced pluripotent stem cell-derived cardiomyocytes demonstrated significant resistance to doxorubicin, suggesting that these genes play a role in anthracycline-induced cardiotoxicity. Successfully replicated DDR pathways demonstrating main-effect association included base excision repair (P=2.7×10^-4); role of BRCA1 in DDR (P=9.2×10^-5); p53 signaling (P<1×10^-16); role of checkpoint kinases proteins in cell cycle checkpoint control (P<1×10^-16); mismatch repair (P<10^-16); and double-strand break repair by homologous recombination (P<1×10^-16). Successfully replicated DDR pathways demonstrating significant interaction effects included role of BRCA1 in DDR (P=1.4×10^-4); p53 signaling (P<1×10^-16); the role of checkpoint kinases proteins in cell cycle checkpoint control (P<1×10^-16); mismatch repair (P<1×10^-16); cell cycle: G2/M DNA damage checkpoint regulation (P=0.002); double-strand break repair by homologous recombination (P=0.009); GADD45 signaling (P=4.8×10^-4); and cell cycle control of chromosomal replication (P=4.5×10^-4).

Conclusions: These findings provide evidence for the role of DDR genes and pathways in anthracycline-induced cardiomyopathy and provide a framework for targeted therapeutic interventions.

Background: In the MI-GENES clinical trial (URL: https://www.clinicaltrials.gov; Unique identifier: NCT01936675), participants at intermediate risk of coronary heart disease (CHD) were randomized to receive a Framingham risk score (Framingham risk score group, n=103) or an integrated risk score (integrated risk score group [IRS_g], n=104) that additionally included a polygenic risk score. After 6 months, IRS_g participants had higher statin initiation and lower low-density lipoprotein cholesterol. We conducted a post hoc 10-year follow-up analysis to investigate whether disclosure of a polygenic risk score for CHD was associated with a reduction in major adverse cardiovascular events (MACE).

Methods: Participants were followed from randomization in October 2013 to September 2023 to ascertain MACE, testing for CHD, and changes in risk factors. The primary outcome was time to first MACE, defined as cardiovascular death, nonfatal myocardial infarction, coronary revascularization, and nonfatal stroke. Statistical analyses included Cox proportional hazards regression and linear mixed-effects models.

Results: We followed all participants who completed the trial, 100 in Framingham risk score group and 103 in IRS_g (mean age at the end of follow-up, 68.2±5.2; 48% male). During a median follow-up of 9.5 years, 9 MACEs occurred in Framingham risk score group and 2 in IRS_g (hazard ratio, 0.20 [95% CI, 0.04-0.94]; P=0.042). In Framingham risk score group, 47 (47%) underwent at least 1 diagnostic test for CHD, compared with 30 (29%) in IRS_g (hazard ratio, 0.51 [95% CI, 0.32-0.81]; P=0.004). A higher proportion of IRS_g participants were on statin therapy during the first 4 years postrandomization and had a greater reduction in low-density lipoprotein cholesterol for up to 3 years postrandomization. No significant differences were observed between 2 groups in other traditional cardiovascular risk factors during follow-up.

Conclusions: Disclosure of an integrated risk score that included a polygenic risk score to individuals at intermediate risk for CHD was associated with lower MACE incidence after 10 years, likely due to higher statin initiation, leading to lower low-density lipoprotein cholesterol levels.