Circulation: Genomic and Precision Medicine最新文献

Calmodulin, a protein critically important for the regulation of all major cardiac ion channels, is the quintessential cellular calcium sensor and plays a key role in preserving cardiac electrical stability. Its unique importance is highlighted by the presence of 3 genes in 3 different chromosomes encoding for the same protein and by their extreme conservation. Indeed, all 3 calmodulin (CALM) genes are among the most constrained genes in the human genome, that is, the observed variants are much less than expected by chance. Not surprisingly, CALM variants are poorly tolerated and accompany significant clinical phenotypes, of which the most important are those associated with increased risk for life-threatening arrhythmias. Here, we review the current knowledge about calmodulin, its specific physiological, structural, and functional characteristics, and its importance for cardiovascular disease. Given our role in the development of this knowledge, we also share some of our views about currently unanswered questions, including the rational approaches to the clinical management of the affected patients. Specifically, we present some of the most critical information emerging from the International Calmodulinopathy Registry, which we established 10 years ago. Further progress clearly requires deep phenotypic information on as many carriers as possible through international contributions to the registry, in order to expand our knowledge about Calmodulinopathies and guide clinical management.

Background: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. However, the current understanding of its underlying biological pathways remains limited.

Methods: In this study, we performed a cross-platform proteome- and transcriptome-wide genetic analysis aimed at evaluating the causal relevance of >2000 circulating proteins with preeclampsia, supported by data on the expression of over 15 000 genes across 36 tissues leveraging large-scale preeclampsia genetic association data from women of European ancestry.

Results: We demonstrate genetic associations of 18 circulating proteins with preeclampsia (SULT1A1 [sulfotransferase 1A1], SH2B3 [SH2B adapter protein 3], SERPINE2 [serpin family E member 2], RGS18 [regulator of G-protein signaling 18], PZP [pregnancy zone protein], NOTUM [notum, palmitoleoyl-protein carboxylesterase], METAP1 [methionyl aminopeptidase 1], MANEA [mannosidase endo-alpha], jun-D [JunD proto-oncogene], GDF15 [growth differentiation factor 15], FGL1 [fibrinogen like 1], FGF5 [fibroblast growth factor 5], FES [FES proto-oncogene], APOBR [apolipoprotein B receptor], ANP [natriuretic peptide A], ALDH-E2 [aldehyde dehydrogenase 2 family member], ADAMTS13 [ADAM metallopeptidase with thrombospondin type 1 motif 13], and 3MG [N-methylpurine DNA glycosylase]), among which 11 were either directly or indirectly supported by gene expression data, 9 were supported by Bayesian colocalization analyses, and 5 (SERPINE2, PZP, FGF5, FES, and ANP) were supported by all lines of evidence examined. Protein interaction mapping identified potential shared biological pathways through natriuretic peptide signaling, blood pressure regulation, immune tolerance, and thrombin activity regulation.

Conclusions: This investigation identified multiple targetable proteins linked to cardiovascular, inflammatory, and coagulation pathways, with SERPINE2, PZP, FGF5, FES, and ANP identified as pivotal proteins with likely causal roles in the development of preeclampsia. The identification of these potential targets may guide the development of targeted therapies for preeclampsia.

Background: Coronary atherosclerotic burden and adverse coronary heart disease events are related phenotypes with likely shared genetic cause.

Methods: We analyzed 6021 patients with available coronary angiography, genotyping, and exome sequencing data. We tested for associations of polygenic risk scores for coronary heart disease (PRS_CHD) with multiple measures of coronary artery disease (CAD) severity. We assessed the joint associations of PRS_CHD and pathogenic/likely pathogenic variants in 3 familial hypercholesterolemia genes, with CAD severity. We performed mediation analyses to explore whether CAD severity mediated the association of PRS_CHD with prevalent coronary heart disease and incident myocardial infarction.

Results: A 1-SD increase in PRS_CHD was associated with multiple measures of CAD severity, including the log Gensini score (β, 0.31 [95% CI, 0.28-0.33]). Carrying a pathogenic/likely pathogenic familial hypercholesterolemia variant was associated with a higher log Gensini score after adjustment for PRS_CHD (β, 0.21 [95% CI, 0.03-0.38]). A 1-SD increase in PRS_CHD was associated with incident myocardial infarction over a mean follow-up of 9.2 years (hazard ratio, 1.20 [95% CI, 1.13-1.27]; P=5×10^-10), and the Gensini score mediated 90% of this association.

Conclusions: PRS_CHD was associated with multiple measures of CAD severity. The association of PRS_CHD with incident myocardial infarction was almost fully mediated by CAD severity, indicating a considerable genetic overlap between the 2 phenotypes.

Background: Genetic testing for cardiac channelopathies is the standard of care. However, many rare genetic variants remain classified as variants of uncertain significance (VUS) due to lack of epidemiological and functional data. Whether deep protein language models may aid in VUS resolution remains unknown. Here, we set out to compare how 2 deep protein language models perform at VUS resolution in the 3 most common long-QT syndrome-causative genes compared with the gold-standard patch clamp.

Methods: A total of 72 rare nonsynonymous VUS (9 KCNQ1, 19 KCNH2, and 50 SCN5A) were engineered by site-directed mutagenesis and expressed in either HEK293 cells or TSA201 cells. Whole-cell patch-clamp technique was used to functionally characterize these variants. The protein language models, evolutionary scale modeling, version 1b and AlphaMissense, were used to predict the variant effect of missense variants and compared with patch clamp.

Results: Considering variants in all 3 genes, the evolutionary scale modeling, version 1b model had a receiver operating characteristic curve-area under the curve of 0.75 (P=0.0003). It had a sensitivity of 88% and a specificity of 50%. AlphaMissense performed well compared with patch-clamp with an receiver operating characteristic curve-area under the curve of 0.85 (P<0.0001), sensitivity of 80%, and specificity of 76%.

Conclusions: Deep protein language models aid in VUS resolution with high sensitivity but lower specificity. Thus, these tools cannot fully replace functional characterization but can aid in reducing the number of variants that may require functional analysis.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) occurs due to acquired mutations in bone marrow progenitor cells. CHIP confers a 2-fold risk of atherosclerotic cardiovascular disease. However, there are limited data regarding specific cardiovascular phenotypes. The purpose of this study was to define the coronary artery disease phenotype of the CHIP population-based on coronary angiography.

Methods: We recruited 1142 patients from the Vanderbilt University Medical Center cardiac catheterization laboratory and performed DNA sequencing to determine CHIP status. Multivariable logistic regression models and proportional odds models were used to assess the association between CHIP status and angiography phenotypes.

Results: We found that 18.4% of patients undergoing coronary angiography had a CHIP mutation. Those with CHIP had a higher risk of having obstructive left main (odds ratio, 2.44 [95% CI, 1.40-4.27]; P=0.0018) and left anterior descending (odds ratio, 1.59 [1.12-2.24]; P=0.0092) coronary artery disease compared with non-CHIP carriers. We additionally found that a specific CHIP mutation, ten eleven translocase 2 (TET2), has a larger effect size on left main stenosis compared with other CHIP mutations.

Conclusions: This is the first invasive assessment of coronary artery disease in CHIP and offers a description of a specific atherosclerotic phenotype in CHIP wherein there is an increased risk of obstructive left main and left anterior descending artery stenosis, especially among TET2 mutation carriers. This serves as a basis for understanding enhanced morbidity and mortality in CHIP.

Background: Accessory pathways are a common cause of supraventricular tachycardia (SVT) and can lead to sudden cardiac death in otherwise healthy children and adults when associated with Wolff-Parkinson-White syndrome. The goal of this study was to identify genetic variants within a large family with structurally normal hearts affected by SVT and Wolff-Parkinson-White syndrome and determine causality of the gene deficit in a corresponding mouse model.

Methods: Whole exome sequencing performed on 2 distant members of a 3-generation family in which multiple members were affected by SVT or Wolff-Parkinson-White pattern (preexcitation) on ECG identified MRC2 as a candidate gene. Serial electrocardiograms, intracardiac electrophysiology studies, echocardiography, optical mapping studies, and histology were performed on both Mrc2 mutant and WT (wild-type) mice.

Results: A rare HET (heterozygous) missense variant c.2969A>G;p.Glu990Gly (E990G) in MRC2 was identified as the leading candidate gene variant segregating with the cardiac phenotype following an autosomal-dominant Mendelian trait segregation pattern with variable expressivity. In vivo electrophysiology studies revealed reentrant SVT in E990G mice. Optical mapping studies in E990G mice demonstrated abnormal retrograde conduction, suggesting the presence of an accessory pathway. Histological analysis of E990G mouse hearts showed a disordered ECM (extracellular matrix) in the annulus fibrosus. Finally, Mrc2 knockdown in human cardiac fibroblasts enhanced accelerated cell migration.

Conclusions: This study identified a rare nonsynonymous variant in the MRC2 gene in individuals with familial reentrant SVT, Wolff-Parkinson-White ECG pattern, and structurally normal hearts. Furthermore, Mrc2 knock-in mice revealed an increased incidence of reentrant SVT and bypass tract formation in the setting of preserved cardiac structure and function.