Scholarlink

<p>Atrial fibrillation (AF), the most common sustained arrhythmia, has a complex genetic basis; however, the molecular mechanisms linking rare and common variants remain poorly understood. Polygenic risk score (PRS) analysis in the UK Biobank and All of Us cohorts reveals that carriers of protein-altering <i>LMNA</i> variants (PAVs) have a significantly higher risk of incident AF than predicted by PRS alone, supporting an additive effect of common polymorphisms and <i>LMNA</i> variants. Induced pluripotent stem cell derived atrial cardiomyocytes (iPSC-aCMs) from individuals carrying the pathogenic missense variant p.S143P in <i>LMNA</i> exhibit widespread disruption of chromatin architecture and perturbation of atrial gene regulatory networks, particularly at loci harboring AF-associated variants and transcription factors essential for atrial rhythm control and contractility. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based epigenetic editing validates the function of several AF-associated regulatory elements and their downstream targets. Notably, reduced accessibility at an intronic <i>SCN10A</i> enhancer harboring the AF-associated SNP rs6801957 is associated with reduced sodium current in p.S143P iPSC-aCMs. These findings are reproduced in iPSC-aCMs derived from an additional individual carrying a distinct pathogenic <i>LMNA</i> variant, supporting a broader mechanism in which rare <i>LMNA</i> variants and common polymorphisms converge on shared regulatory networks to influence AF susceptibility and highlighting the value of integrating both in arrhythmia risk assessment.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Gene-gene interactions between a LMNA variant and common polymorphisms drive early-onset atrial fibrillation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月19日

查看全文
  • Asia Owais,
  • Hanna Chen,
  • Hammad Farooq,
  • Prisca K. Thami,
  • Kathryn A. McGurk,
  • George J. Powell,
  • Jaime DeSantiago,
  • Talla Abbas,
  • Arvind Sridhar,
  • Arif Pavel,
  • Gregory Webster,
  • Bradley Merrill,
  • James S. Ware,
  • Fu Siong Ng,
  • Dawood Darbar

摘要

Atrial fibrillation (AF), the most common sustained arrhythmia, has a complex genetic basis; however, the molecular mechanisms linking rare and common variants remain poorly understood. Polygenic risk score (PRS) analysis in the UK Biobank and All of Us cohorts reveals that carriers of protein-altering LMNA variants (PAVs) have a significantly higher risk of incident AF than predicted by PRS alone, supporting an additive effect of common polymorphisms and LMNA variants. Induced pluripotent stem cell derived atrial cardiomyocytes (iPSC-aCMs) from individuals carrying the pathogenic missense variant p.S143P in LMNA exhibit widespread disruption of chromatin architecture and perturbation of atrial gene regulatory networks, particularly at loci harboring AF-associated variants and transcription factors essential for atrial rhythm control and contractility. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based epigenetic editing validates the function of several AF-associated regulatory elements and their downstream targets. Notably, reduced accessibility at an intronic SCN10A enhancer harboring the AF-associated SNP rs6801957 is associated with reduced sodium current in p.S143P iPSC-aCMs. These findings are reproduced in iPSC-aCMs derived from an additional individual carrying a distinct pathogenic LMNA variant, supporting a broader mechanism in which rare LMNA variants and common polymorphisms converge on shared regulatory networks to influence AF susceptibility and highlighting the value of integrating both in arrhythmia risk assessment.