Rare Genetic Variants Associated With Myocardial Fibrosis: Multi-Ethnic Study of Atherosclerosis

Mahsima Shabani; Diptavo Dutta; Bharath Ambale-Venkatesh; Wendy S. Post; Kent D. Taylor; Stephen S. Rich; Colin O. Wu; Naveen L. Pereira; Sanjiv J. Shah; Nilanjan Chatterjee; Jerome I. Rotter; Dan E. Arking; Joao A.C. Lima

doi:10.3389/fcvm.2022.804788

Rare Genetic Variants Associated With Myocardial Fibrosis: Multi-Ethnic Study of Atherosclerosis

Mahsima Shabani, Diptavo Dutta, Bharath Ambale-Venkatesh, Wendy S. Post, Kent D. Taylor, Stephen S. Rich, Colin O. Wu, Naveen L. Pereira, Sanjiv J. Shah, Nilanjan Chatterjee, Jerome I. Rotter, Dan E. Arking, Joao A.C. Lima^*

^*Corresponding author for this work

Medicine, Cardiology Division

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Background: Rare pathogenic variants in cardiomyopathy (CM) genes can predispose to cardiac remodeling or fibrosis. We studied the carrier status for such variants in adults without clinical cardiovascular disease (CVD) in whom cardiac MRI (CMR)-derived measures of myocardial fibrosis were obtained in the Multi-Ethnic Study of Atherosclerosis (MESA). Objectives: To identify CM-associated pathogenic variants and assess their relative prevalence in participants with extensive myocardial fibrosis by CMR. Methods: MESA whole-genome sequencing data was evaluated to capture variants in CM-associated genes (n = 82). Coding variants with a frequency of <0.1% in gnomAD and 1,000 Genomes Project databases and damaging/deleterious effects based on in-silico scoring tools were assessed by ClinVar database and ACMG curation guidelines for evidence of pathogenicity. Cases were participants with high myocardial fibrosis defined as highest quartile of extracellular volume (ECV) or native T1 time in T1-mapping CMR and controls were the remainder of participants. Results: A total of 1,135 MESA participants had available genetic data and phenotypic measures and were free of clinical CVD at the time of CMR. We identified 6,349 rare variants in CM-associated genes in the overall MESA population, of which six pathogenic/likely pathogenic (P/LP) variants were present in the phenotyped subpopulation. The genes harboring P/LP variants in the case group were MYH7, CRYAB, and SCN5A. The prevalence of P/LP rare variants in cases was higher than controls (5 in 420 [1.1%] vs. 1 in 715 [0.1%], p = 0.03). We identified two MYBPC3 Variants of Unknown Significance (VUS)s with borderline pathogenicity in the case group. The left ventricle (LV) volume, mass, ejection fraction (EF), and longitudinal and circumferential strain in participants with the variants were not different compared to the overall cohort. Conclusions: We observed a higher prevalence of rare potentially pathogenic CM associated genetic variants in participants with significant myocardial fibrosis quantified in CMR as compared to controls without significant fibrosis. No cardiac structural or functional differences were found between participants with or without P/LP variants.

Original language	English (US)
Article number	804788
Journal	Frontiers in Cardiovascular Medicine
Volume	9
DOIs	https://doi.org/10.3389/fcvm.2022.804788
State	Published - Feb 21 2022

Funding

WGS for the TOPMed program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for ‘NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA) (phs001416.v1.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1, contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL-120393; U01HL-120393; contract HHSN268180001I). The MESA project is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. Also supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center.

Keywords

T1
cardiomyopathy
fibrosis
genetics
interstitial
magnetic resonance imaging
rare

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3389/fcvm.2022.804788

Cite this

Shabani, M., Dutta, D., Ambale-Venkatesh, B., Post, W. S., Taylor, K. D., Rich, S. S., Wu, C. O., Pereira, N. L., Shah, S. J., Chatterjee, N., Rotter, J. I., Arking, D. E., & Lima, J. A. C. (2022). Rare Genetic Variants Associated With Myocardial Fibrosis: Multi-Ethnic Study of Atherosclerosis. Frontiers in Cardiovascular Medicine, 9, Article 804788. https://doi.org/10.3389/fcvm.2022.804788

@article{7e2dc44038dc45069ccf681a389c45a6,

title = "Rare Genetic Variants Associated With Myocardial Fibrosis: Multi-Ethnic Study of Atherosclerosis",

abstract = "Background: Rare pathogenic variants in cardiomyopathy (CM) genes can predispose to cardiac remodeling or fibrosis. We studied the carrier status for such variants in adults without clinical cardiovascular disease (CVD) in whom cardiac MRI (CMR)-derived measures of myocardial fibrosis were obtained in the Multi-Ethnic Study of Atherosclerosis (MESA). Objectives: To identify CM-associated pathogenic variants and assess their relative prevalence in participants with extensive myocardial fibrosis by CMR. Methods: MESA whole-genome sequencing data was evaluated to capture variants in CM-associated genes (n = 82). Coding variants with a frequency of <0.1% in gnomAD and 1,000 Genomes Project databases and damaging/deleterious effects based on in-silico scoring tools were assessed by ClinVar database and ACMG curation guidelines for evidence of pathogenicity. Cases were participants with high myocardial fibrosis defined as highest quartile of extracellular volume (ECV) or native T1 time in T1-mapping CMR and controls were the remainder of participants. Results: A total of 1,135 MESA participants had available genetic data and phenotypic measures and were free of clinical CVD at the time of CMR. We identified 6,349 rare variants in CM-associated genes in the overall MESA population, of which six pathogenic/likely pathogenic (P/LP) variants were present in the phenotyped subpopulation. The genes harboring P/LP variants in the case group were MYH7, CRYAB, and SCN5A. The prevalence of P/LP rare variants in cases was higher than controls (5 in 420 [1.1%] vs. 1 in 715 [0.1%], p = 0.03). We identified two MYBPC3 Variants of Unknown Significance (VUS)s with borderline pathogenicity in the case group. The left ventricle (LV) volume, mass, ejection fraction (EF), and longitudinal and circumferential strain in participants with the variants were not different compared to the overall cohort. Conclusions: We observed a higher prevalence of rare potentially pathogenic CM associated genetic variants in participants with significant myocardial fibrosis quantified in CMR as compared to controls without significant fibrosis. No cardiac structural or functional differences were found between participants with or without P/LP variants.",

keywords = "T1, cardiomyopathy, fibrosis, genetics, interstitial, magnetic resonance imaging, rare",

author = "Mahsima Shabani and Diptavo Dutta and Bharath Ambale-Venkatesh and Post, {Wendy S.} and Taylor, {Kent D.} and Rich, {Stephen S.} and Wu, {Colin O.} and Pereira, {Naveen L.} and Shah, {Sanjiv J.} and Nilanjan Chatterjee and Rotter, {Jerome I.} and Arking, {Dan E.} and Lima, {Joao A.C.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 Shabani, Dutta, Ambale-Venkatesh, Post, Taylor, Rich, Wu, Pereira, Shah, Chatterjee, Rotter, Arking and Lima.",

year = "2022",

month = feb,

day = "21",

doi = "10.3389/fcvm.2022.804788",

language = "English (US)",

volume = "9",

journal = "Frontiers in Cardiovascular Medicine",

issn = "2297-055X",

publisher = "Frontiers Media SA",

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TY - JOUR

T1 - Rare Genetic Variants Associated With Myocardial Fibrosis

T2 - Multi-Ethnic Study of Atherosclerosis

AU - Shabani, Mahsima

AU - Dutta, Diptavo

AU - Ambale-Venkatesh, Bharath

AU - Post, Wendy S.

AU - Taylor, Kent D.

AU - Rich, Stephen S.

AU - Wu, Colin O.

AU - Pereira, Naveen L.

AU - Shah, Sanjiv J.

AU - Chatterjee, Nilanjan

AU - Rotter, Jerome I.

AU - Arking, Dan E.

AU - Lima, Joao A.C.

PY - 2022/2/21

Y1 - 2022/2/21

N2 - Background: Rare pathogenic variants in cardiomyopathy (CM) genes can predispose to cardiac remodeling or fibrosis. We studied the carrier status for such variants in adults without clinical cardiovascular disease (CVD) in whom cardiac MRI (CMR)-derived measures of myocardial fibrosis were obtained in the Multi-Ethnic Study of Atherosclerosis (MESA). Objectives: To identify CM-associated pathogenic variants and assess their relative prevalence in participants with extensive myocardial fibrosis by CMR. Methods: MESA whole-genome sequencing data was evaluated to capture variants in CM-associated genes (n = 82). Coding variants with a frequency of <0.1% in gnomAD and 1,000 Genomes Project databases and damaging/deleterious effects based on in-silico scoring tools were assessed by ClinVar database and ACMG curation guidelines for evidence of pathogenicity. Cases were participants with high myocardial fibrosis defined as highest quartile of extracellular volume (ECV) or native T1 time in T1-mapping CMR and controls were the remainder of participants. Results: A total of 1,135 MESA participants had available genetic data and phenotypic measures and were free of clinical CVD at the time of CMR. We identified 6,349 rare variants in CM-associated genes in the overall MESA population, of which six pathogenic/likely pathogenic (P/LP) variants were present in the phenotyped subpopulation. The genes harboring P/LP variants in the case group were MYH7, CRYAB, and SCN5A. The prevalence of P/LP rare variants in cases was higher than controls (5 in 420 [1.1%] vs. 1 in 715 [0.1%], p = 0.03). We identified two MYBPC3 Variants of Unknown Significance (VUS)s with borderline pathogenicity in the case group. The left ventricle (LV) volume, mass, ejection fraction (EF), and longitudinal and circumferential strain in participants with the variants were not different compared to the overall cohort. Conclusions: We observed a higher prevalence of rare potentially pathogenic CM associated genetic variants in participants with significant myocardial fibrosis quantified in CMR as compared to controls without significant fibrosis. No cardiac structural or functional differences were found between participants with or without P/LP variants.

AB - Background: Rare pathogenic variants in cardiomyopathy (CM) genes can predispose to cardiac remodeling or fibrosis. We studied the carrier status for such variants in adults without clinical cardiovascular disease (CVD) in whom cardiac MRI (CMR)-derived measures of myocardial fibrosis were obtained in the Multi-Ethnic Study of Atherosclerosis (MESA). Objectives: To identify CM-associated pathogenic variants and assess their relative prevalence in participants with extensive myocardial fibrosis by CMR. Methods: MESA whole-genome sequencing data was evaluated to capture variants in CM-associated genes (n = 82). Coding variants with a frequency of <0.1% in gnomAD and 1,000 Genomes Project databases and damaging/deleterious effects based on in-silico scoring tools were assessed by ClinVar database and ACMG curation guidelines for evidence of pathogenicity. Cases were participants with high myocardial fibrosis defined as highest quartile of extracellular volume (ECV) or native T1 time in T1-mapping CMR and controls were the remainder of participants. Results: A total of 1,135 MESA participants had available genetic data and phenotypic measures and were free of clinical CVD at the time of CMR. We identified 6,349 rare variants in CM-associated genes in the overall MESA population, of which six pathogenic/likely pathogenic (P/LP) variants were present in the phenotyped subpopulation. The genes harboring P/LP variants in the case group were MYH7, CRYAB, and SCN5A. The prevalence of P/LP rare variants in cases was higher than controls (5 in 420 [1.1%] vs. 1 in 715 [0.1%], p = 0.03). We identified two MYBPC3 Variants of Unknown Significance (VUS)s with borderline pathogenicity in the case group. The left ventricle (LV) volume, mass, ejection fraction (EF), and longitudinal and circumferential strain in participants with the variants were not different compared to the overall cohort. Conclusions: We observed a higher prevalence of rare potentially pathogenic CM associated genetic variants in participants with significant myocardial fibrosis quantified in CMR as compared to controls without significant fibrosis. No cardiac structural or functional differences were found between participants with or without P/LP variants.

KW - T1

KW - cardiomyopathy

KW - fibrosis

KW - genetics

KW - interstitial

KW - magnetic resonance imaging

KW - rare

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U2 - 10.3389/fcvm.2022.804788

DO - 10.3389/fcvm.2022.804788

M3 - Article

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AN - SCOPUS:85138562206

SN - 2297-055X

VL - 9

JO - Frontiers in Cardiovascular Medicine

JF - Frontiers in Cardiovascular Medicine

M1 - 804788

ER -

Rare Genetic Variants Associated With Myocardial Fibrosis: Multi-Ethnic Study of Atherosclerosis

Abstract

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UN SDGs

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