[R01] Titin, Genome-First: Disease Spectrum and Modifiers of Heritable Cardiomyopathy
Ente: National Heart Lung and Blood Institute
Scadenza: 2031-05-31
Importo max: 823.655 EUR
Paese: US
Descrizione
PROJECT SUMMARY / ABSTRACT
Protein-truncating variants in the titin gene TTN (TTNtv) are the most common cause of familial and idiopathic
dilated cardiomyopathy (DCM), accounting for roughly 20% of cases. TTNtv are also implicated in other
cardiomyopathies, arrhythmias, and even sudden cardiac death. Because of these risks, it is recommended to
report “secondary” TTNtv findings ascertained through genomic screening. However, TTNtv are much more
common (~1% prevalence in the general population) than familial DCM (~0.1% prevalence). Therefore, if an
otherwise healthy individual is identified with a TTNtv, the risk of developing heart disease is poorly understood.
The observed variability in outcomes for individuals with TTNtv may be due to: 1) differences in variant
pathogenicity across the TTN gene, 2) a resultant spectrum of cardiac structure and function that remains
clinically undetected, and 3) the 'two-hit' hypothesis, where DCM and associated comorbidities in TTNtv are
influenced by secondary factors such as chemotherapy and pregnancy. Understanding the impact of each of
these phenomena and their links to disease will advance precision therapies and inform clinical management of
genomic screening identification of TTNtv. This proposal leverages three large biobanks approaching one million
individuals to address these hypotheses in the following ways:
In Aim 1, we will assemble and harmonize genomic and phenotypic data across three of the largest biobanks
with genome-wide sequencing data linked to extensive phenotypic (i.e. health record) information: MyCode at
Geisinger, BioVU, and the UK Biobank. We will then test how TTNtv variant type and location modulates
penetrance of arrhythmias and cardiomyopathy to identify variants that may warrant close clinical management.
All three biobanks include cardiac imaging data for many participants, including echocardiogram and cardiac
MRI data. In Aim 2, these data will be used to make group-wise comparisons of both clinical and sub-clinical
cardiac structure (muscle mass, chamber volumes, tissue composition) and function (ejection fraction, filling
ratio, strains, and strain rates). Further, MyCode supports targeted participant recontact for prospective study.
To determine if TTNtv causes subclinical cardiac damage, we will recruit and compare MyCode participants with
TTNtv but no history of diagnosed heart disease to matched controls using advanced cardiac MRI to assess
diastolic dysfunction, myocardial strain, torsion, and dyssynchrony.
In Aim 3, we will test how candidate second “hits”, such as hypertension or coronary artery disease, interact with
TTNtv to heighten disease risk. The unique resources amalgamated through this project will enable us to
comprehensively investigate for the first time this two-hit hypothesis from a genome-first perspective and conduct
a comprehensive investigation to identify yet unknown secondary triggers that will launch future clinical trials.
Upon completion, these
Istituzione: GEISINGER CLINIC
PI: Eric David Carruth
Progetto: 1R01HL183397-01A1
Settori: National Heart Lung and Blood Institute
Vai al bando originale
Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.