Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes in over 200,000 adults
Author(s)
Type
Conference Paper
Abstract
Background
Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.
Purpose
To determine the population prevalence of HCM-associated sarcomeric variants, characterise their phenotypic manifestations, estimate penetrance, and identify associations between sarcomeric variants and clinical outcomes, we performed an observational study of 218,813 adults in the UK Biobank (UKBB), of whom 200,584 have whole exome sequencing (WES).
Methods
We carried out an integrated analysis of WES and cardiac magnetic resonance (CMR) imaging in UK Biobank participants stratified by sarcomere-encoding variant status. Computer vision techniques were used to automatically segment the four chambers of the heart (Figure 1). Cardiac motion analysis was used to derive strain and strain rates. Regional analysis of left ventricular wall thickness was performed using three-dimensional modelling of these segmentations.
Results
Median age at recruitment was 58 (IQR 50–63 years), and participants were followed up for a median of 10.8 years (IQR 9.9–11.6 years) with a total of 19,507 primary clinical events reported.
The prevalence of rare variants (allele frequency <0.ehab724.17314) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n=5,727; 1 in 35), and the prevalence of pathogenic or likely pathogenic variants (SARC-P/LP) was 0.24% (n=474, 1 in 423).
SARC-P/LP variants were associated with increased risk of death or major adverse cardiac events (MACE) compared to controls (HR 1.68, 95% CI 1.37–2.06, p<0.001), mainly due to heart failure endpoints (Figure 2: cumulative hazard curves with zoomed plots for lifetime risk of A) death and MACE or B) heart failure, stratified by genotype; genotype negative (SARC-NEG), carriers of indeterminate sarcomeric variants (SARC-IND) or SARC-P/LP; C) Forest plot of comparative lifetime risk of clinical endpoints by genotype).
While males had a higher overall risk of adverse outcomes, the incremental genetic risk from SARC-P/LP mutations was greater in females (HR for females: 2.18 CI 1.65–2.89, p<0.001; HR for males: 1.42 CI 1.05–1.9, p=0.02).
In 21,322 participants with CMR, SARC-P/LP were associated with asymmetric increase in left ventricular maximum wall thickness (10.9±2.7 vs 9.4±1.6 mm, p<0.001) but hypertrophy (≥13mm) was only present in 16% (n=7/43, 95% CI 7–31%). Other rare sarcomere-encoding variants had a weak effect on wall thickness (9.5±1.7 vs 9.4±1.6 mm, p=0.002) with no combined excess cardiovascular risk.
Conclusions
In the general population, SARC-P/LP variants have low aggregate penetrance for overt HCM but are associated with increased risk of adverse cardiovascular outcomes and a sub-clinical cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease.
Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The study was supported by the Medical Research Council, UK (MC-A651-53301); National Institute for Health Research (NIHR) Imperial College Biomedical Research Centre; NIHR Royal Brompton Cardiovascular Biomedical Research Unit; British Heart Foundation (NH/17/1/32725, RG/19/6/34387, RE/18/4/34215).
Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.
Purpose
To determine the population prevalence of HCM-associated sarcomeric variants, characterise their phenotypic manifestations, estimate penetrance, and identify associations between sarcomeric variants and clinical outcomes, we performed an observational study of 218,813 adults in the UK Biobank (UKBB), of whom 200,584 have whole exome sequencing (WES).
Methods
We carried out an integrated analysis of WES and cardiac magnetic resonance (CMR) imaging in UK Biobank participants stratified by sarcomere-encoding variant status. Computer vision techniques were used to automatically segment the four chambers of the heart (Figure 1). Cardiac motion analysis was used to derive strain and strain rates. Regional analysis of left ventricular wall thickness was performed using three-dimensional modelling of these segmentations.
Results
Median age at recruitment was 58 (IQR 50–63 years), and participants were followed up for a median of 10.8 years (IQR 9.9–11.6 years) with a total of 19,507 primary clinical events reported.
The prevalence of rare variants (allele frequency <0.ehab724.17314) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n=5,727; 1 in 35), and the prevalence of pathogenic or likely pathogenic variants (SARC-P/LP) was 0.24% (n=474, 1 in 423).
SARC-P/LP variants were associated with increased risk of death or major adverse cardiac events (MACE) compared to controls (HR 1.68, 95% CI 1.37–2.06, p<0.001), mainly due to heart failure endpoints (Figure 2: cumulative hazard curves with zoomed plots for lifetime risk of A) death and MACE or B) heart failure, stratified by genotype; genotype negative (SARC-NEG), carriers of indeterminate sarcomeric variants (SARC-IND) or SARC-P/LP; C) Forest plot of comparative lifetime risk of clinical endpoints by genotype).
While males had a higher overall risk of adverse outcomes, the incremental genetic risk from SARC-P/LP mutations was greater in females (HR for females: 2.18 CI 1.65–2.89, p<0.001; HR for males: 1.42 CI 1.05–1.9, p=0.02).
In 21,322 participants with CMR, SARC-P/LP were associated with asymmetric increase in left ventricular maximum wall thickness (10.9±2.7 vs 9.4±1.6 mm, p<0.001) but hypertrophy (≥13mm) was only present in 16% (n=7/43, 95% CI 7–31%). Other rare sarcomere-encoding variants had a weak effect on wall thickness (9.5±1.7 vs 9.4±1.6 mm, p=0.002) with no combined excess cardiovascular risk.
Conclusions
In the general population, SARC-P/LP variants have low aggregate penetrance for overt HCM but are associated with increased risk of adverse cardiovascular outcomes and a sub-clinical cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease.
Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The study was supported by the Medical Research Council, UK (MC-A651-53301); National Institute for Health Research (NIHR) Imperial College Biomedical Research Centre; NIHR Royal Brompton Cardiovascular Biomedical Research Unit; British Heart Foundation (NH/17/1/32725, RG/19/6/34387, RE/18/4/34215).
Date Issued
2021-10-14
Date Acceptance
2021-10-01
Citation
European Heart Journal, 2021, 42, pp.1731-1731
ISSN
0195-668X
Publisher
European Society of Cardiology
Start Page
1731
End Page
1731
Journal / Book Title
European Heart Journal
Volume
42
Copyright Statement
© The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.
This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
Sponsor
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
British Heart Foundation
British Heart Foundation
Engineering & Physical Science Research Council (EPSRC)
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000720456901832&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
RDC04
RDB02
RE/18/4/34215
RG/19/6/34387
EP/P001009/1
Source
ESC Congress 2021
Subjects
Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Cardiovascular System & Cardiology
Publication Status
Published
Start Date
2021-08-27
Finish Date
2021-08-30
Coverage Spatial
Digital Congress
Date Publish Online
2021-10-14