A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene

Ding, Yonghe; Long, Pamela A.; Bos, J. Martijn; Shih, Yu; Ma, Xiao; Sundsbak, Rhianna S.; Chen, Jianhua; Jiang, Yi-Wen; Zhao, Liqun; Hu, Xinyang; Wang, Jianan; Shi, Yongyong; Ackerman, Michael J.; Lin, Xueying; Ekker, Stephen C.; Redfield, Margaret M.; Olson, Timothy M.; Xu, Xiaolei

doi:10.1172/jci.insight.88797

Cited by 45 publications

(100 citation statements)

References 28 publications

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“…Recognizing this weakness, we scanned the literature for reported cardiac modifying genes in animal models. This led us to examine four genes ( SORBS2 , RXRA , DNAJB6 and ANO5 ) reported as cardiac modifiers of doxorubicin-induced cardiotoxicity in zebrafish and/or mouse models 46,47 . Suggesting that our data can be replicated we also identified variants in our study of N9831 in SORBS2 and RXRA and p<0.01 in DNAJB6 , p<0.001 (Supplementary Table 3).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of cardiotoxicity in the NCCTG N9831 (Alliance) adjuvant trastuzumab trial

Serie

Crook²,

Necela

et al. 2017

Pharmacogenetics and Genomics

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Objectives The major clinical side-effect of the ERBB2 targeted breast cancer therapy, trastuzumab, is a decline in left ventricular ejection fraction (LVEF). Improved markers are needed to better identify patients susceptible to cardiotoxicity. Methods The NCCTG N9831 trial compared adjuvant doxorubicin and cyclophosphamide followed by either weekly paclitaxel (Arm A); paclitaxel then trastuzumab (Arm B); or concurrent paclitaxel and trastuzumab (Arm C) in patients with HER2-positive breast cancer. A GWAS was performed on all patients with available DNA (N=1,446). We used linear regression to identify SNPs associated with decline in LVEF, adjusting for age, baseline LVEF, anti-hypertensive medications and the first two principle components. Results 618,863 SNPs passed quality control (QC) and DNA from 1,191 patients passed genotyping QC and were identified as whites of non-Hispanic origin. SNPs at six loci were associated with a decline in LVEF (p=7.73×10−6 to 8.93×10−8), LDB2, BRINP1, chr6 intergenic, RAB22A, TRPC6 and LINC01060, in patients who received chemotherapy plus trastuzumab (Arms BC, N=800). None of these loci were significant in patients who received chemotherapy only (Arm A, N=391) and did not increase in significance in analysis of all patients combined. We did not observe association, p<0.05 with SNPs previously associated with trastuzumab induced cardiotoxicity at ERBB2, I655V and P1170A. We replicated association, p<0.05, with SNPs previously associated with anthracycline cardiotoxicity at CBR3 and ABCB1. Conclusions Our study identified six putative novel cardiotoxicity loci in patients treated with combination chemotherapy and trastuzumab that require further investigation and confirmed known associations of anthracycline-induced cardiotoxicity.

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Section: Discussionmentioning

confidence: 99%

Genome-wide association study of cardiotoxicity in the NCCTG N9831 (Alliance) adjuvant trastuzumab trial

Serie

Crook²,

Necela

et al. 2017

Pharmacogenetics and Genomics

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“…Several studies have investigated the role of non-sarcomeric polymorphisms as potential disease modifiers, yet, additional studies are needed to replicate and further explore potential impact on disease. 34, 35 In general, there is limited understanding of genetic, environmental, and other, as of yet undiscovered, modifying factors in pediatric cardiomyopathy.…”

Section: Overviewmentioning

confidence: 99%

Pediatric Cardiomyopathies

Lee

Hsu

Kantor

et al. 2017

Circulation Research

246

218

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Pediatric cardiomyopathies are rare diseases with an annual incidence of 1.1–1.5 per 100,000. Dilated and hypertrophic cardiomyopathies are the most common; restrictive, noncompaction, and mixed cardiomyopathies occur infrequently; and arrhythmogenic right ventricular cardiomyopathy is rare. Pediatric cardiomyopathies can result from coronary artery abnormalities, tachyarrhythmias, exposure to infection or toxins, or secondary to other underlying disorders. Increasingly, the importance of genetic mutations in the pathogenesis of isolated or syndromic pediatric cardiomyopathies is becoming apparent. Pediatric cardiomyopathies often occur in the absence of co-morbidities such as atherosclerosis, hypertension, renal dysfunction, and diabetes; as a result, they offer insights into the primary pathogenesis of myocardial dysfunction. Large international registries have characterized the epidemiology, etiology, and outcomes of pediatric cardiomyopathies. Although adult and pediatric cardiomyopathies have similar morphologic and clinical manifestations, their outcomes differ significantly. Within two years of presentation, normalization of function occurs in 20% of children with dilated cardiomyopathy, and 40% die or undergo transplantation. Infants with hypertrophic cardiomyopathy have a two-year mortality of 30%, whereas death is rare in older children. Sudden death is rare. Molecular evidence indicates that gene expression differs between adult and pediatric cardiomyopathies, suggesting treatment response may differ as well. Clinical trials to support evidence-based treatments and the development of disease-specific therapies for pediatric cardiomyopathies are in their infancy. This compendium summarizes current knowledge of the genetic and molecular origins, clinical course, and outcomes of the most common phenotypic presentations of pediatric cardiomyopathies, and highlights key areas where additional research is required.

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“…Chemical mutagenesis was recently used in zebrafish to identify genetic modifiers of cardiomyopathy, and a similar approach in mice was employed to identify genetic mechanisms of congenital heart disease. 59, 60 Future efforts must be placed on identifying genes and elucidating mechanisms that contribute to the phenotypic variability associated with ANK2 variants.…”

Section: Future Investigationsmentioning

confidence: 99%

The evolving role of ankyrin-B in cardiovascular disease

Koenig

Mohler

2017

Heart Rhythm

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Over the last decade, ankyrin-B has been identified as a prominent player in cardiac physiology. Ankyrin-B has a multitude of functions, with roles in expression, localization, and regulation of proteins critical for cardiac excitability, cytoskeletal integrity, and signaling. Further, human ANK2 variants that result in ankyrin-B loss-of-function are associated with ‘Ankyrin-B syndrome’, a complex cardiac phenotype that may include bradycardia and heart rate variability, conduction block, atrial fibrillation, QT interval prolongation, and potentially fatal catecholaminergic polymorphic ventricular tachycardia. However, our understanding of the molecular mechanisms underlying ankyrin-B function at baseline and in disease is still not fully resolved due to the complexity of ankyrin-B gene regulation, number of ankyrin-B-associated molecules, multiple roles of ankyrin-B in the heart and other organs that modulate cardiac function, and a host of unexpected clinical phenotypes. Here, we summarize known roles of ankyrin-B in the heart and the impact of ankyrin-B dysfunction in animal models and in human disease, as well as highlight important new findings illustrating the complexity of ankyrin-B signaling.

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A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene

Cited by 45 publications

References 28 publications

Genome-wide association study of cardiotoxicity in the NCCTG N9831 (Alliance) adjuvant trastuzumab trial

Genome-wide association study of cardiotoxicity in the NCCTG N9831 (Alliance) adjuvant trastuzumab trial

Pediatric Cardiomyopathies

The evolving role of ankyrin-B in cardiovascular disease

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