Prognostic implications of troponin T variations in inherited cardiomyopathies using systems biology

Abstract The cardiac troponin T variations have often been used as an example of the application of clinical genotyping for prognostication and risk stratification measures for the management of patients with a family history of sudden cardiac death or familial cardiomyopathy. Given the disparity in...

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Autores principales:	Rameen Shakur, Juan Pablo Ochoa, Alan J. Robinson, Abhishek Niroula, Aneesh Chandran, Taufiq Rahman, Mauno Vihinen, Lorenzo Monserrat
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/d83b655e70d2430db526ecf35be2769f
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spelling	oai:doaj.org-article:d83b655e70d2430db526ecf35be2769f2021-12-02T16:04:14ZPrognostic implications of troponin T variations in inherited cardiomyopathies using systems biology10.1038/s41525-021-00204-w2056-7944https://doaj.org/article/d83b655e70d2430db526ecf35be2769f2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00204-whttps://doaj.org/toc/2056-7944Abstract The cardiac troponin T variations have often been used as an example of the application of clinical genotyping for prognostication and risk stratification measures for the management of patients with a family history of sudden cardiac death or familial cardiomyopathy. Given the disparity in patient outcomes and therapy options, we investigated the impact of variations on the intermolecular interactions across the thin filament complex as an example of an unbiased systems biology method to better define clinical prognosis to aid future management options. We present a novel unbiased dynamic model to define and analyse the functional, structural and physico-chemical consequences of genetic variations among the troponins. This was subsequently integrated with clinical data from accessible global multi-centre systematic reviews of familial cardiomyopathy cases from 106 articles of the literature: 136 disease-causing variations pertaining to 981 global clinical cases. Troponin T variations showed distinct pathogenic hotspots for dilated and hypertrophic cardiomyopathies; considering the causes of cardiovascular death separately, there was a worse survival in terms of sudden cardiac death for patients with a variation at regions 90–129 and 130–179 when compared to amino acids 1–89 and 200–288. Our data support variations among 90–130 as being a hotspot for sudden cardiac death and the region 131–179 for heart failure death/transplantation outcomes wherein the most common phenotype was dilated cardiomyopathy. Survival analysis into regions of high risk (regions 90–129 and 130–180) and low risk (regions 1–89 and 200–288) was significant for sudden cardiac death (p = 0.011) and for heart failure death/transplant (p = 0.028). Our integrative genomic, structural, model from genotype to clinical data integration has implications for enhancing clinical genomics methodologies to improve risk stratification.Rameen ShakurJuan Pablo OchoaAlan J. RobinsonAbhishek NiroulaAneesh ChandranTaufiq RahmanMauno VihinenLorenzo MonserratNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 Rameen Shakur Juan Pablo Ochoa Alan J. Robinson Abhishek Niroula Aneesh Chandran Taufiq Rahman Mauno Vihinen Lorenzo Monserrat Prognostic implications of troponin T variations in inherited cardiomyopathies using systems biology
description	Abstract The cardiac troponin T variations have often been used as an example of the application of clinical genotyping for prognostication and risk stratification measures for the management of patients with a family history of sudden cardiac death or familial cardiomyopathy. Given the disparity in patient outcomes and therapy options, we investigated the impact of variations on the intermolecular interactions across the thin filament complex as an example of an unbiased systems biology method to better define clinical prognosis to aid future management options. We present a novel unbiased dynamic model to define and analyse the functional, structural and physico-chemical consequences of genetic variations among the troponins. This was subsequently integrated with clinical data from accessible global multi-centre systematic reviews of familial cardiomyopathy cases from 106 articles of the literature: 136 disease-causing variations pertaining to 981 global clinical cases. Troponin T variations showed distinct pathogenic hotspots for dilated and hypertrophic cardiomyopathies; considering the causes of cardiovascular death separately, there was a worse survival in terms of sudden cardiac death for patients with a variation at regions 90–129 and 130–179 when compared to amino acids 1–89 and 200–288. Our data support variations among 90–130 as being a hotspot for sudden cardiac death and the region 131–179 for heart failure death/transplantation outcomes wherein the most common phenotype was dilated cardiomyopathy. Survival analysis into regions of high risk (regions 90–129 and 130–180) and low risk (regions 1–89 and 200–288) was significant for sudden cardiac death (p = 0.011) and for heart failure death/transplant (p = 0.028). Our integrative genomic, structural, model from genotype to clinical data integration has implications for enhancing clinical genomics methodologies to improve risk stratification.
format	article
author	Rameen Shakur Juan Pablo Ochoa Alan J. Robinson Abhishek Niroula Aneesh Chandran Taufiq Rahman Mauno Vihinen Lorenzo Monserrat
author_facet	Rameen Shakur Juan Pablo Ochoa Alan J. Robinson Abhishek Niroula Aneesh Chandran Taufiq Rahman Mauno Vihinen Lorenzo Monserrat
author_sort	Rameen Shakur
title	Prognostic implications of troponin T variations in inherited cardiomyopathies using systems biology
title_short	Prognostic implications of troponin T variations in inherited cardiomyopathies using systems biology
title_full	Prognostic implications of troponin T variations in inherited cardiomyopathies using systems biology
title_fullStr	Prognostic implications of troponin T variations in inherited cardiomyopathies using systems biology
title_full_unstemmed	Prognostic implications of troponin T variations in inherited cardiomyopathies using systems biology
title_sort	prognostic implications of troponin t variations in inherited cardiomyopathies using systems biology
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/d83b655e70d2430db526ecf35be2769f
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Prognostic implications of troponin T variations in inherited cardiomyopathies using systems biology

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