Genetic architecture of hypertrophic cardiomyopathy in individuals of Chinese and United Kingdom ancestry

Abstract

Background: No studies have explored the genetic differences between the Chinese and other ethnic hypertrophic cardiomyopathy (HCM) populations.

Methods: This cross-sectional study included Chinese patients ( n = 593) with HCM and controls ( n= 491) who underwent whole-exome sequencing. Rare variants in 16 validated HCM genes were assessed and compared with a United Kingdom HCM cohort ( n = 1 232) and controls ( n= 344 745).

Results: Chinese HCM patients have a higher proportion of rare variants (52.8% vs 13.6%, P< 0.001) but have a similar proportion of pathogenic (P) or likely pathogenic (LP) variants compared to the UK cohort. In addition, the Chinese cohort had additional associations with the combined thin filament genes ( P= 1.29E −9) and myosin light chain genes ( P= 4.43E −3). The United Kingdom cohort was significantly associated with MYBPC3non-truncating variants ( P= 2.99E −7). By classifying variants using the tool genebe, the variants of uncertain significance were minimized to 46.8% compared to other tools (63.3% by Intervar; 91.3% by CardioClassifier). Furthermore, we report that c.3624del in MYBPC3and c.300C > G in TNNT2account for 2.9% and 1.5% of all Chinese HCM cases, respectively.

Conclusion: Our findings suggested that patients of Chinese ancestry with HCM have a higher proportion of rare variants but are less likely to be classified as P/LP variants in HCM genes than those of European origin. The variants of c.3624del in MYBPC3and c.300C > G in TNNT2were specific to Chinese individuals and provide important insights into the ethnic differences of HCM genetic architecture.

Keywords

hypertrophic cardiomyopathy / United Kingdom (UK) Biobank / whole exome sequencing (WES) / pathogenicity

Ethics statement

This prospective cohort study was approved by the Ethical Committee of West China Hospital, Sichuan University (No. 2019-166). Written informed consent of the Chinese cohort was obtained from each participant. This prospective Chinese cohort study was registered in the Chinese Clinical Trial Registry (URL: https://www.chictr.org.cn/searchprojEN.html; Registry number: ChiCTR1900022965).

Acknowledgments

This work was supported by grants from the Natural Science Foundation of China (grant No. 82202248), the Natural Science Foundation of Sichuan Province (grant No. 23NSFSC4589), and 1·3·5 projects for Artificial Intelligence, West China Hospital, Sichuan University (grant No. ZYAI24003). The authors thank Dr. Daniel Reichart from the Gene Center Ludwig-Maximilians-Universität München for helping us to provide suggestions and revise the manuscript. The analyses were conducted on the Research Analysis Platform (https://ukbiobank.dnanexus.com). This research has been conducted using the UK Biobank Resource under application number 31224. In addition, we extend our gratitude to the Genome Sequencing of Rare Disease-100K WCH Project participants for their involvement in this study. G.V.G. and D.R. acknowledge support from the NIHR Birmingham HPRU, NIHR Birmingham BRC, Nanocommons H2020-EU (731032), MAESTRIA (grant agreement ID 965286), CRUCK (PRCNPG-Nov23/100001), HYPERMARKER (grant agreement ID 101095480), PARC (grant Agreement No 101057014), and the MRC Heath Data Research UK (HDRUK/CFC/01) and HDRUK midlands regional community project (QQ2), initiatives funded by UK Research and Innovation, Department of Health and Social Care (England) and the devolved administrations, and leading medical research charities. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, the Medical Research Council, or the Department of Health.

Author contributions

Jie Wang (Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing—original draft, Writing—review & editing), Dominic Russ (Data curation, Formal analysis, Methodology, Resources, Software, Visualization, Writing—original draft), Yongsan Yang (Data curation, Formal analysis, Methodology, Validation, Visualization, Writing—original draft, Writing—review & editing), Lutong Pu (Data curation, Formal analysis, Investigation, Methodology, Software, Visualization, Writing—original draft), Mengdi Yu (Data curation, Formal analysis, Investigation, Methodology, Writing—original draft), Jinquan Zhang (Data curation, Formal analysis, Investigation, Methodology, Software, Visualization, Writing—original draft), Jiajun Guo (Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing—review & editing), Yuanwei Xu (Data curation, Investigation, Methodology, Validation, Visualization, Writing—review & editing), Ke Wan (Data curation, Formal Analysis, Investigation, Methodology, Validation, Visualization, Writing—review & editing), Heng Xu (Conceptualization, Formal analysis, Methodology, Supervision, Writing—review & editing), Yuchi Han (Conceptualization, Methodology, Project administration, Supervision, Writing—review & editing), Georgios V. Gkoutos (Conceptualization, Project administration, Resources, Supervision, Validation, Writing—review & editing), and Yucheng Chen (Conceptualization, Data curation, Funding acquisition, Methodology, Project administration, Resources, Supervision, Writing—review & editing)

Supplementary data

Supplementary data are available at PCMEDI online.

Conflict of interest

None declared. In addition, as an Editorial Board Member of Precision Clinical Medicine, the corresponding author G.V.G. was blinded from reviewing and making decisions on this manuscript.

Data availability

Data from the UKB (https://www.ukbiobank.ac.uk/use-our-data/apply-for-access/) are available to all researchers upon making an application. This research has been conducted using the UK Biobank Resource under application number 31224. In addition, data from the Chinese cohort are available under accession numbers GVM000832 and GVM000833 via the Genome Variation Map (GVM) at the National Genomics Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences, and China National Center for Bioinformation (China). While restrictions apply due to licensing agreements, external researchers may request access through the corresponding author (Y.C.), subject to approval by the West China Hospital Ethics Committee and compliance with data transfer agreements.

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