Characterizing genetic variation of adrenergic signalling pathways in Takotsubo (stress) cardiomyopathy exomes

Adele H. Goodloe, Jared M. Evans, Sumit Middha, Abhiram Prasad, Timothy Mark Olson

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Aims Exome sequencing was used to genotype comprehensively a Takotsubo (stress) cardiomyopathy (TC) cohort, enabling investigation of a vast 486 gene network for adrenergic signalling.

Methods and results Twenty-eight TC subjects, including a mother-daughter pair and five recurrent cases, underwent whole-exome sequencing. Frequencies of 17 common, functional adrenergic polymorphisms were statistically similar to those of population controls. Filtering for rare, predicted-deleterious, catecholamine/adrenergic signalling variants revealed heterozygosity in 55 genes in TC cases and 59 genes in healthy controls. Overall allele burden was similar and did not discriminate clinical variables among TC subjects, but gene identities were largely cohort specific, and TC cases were enriched for variants within functional domains (68% vs. 48%, P =0.031). Two-thirds of TC cases carried more than one filtered adrenergic pathway variant, and 11 genes harboured a variant in ≥2 cases. The mother-daughter pair shared missense variants in highly conserved functional domains of ADH5, CACNG1, EPHA4, and PRKCA. An adrenergic pathway-independent analysis of the cohort exposed no common gene for TC.

Conclusions Overall, these data support genetic heterogeneity in TC susceptibility and a likely polygenic basis, conferring a cumulative effect on adrenergic pathway dysregulation in a subset of individual subjects. Study of larger cohorts and non-coding regulatory regions is warranted to define genetic risk factors for TC further.

Original languageEnglish (US)
Pages (from-to)942-949
Number of pages8
JournalEuropean Journal of Heart Failure
Volume16
Issue number9
DOIs
StatePublished - 2014

Fingerprint

Takotsubo Cardiomyopathy
Exome
Adrenergic Agents
Genes
Cohort Studies
Population Control
Genetic Heterogeneity
Gene Regulatory Networks
Nucleic Acid Regulatory Sequences
Catecholamines
Alleles
Genotype

Keywords

  • Cardiomyopathy
  • Exome
  • Genomics
  • Sequencing
  • Stress
  • Takotsubo
  • Women

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Characterizing genetic variation of adrenergic signalling pathways in Takotsubo (stress) cardiomyopathy exomes. / Goodloe, Adele H.; Evans, Jared M.; Middha, Sumit; Prasad, Abhiram; Olson, Timothy Mark.

In: European Journal of Heart Failure, Vol. 16, No. 9, 2014, p. 942-949.

Research output: Contribution to journalArticle

Goodloe, Adele H. ; Evans, Jared M. ; Middha, Sumit ; Prasad, Abhiram ; Olson, Timothy Mark. / Characterizing genetic variation of adrenergic signalling pathways in Takotsubo (stress) cardiomyopathy exomes. In: European Journal of Heart Failure. 2014 ; Vol. 16, No. 9. pp. 942-949.
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