title: Genetic variation at the delta-sarcoglycan (SGCD) locus elevates heritable sympathetic nerve activity in human twin pairs.
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 (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.
authors.affiliation: Departments of Medicine (0838) and Pharmacology and Institute for Genomic Medicine, VA San Diego Healthcare System University of California, San Diego, California, USA.
authors.forename: C Makena
authors.initials: CM
authors.lastname: Hightower
authors.forename: Kuixing
authors.initials: K
authors.lastname: Zhang
authors.forename: José P
authors.initials: JP
authors.lastname: Miramontes-González
authors.forename: Fangwen
authors.initials: F
authors.lastname: Rao
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Wei
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Schork
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Nievergelt
authors.forename: Nilima
authors.initials: N
authors.lastname: Biswas
authors.forename: Manjula
authors.initials: M
authors.lastname: Mahata
authors.forename: Nina
authors.initials: N
authors.lastname: Elkelis
authors.forename: Laurent
authors.initials: L
authors.lastname: Taupenot
authors.forename: Mats
authors.initials: M
authors.lastname: Stridsberg
authors.forename: Michael G
authors.initials: MG
authors.lastname: Ziegler
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D053379:Chromogranin A / Q000378:metabolism; D005089:Exocytosis; D056426:Genetic Loci; D058685:Genetic Pleiotropy; D006801:Humans; D040582:Inheritance Patterns; D008875:Middle Aged; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism; D016716:PC12 Cells; D020641:Polymorphism, Single Nucleotide; D021381:Protein Transport; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D051381:Rats; D049031:Sarcoglycans / Q000235:genetics* / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000502:physiology*; D055815:Young Adult
chemical_list: C506150:CHGA protein, human; D053379:Chromogranin A; D049031:Sarcoglycans; D009638:Norepinephrine
keywords: catecholamine; cytoskeleton; delta-sarcoglycan; norepinephrine; secretion