GAREM1 regulates the PR interval on electrocardiograms

Hye Ok Kim, Ji Eun Lim, Myung Jun Kim, Ji One Kang, Sung Moon Kim, Jeong Min Nam, Jihoon Tak, Hiroaki Konishi, Tasuku Nishino, In Song Koh, Young Ho Jin, Hyung Hwan Baik, Jin Bae Kim, Mi Kyung Kim, Bo Youl Choi, Sang Hak Lee, Yangsoo Jang, Jinho Shin, Bermseok Oh

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Abstract

PR interval is the period from the onset of P wave to the start of the QRS complex on electrocardiograms. A recent genomewide association study (GWAS) suggested that GAREM1 was linked to the PR interval on electrocardiograms. This study was designed to validate this correlation using additional subjects and examined the function of Garem1 in a mouse model. We analyzed the association of rs17744182, a variant in the GAREM1 locus, with the PR interval in 5646 subjects who were recruited from 2 Korean replication sets, Yangpyeong (n = 2471) and Yonsei (n = 3175), and noted a significant genomewide association by meta-analysis (P = 2.39 × 10-8). To confirm the function of Garem1 in mice, Garem1 siRNA was injected into mouse tail veins to reduce the expression of Garem1. Garem1 transcript levels declined by 53% in the atrium of the heart (P = 0.029), and Garem1-siRNA injected mice experienced a significant decrease in PR interval (43.27 ms vs. 44.89 ms in control, P = 0.007). We analyzed the expression pattern of Garem1 in the heart by immunohistology and observed specific expression of Garem1 in intracardiac ganglia. Garem1 was expressed in most neurons of the ganglion, including cholinergic and adrenergic cells. We have provided evidence that GAREM1 is involved in the PR interval of ECGs. These findings increase our understanding of the regulatory signals of heart rhythm through intracardiac ganglia of the autonomic nervous system and can be used to guide the development of a therapeutic target for heart conditions, such as atrial fibrillation.

Original languageEnglish
Pages (from-to)297-307
Number of pages11
JournalJournal of human genetics
Volume63
Issue number3
DOIs
Publication statusPublished - 2018 Mar 1

Bibliographical note

Funding Information:
Acknowledgements This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (nos. 2014R1A2A2A01005277 and 2015R1C1A2A01052431). Genotype data were produced using the Korean Chip (K-CHIP) available through the K-CHIP consortium. K-CHIP was designed by Center for Genome Science, Korea National Institute of Health, Korea (4845-301, 3000-3031).

Publisher Copyright:
© 2017 The Japan Society of Human Genetics.

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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