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Genetic variation at the delta‐sarcoglycan ( SGCD ) locus elevates heritable sympathetic nerve activity in human twin pairs
Author(s) -
Makena Hightower C.,
Zhang Kuixing,
MiramontesGonzález José P.,
Rao Fangwen,
Wei Zhiyun,
Schork Andrew J.,
Nievergelt Caroline M.,
Biswas Nilima,
Mahata Manjula,
Elkelis Nina,
Taupenot Laurent,
Stridsberg Mats,
Ziegler Michael G.,
O'Connor Daniel T.
Publication year - 2013
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12346
Subject(s) - locus (genetics) , variation (astronomy) , biology , genetic variation , genetics , gene , physics , astrophysics
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 ( h 2 ) and genetic covariance (pleiotropy; shared h 2 ) 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 ( p < 0.05) genetic determination with circulating and urinary catecholamines, CHGB, eGFR , and several cardio‐metabolic traits. Participants with higher pNE showed significant ( p < 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.