Genetic variation at the delta-sarcoglycan (SGCD) locus elevates heritable sympathetic nerve activity in human twin pairs

Authors

  • C. Makena Hightower,

    1. Departments of Medicine (0838) and Pharmacology and Institute for Genomic Medicine, VA San Diego Healthcare System University of California, San Diego, California, USA
    Search for more papers by this author
  • Kuixing Zhang,

    1. Departments of Medicine (0838) and Pharmacology and Institute for Genomic Medicine, VA San Diego Healthcare System University of California, San Diego, California, USA
    Search for more papers by this author
  • José P. Miramontes-González,

    1. Departments of Medicine (0838) and Pharmacology and Institute for Genomic Medicine, VA San Diego Healthcare System University of California, San Diego, California, USA
    2. Fundación Alfonso Martin Escudero – Spain and Medicina Interna Hospital, Universitario de Salamanca, Salamanca, Spain
    Search for more papers by this author
  • Fangwen Rao,

    1. Departments of Medicine (0838) and Pharmacology and Institute for Genomic Medicine, VA San Diego Healthcare System University of California, San Diego, California, USA
    Search for more papers by this author
  • Zhiyun Wei,

    1. Departments of Medicine (0838) and Pharmacology and Institute for Genomic Medicine, VA San Diego Healthcare System University of California, San Diego, California, USA
    Search for more papers by this author
  • Andrew J. Schork,

    1. Departments of Medicine (0838) and Pharmacology and Institute for Genomic Medicine, VA San Diego Healthcare System University of California, San Diego, California, USA
    Search for more papers by this author
  • Caroline M. Nievergelt,

    1. Departments of Medicine (0838) and Pharmacology and Institute for Genomic Medicine, VA San Diego Healthcare System University of California, San Diego, California, USA
    Search for more papers by this author
  • Nilima Biswas,

    1. Departments of Medicine (0838) and Pharmacology and Institute for Genomic Medicine, VA San Diego Healthcare System University of California, San Diego, California, USA
    Search for more papers by this author
  • Manjula Mahata,

    1. Departments of Medicine (0838) and Pharmacology and Institute for Genomic Medicine, VA San Diego Healthcare System University of California, San Diego, California, USA
    Search for more papers by this author
  • Nina Elkelis,

    1. Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
    Search for more papers by this author
  • Laurent Taupenot,

    1. Departments of Medicine (0838) and Pharmacology and Institute for Genomic Medicine, VA San Diego Healthcare System University of California, San Diego, California, USA
    Search for more papers by this author
  • Mats Stridsberg,

    1. Department of Medical Sciences, Uppsala University, Uppsala, Sweden
    Search for more papers by this author
  • Michael G. Ziegler,

    1. Departments of Medicine (0838) and Pharmacology and Institute for Genomic Medicine, VA San Diego Healthcare System University of California, San Diego, California, USA
    Search for more papers by this author
  • Daniel T. O'Connor

    Corresponding author
    1. Departments of Medicine (0838) and Pharmacology and Institute for Genomic Medicine, VA San Diego Healthcare System University of California, San Diego, California, USA
    • Address correspondence and reprint requests to Daniel T. O'Connor, Department of Medicine (0838), UCSD School of Medicine and VASDHS, 9500 Gilman Drive, La Jolla, CA 92093-0838, USA. E-mail: doconnor@ucsd.edu

    Search for more papers by this author

Abstract

The Syrian Cardiomyopathic Hamster (BIO-14.6/53.58 strains) model of cardiac failure, resulting from naturally occurring deletion at the SGCD (delta-sarcoglycan) locus, displays widespread disturbances in catecholamine metabolism. Rare Mendelian myopathy disorders of human SGCD occur, although common naturally occurring SGCD genetic variation has not been evaluated for effects on human norepinephrine (NE) secretion. This study investigated the effect of SGCD genetic variation on control of NE secretion in healthy twin pairs. Genetic associations profiled SNPs across the SGCD locus. Trait heritability (h2) and genetic covariance (pleiotropy; shared h2) were evaluated. Sympathochromaffin exocytosis in vivo was probed in plasma by both catecholamines and Chromogranin B (CHGB). Plasma NE is substantially heritable (p = 3.19E-16, at 65.2 ± 5.0% of trait variance), sharing significant (< 0.05) genetic determination with circulating and urinary catecholamines, CHGB, eGFR, and several cardio-metabolic traits. Participants with higher pNE showed significant (< 0.05) differences in several traits, including increased BP and hypertension risk factors. Peak SGCD variant rs1835919 predicted elevated systemic vascular compliance, without changes in specifically myocardial traits. We used a chimeric-regulated secretory pathway photoprotein (CHGA-EAP) to evaluate the effect of SGCD on the exocytotic pathway in transfected PC12 cells; in transfected cells, expression of SGCD augmented CHGA trafficking into the exocytotic regulated secretory pathway. Thus, our investigation determined human NE secretion to be a highly heritable trait, influenced by common genetic variation within the SGCD locus. Circulating NE aggregates with BP and hypertension risk factors. In addition, coordinate NE and CHGB elevation by rs1835919 implicates exocytosis as the mechanism of release.

Ancillary