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Characterizing modifier genes of cardiac fibrosis phenotype in hypertrophic cardiomyopathy

Fuyi Xu1, Yuanjian Chen1, Kaitlin A Tillman1

  • 1Division of Cardiovascular Diseases, Department of Medicine, Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, United States of America.

International Journal of Cardiology
|February 2, 2021
PubMed

Insights

Genetic modifiers for cardiac fibrosis in hypertrophic cardiomyopathy (HCM) differ between sexes. This study identified distinct candidate genes, Nek6 and Nr6a1 in males, and Nipsnap3b and Fktn in females, influencing fibrosis severity.

Area of Science:

  • Genetics
  • Cardiovascular Biology
  • Animal Models

Background:

  • Hypertrophic cardiomyopathy (HCM) exhibits variable clinical phenotypes, even with identical gene mutations.
  • Unidentified modifier loci are believed to regulate this phenotypic variability.
  • Cardiac fibrosis is a major HCM phenotype requiring investigation into its genetic underpinnings.

Purpose of the Study:

  • To identify modifier genes contributing to cardiac fibrosis in hypertrophic cardiomyopathy.
  • Utilize the BXD family of mice as a cohort for genetic mapping.
  • Investigate sex-specific genetic influences on cardiac fibrosis.

Main Methods:

  • Quantified cardiac collagen volume fraction (CCVF) to assess fibrosis severity in 66 BXD mice.
  • Performed quantitative trait locus (QTL) mapping for cardiac fibrosis using GeneNetwork.
  • Prioritized candidate modifier genes using a scoring system and analyzed transcriptome correlations.

Main Results:

  • Significant CCVF-related QTLs were identified on chromosome 2 in males and chromosome 4 in females.
  • Nek6 and Nr6a1 emerged as strong candidate genes on chromosome 2, with Nek6 mRNA levels correlating with CCVF.
  • Nipsnap3b and Fktn were identified as top candidate genes on chromosome 4, with Nipsnap3b expression correlating with CCVF.

Conclusions:

  • Candidate modifier genes for cardiac fibrosis in HCM are sex-specific.
  • Nek6 and Nr6a1 are identified as key male-specific modifiers.
  • Nipsnap3b and Fktn are identified as key female-specific modifiers.
Abstract

Keywords:
Cardiac fibrosisHypertrophic cardiomyopathyModifier genesMurine genetic reference population

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