Previous studies have revealed that patients with hypertrophic cardiomyopathy(HCM)exhibit differences in symptom severity and prognosis,indicating potential HCM subtypes among these patients.Here,793 patients with HCM...Previous studies have revealed that patients with hypertrophic cardiomyopathy(HCM)exhibit differences in symptom severity and prognosis,indicating potential HCM subtypes among these patients.Here,793 patients with HCM were recruited at an average follow-up of 32.78±27.58 months to identify potential HCM subtypes by performing consensus clustering on the basis of their echocardiography features.Furthermore,we proposed a systematic method for illustrating the relationship between the phenotype and genotype of each HCM subtype by using machine learning modeling and interactome network detection techniques based on whole-exome sequencing data.Another independent cohort that consisted of 414 patients with HCM was recruited to replicate the findings.Consequently,two subtypes characterized by different clinical outcomes were identified in HCM.Patients with subtype 2 presented asymmetric septal hypertrophy associated with a stable course,while those with subtype 1 displayed left ventricular systolic dysfunction and aggressive progression.Machine learning modeling based on personal whole-exome data identified 46 genes with mutation burden that could accurately predict subtype propensities.Furthermore,the patients in another cohort predicted as subtype 1 by the 46-gene model presented increased left ventricular end-diastolic diameter and reduced left ventricular ejection fraction.By employing echocardiography and genetic screening for the 46 genes,HCM can be classified into two subtypes with distinct clinical outcomes.展开更多
MicroRNAs(miRNAs)are aberrantly expressed in the pathophysiologic process of heart failure(HF).However,the functions of a certain miRNA in different cardiac cell types during HF are scarcely reported,which might be co...MicroRNAs(miRNAs)are aberrantly expressed in the pathophysiologic process of heart failure(HF).However,the functions of a certain miRNA in different cardiac cell types during HF are scarcely reported,which might be covered by the globe effects of it on the heart.In the current study,Langendorff system was applied to isolate card io myocytes(CMs)and cardiac fibroblasts(CFs)from transverse aortic constriction(TAC)-induced mice.Slight increase of miR-320 expression was observed in the whole heart tissue of TAC mice.Interestingly,miR-320 was significantly elevated in CMs but decreased in CFs from TAC mice at different time points.Then,recombinant adeno-associated virus 9 with cell-type-specific promoters were used to manipulate miR-320 expressions in vivo.Both in vitro and in vivo experiments showed the miR-320 overexpression in CMs exacerbated cardiac dysfunction,whereas overexpression of miR-320 in CFs alleviated cardiac fibrosis and hypertrophy.Mechanically,downstream signaling pathway analyses revealed that miR-320 might induce various effects via targeting PLEKHM3 and IFITM1 in CMs and CFs,respectively.Moreover,miR-320 mediated effects could be abolished by PLEKHM3 re-expression in CMs or IFITM1 re-expression in CFs.Interestingly,miR-320 treated CFs were able to indirectly affect CMs function,but not vice versa.Meanwhile,upstream signaling pathway analyses showed that miR-320 expression and decay rate were rigorously manipulated by Ago2,which was regulated by a cluster of cell-type-specific TFs distinctively expressed in CMs and CFs,respectively.Together,we demonstrated that miR-320 functioned differently in various cell types of the heart during the progression of HF.展开更多
To reveal genetic risks of early-onset sporadic dilated cardiomyopathy(DCM) patients in the Chinese Han population, we enlisted 363 DCM cases and 414 healthy controls. Whole-exome sequencing and phenotypic characteriz...To reveal genetic risks of early-onset sporadic dilated cardiomyopathy(DCM) patients in the Chinese Han population, we enlisted 363 DCM cases and 414 healthy controls. Whole-exome sequencing and phenotypic characterization were conducted. In total, we identified 26 loss-of-function(LOF) candidates and 66 pathogenic variants from 33 genes, most of which were novel.The deleterious variants can account for 25.07%(91/363) of all patients. Furthermore, rare missense variants in 21 genes were found to be significantly associated with DCM in burden tests. Other than rare variants, twelve common SNPs were significantly associated with an increased risk of DCM in allele-based genetic model association analysis. Of note, in the cumulative risk model, high-risk subjects had a 3.113-fold higher risk of developing DCM than low-risk subjects. Also, DCM in the high-risk group had a younger age of onset than that in the low-risk group. In terms of cardiac function, the mean left ventricular ejection fraction of patients with the deleterious variants was lower than those without(27.73%±10.02% vs. 30.61%±10.85%, P=0.026).To conclude, we mapped a comprehensive atlas of genetic risks in Chinese patients with DCM that might lead to new insights into the mechanisms and risk stratification for DCM.展开更多
Thoracic aortic dissection(TAD)without familial clustering or syndromic features is known as sporadic TAD(STAD).So far,the genetic basis of STAD remains unknown.Whole exome sequencing was performed in 223 STAD patient...Thoracic aortic dissection(TAD)without familial clustering or syndromic features is known as sporadic TAD(STAD).So far,the genetic basis of STAD remains unknown.Whole exome sequencing was performed in 223 STAD patients and 414 healthy controls from the Chinese Han population(N=637).After population structure and genetic relationship and ancestry analyses,we used the optimal sequence kernel association test to identify the candidate genes or variants of STAD.We found that COL3A1 was significantly relevant to STAD(P=7.35×10^(−6))after 10000 times permutation test(P=2.49×10^(−3)).Moreover,another independent cohort,including 423 cases and 734 non-STAD subjects(N=1157),replicated our results(P=0.021).Further bioinformatics analysis showed that COL3A1 was highly expressed in dissected aortic tissues,and its expression was related to the extracellular matrix(ECM)pathway.Our study identified a profile of known heritable TAD genes in the Chinese STAD population and found that COL3A1 could increase the risk of STAD through the ECM pathway.We wanted to expand the knowledge of the genetic basis and pathology of STAD,which may further help in providing better genetic counseling to the patients.展开更多
基金the National Key R&D Program of China(No.2017YFC0909400)the National Natural Science Foundation of China(Nos.91439203,91839302,and 81700413)+1 种基金Shanghai Municipal Science and Technology Major Project(No.2017SHZDZX01)the Fundamental Research Funds for the Central Universities,HUST(No.2016JCTD117).
文摘Previous studies have revealed that patients with hypertrophic cardiomyopathy(HCM)exhibit differences in symptom severity and prognosis,indicating potential HCM subtypes among these patients.Here,793 patients with HCM were recruited at an average follow-up of 32.78±27.58 months to identify potential HCM subtypes by performing consensus clustering on the basis of their echocardiography features.Furthermore,we proposed a systematic method for illustrating the relationship between the phenotype and genotype of each HCM subtype by using machine learning modeling and interactome network detection techniques based on whole-exome sequencing data.Another independent cohort that consisted of 414 patients with HCM was recruited to replicate the findings.Consequently,two subtypes characterized by different clinical outcomes were identified in HCM.Patients with subtype 2 presented asymmetric septal hypertrophy associated with a stable course,while those with subtype 1 displayed left ventricular systolic dysfunction and aggressive progression.Machine learning modeling based on personal whole-exome data identified 46 genes with mutation burden that could accurately predict subtype propensities.Furthermore,the patients in another cohort predicted as subtype 1 by the 46-gene model presented increased left ventricular end-diastolic diameter and reduced left ventricular ejection fraction.By employing echocardiography and genetic screening for the 46 genes,HCM can be classified into two subtypes with distinct clinical outcomes.
基金supported by grant from the National Natural Science Foundation of China(nos.81822002,31771264,31800973,and 81630010).
文摘MicroRNAs(miRNAs)are aberrantly expressed in the pathophysiologic process of heart failure(HF).However,the functions of a certain miRNA in different cardiac cell types during HF are scarcely reported,which might be covered by the globe effects of it on the heart.In the current study,Langendorff system was applied to isolate card io myocytes(CMs)and cardiac fibroblasts(CFs)from transverse aortic constriction(TAC)-induced mice.Slight increase of miR-320 expression was observed in the whole heart tissue of TAC mice.Interestingly,miR-320 was significantly elevated in CMs but decreased in CFs from TAC mice at different time points.Then,recombinant adeno-associated virus 9 with cell-type-specific promoters were used to manipulate miR-320 expressions in vivo.Both in vitro and in vivo experiments showed the miR-320 overexpression in CMs exacerbated cardiac dysfunction,whereas overexpression of miR-320 in CFs alleviated cardiac fibrosis and hypertrophy.Mechanically,downstream signaling pathway analyses revealed that miR-320 might induce various effects via targeting PLEKHM3 and IFITM1 in CMs and CFs,respectively.Moreover,miR-320 mediated effects could be abolished by PLEKHM3 re-expression in CMs or IFITM1 re-expression in CFs.Interestingly,miR-320 treated CFs were able to indirectly affect CMs function,but not vice versa.Meanwhile,upstream signaling pathway analyses showed that miR-320 expression and decay rate were rigorously manipulated by Ago2,which was regulated by a cluster of cell-type-specific TFs distinctively expressed in CMs and CFs,respectively.Together,we demonstrated that miR-320 functioned differently in various cell types of the heart during the progression of HF.
基金supported by the National Key Research and Development Program of China (2017YFC0909400)the National Natural Science Foundation of China (91439203, 81630010 and 91839302)+3 种基金Shanghai Municipal Science and Technology Major Project (2017SHZDZX01)the Fundamental Research Funds for the Central Universities (2015ZDTD044 and 2016JCTD117)the Graduate Innovation and Entrepreneurship Funds of Huazhong University of Science and Technology (2018JYCXJJ004)Tongji Hospital Clinical Research Flagship Program (2019CR207 and 2019YBKY019)
文摘To reveal genetic risks of early-onset sporadic dilated cardiomyopathy(DCM) patients in the Chinese Han population, we enlisted 363 DCM cases and 414 healthy controls. Whole-exome sequencing and phenotypic characterization were conducted. In total, we identified 26 loss-of-function(LOF) candidates and 66 pathogenic variants from 33 genes, most of which were novel.The deleterious variants can account for 25.07%(91/363) of all patients. Furthermore, rare missense variants in 21 genes were found to be significantly associated with DCM in burden tests. Other than rare variants, twelve common SNPs were significantly associated with an increased risk of DCM in allele-based genetic model association analysis. Of note, in the cumulative risk model, high-risk subjects had a 3.113-fold higher risk of developing DCM than low-risk subjects. Also, DCM in the high-risk group had a younger age of onset than that in the low-risk group. In terms of cardiac function, the mean left ventricular ejection fraction of patients with the deleterious variants was lower than those without(27.73%±10.02% vs. 30.61%±10.85%, P=0.026).To conclude, we mapped a comprehensive atlas of genetic risks in Chinese patients with DCM that might lead to new insights into the mechanisms and risk stratification for DCM.
基金This work was supported by the National Natural Science Foundation of China(Nos.91839302,91439203,and 81700413)the National Key R&D Program of China(No.2017YFC0909400)the Municipal Science and Technology Major Project(No.2017SHZDZX01).
文摘Thoracic aortic dissection(TAD)without familial clustering or syndromic features is known as sporadic TAD(STAD).So far,the genetic basis of STAD remains unknown.Whole exome sequencing was performed in 223 STAD patients and 414 healthy controls from the Chinese Han population(N=637).After population structure and genetic relationship and ancestry analyses,we used the optimal sequence kernel association test to identify the candidate genes or variants of STAD.We found that COL3A1 was significantly relevant to STAD(P=7.35×10^(−6))after 10000 times permutation test(P=2.49×10^(−3)).Moreover,another independent cohort,including 423 cases and 734 non-STAD subjects(N=1157),replicated our results(P=0.021).Further bioinformatics analysis showed that COL3A1 was highly expressed in dissected aortic tissues,and its expression was related to the extracellular matrix(ECM)pathway.Our study identified a profile of known heritable TAD genes in the Chinese STAD population and found that COL3A1 could increase the risk of STAD through the ECM pathway.We wanted to expand the knowledge of the genetic basis and pathology of STAD,which may further help in providing better genetic counseling to the patients.