Pancreastatin: Multiple Actions on Human Intermediary Metabolism<i>in Vivo</i>, Variation in Disease, and Naturally Occurring Functional Genetic Polymorphism

O’Connor, Daniel T.; Cadman, Peter E.; Smiley, Clayton; Salem, Rany M.; Rao, Fangwen; Smith, Joshua W.; Funk, Stephen D.; Mahata, Sushil K.; Mahata, Manjula; Wen, Gen; Taupenot, Laurent; González-Yanes, Carmen; Harper, Kimberly L.; Henry, Robert R.; Sánchez‐Margalet, Víctor

doi:10.1210/jc.2005-0408

Cited by 80 publications

(93 citation statements)

References 46 publications

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“…37 We did not score any SNP variants within the pancreastatin/exon-5 region. However, because CHGA promoter variants are associated with albumin ( Figure 5) and are functionally active, 38 it is conceivable that CHGA promoter polymorphism leading to quantitative changes in pancreastatin expression could cause the differences in insulin sensitivity in the albumin quantiles (Table 1).…”

Section: Pancreastatinmentioning

confidence: 99%

Renal Albumin Excretion

et al. 2007

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Abstract-Albumin excretion marks early glomerular injury in hypertension. This study investigated heritability of albumin excretion in twin pairs and its genetic determination by adrenergic pathway polymorphism. Genetic associations used single nucleotide polymorphisms at adrenergic pathway loci spanning catecholamine biosynthesis, storage, catabolism, receptor action, and postreceptor signal transduction. We studied 134 single nucleotide polymorphisms at 46 loci for a total of Ͼ51 000 genotypes. Albumin excretion heritability was 45.2Ϯ7.4% (Pϭ2ϫ10 Ϫ7), and the phenotype aggregated significantly with adrenergic, renal, metabolic, and hemodynamic traits. In the adrenergic system, excretions of both norepinephrine and epinephrine correlated with albumin. In the kidney, albumin excretion correlated with glomerular and tubular traits (Na ϩ and K ϩ excretion; fractional excretion of Na ϩ and Li ϩ ). Albumin excretion shared genetic determination (genetic covariance) with epinephrine excretion, and environmental determination with glomerular filtration rate and electrolyte intake/excretion. Albumin excretion associated with polymorphisms at multiple points in the adrenergic pathway: catecholamine biosynthesis (tyrosine hydroxylase), catabolism (monoamine oxidase A), storage/release (chromogranin A), receptor target (dopamine D1 receptor), and postreceptor signal transduction (sorting nexin 13 and rho kinase). Epistasis (gene-by-gene interaction) occurred between alleles at rho kinase, tyrosine hydroxylase, chromogranin A, and sorting nexin 13. Dopamine D1 receptor polymorphism showed pleiotropic effects on both albumin and dopamine excretion. These studies establish new roles for heredity and environment in albumin excretion. Urinary excretions of albumin and catecholamines are highly heritable, and their parallel suggests adrenergic mediation of early glomerular permeability alterations. Albumin excretion is influenced by multiple adrenergic pathway genes and is, thus, polygenic. Such functional links between adrenergic activity and glomerular injury suggest novel approaches to its prediction, prevention, diagnosis, and treatment. Key Words: hypertension Ⅲ metabolic Ⅲ inflammation Ⅲ glomerulus Ⅲ catecholamine Ⅲ receptor Ⅲ adrenergic A lbumin excretion is a risk factor for adverse cardiovascular events, even in subjects without primary glomerular disease. 1 For example, studies in essential hypertension indicate that the prevalence of microalbuminuria may reach up to 11% to 17% among even nondiabetic individuals. 1 Indeed, even albumin excretion values less than those typically cited as constituting microalbuminuria or incipient nephropathy 1-3 may signal cardiovascular risk.The sympathetic nervous system exerts minute-to-minute control over both blood pressure and renal function. 4 An excess of sympathetic transmitters elevates urinary albumin excretion; indeed, a half-century ago, King and Baldwin 5 showed that systemic infusion of catecholamines (norepinephrine or epinephrine) elevates albumin excretion in asso...

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Section: Pancreastatinmentioning

confidence: 99%

Renal Albumin Excretion

et al. 2007

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“…Indeed, precedent exists for potent, biologically active peptides derived from other regions of CHGA. 31 Of particular note is the threshold concentration of CHGA to trigger ET-1 release ( Figure 4); 10 nmol/L approximates the plasma CHGA concentration circulating in healthy human subjects, 32 raising the likelihood that CHGA exerts not only local/ paracrine effects on the endothelium but also an endocrine/ systemic influence. Indeed, in our twin population, the plasma concentrations of CHGA 116 -439 span the range of 0.04 to 59.8 nmol/L, documenting that healthy humans possess circulating CHGA in the range capable of releasing ET-1.…”

Section: Chga and Endothelial Cell Biologymentioning

confidence: 99%

Heredity of Endothelin Secretion

Lillie

Mahata²,

Khandrika³

et al. 2007

Circulation

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Background-Endothelial dysfunction predisposes to vascular injury in association with hypertension. Endothelin (ET-1) is a potent vasoactive peptide that is synthesized and released by the vascular endothelium and is a marker of endothelial function. Chromogranin A (CHGA) regulates the storage and release of catecholamines and may have direct actions on the microvasculature. CHGA, a candidate gene for intermediate phenotypes that contribute to hypertension, shows a pattern of single nucleotide polymorphism variations that alter the expression and function of this gene both in vivo and in vitro. Methods and Results-In a study of twins (nϭ238 pairs), plasma ET-1 was 58Ϯ5% (PϽ0.0001) heritable. Plasma ET-1 was both correlated and associated with chromogranin fragment levels, and the 2 were influenced by shared genetic determination (pleiotropy [ G ]; for the CHGA precursor, G ϭ0.318Ϯ0.105; Pϭ0.0032). We therefore hypothesized that variation in the CHGA gene may influence ET-1 secretion. Carriers of the CHGA promoter Ϫ988G, Ϫ462A, and Ϫ89A minor alleles showed significantly higher mean plasma ET-1 than their major allele homozygote counterparts (Pϭ0.02, Pϭ0.006, Pϭ0.03, respectively). Analysis of a linkage disequilibrium block that spans these 3 single nucleotide polymorphisms showed a significant association between the GATACA haplotype and plasma ET-1 (Pϭ0.0075). In cultured human umbilical vein endothelial cells, CHGA caused dose-dependent secretion of ET-1 over a brief (Ͻ1 hour) time course at relatively low concentrations of CHGA (10 to 100 nmol/L) with a threshold concentration (10 nmol/L) in the range found circulating in humans in vivo. Conclusions-These results suggest that common, heritable variation in expression of the human CHGA gene influences endothelial ET-1 secretion in vivo, explained by a CHGA stimulus/ET-1 secretion coupling in endothelial cells in vitro.The findings document a previously unsuspected interaction between the sympathochromaffin system and the endothelium and suggest novel genetic and cell biological approaches to the prediction, diagnosis, and mechanism of endothelial dysfunction in human disease.

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“…It is known that protein CHGA is the source of the dysglycemic peptide pancreastatin (PST) (human CHGA 250 to 301 ) [22], which antagonizes the effects of insulin on glucose and lipid metabolism coupled with its inhibitory effect on insulin secretion, and it is hypothesized that PST plays a crucial role in the development of insulin resistance. This hypothesis is supported by the observation that PST levels rise in T2DM [41,42]. Therefore, it is reasonable that the CHGA promoter variants (T-415C) and the Glu264Asp polymorphism could affect T2DM pathogenesis through the functional alteration of PST by regulating insulin secretion.…”

Section: Discussionmentioning

confidence: 80%

“…Alguns autores verificaram que as taxas de fluxo salivar foram significativamente reduzidos em pacientes diabéticos não insulinodependentes (39)(40)(41)(126)(127)(128)(129)(130)(131) Tanto o padrão quanto a taxa de processamento da CgA variam de forma tecido-específica.…”

Section: Diabetes Mellitus E Alterações Salivaresunclassified

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Concentração e perfil genético da Cromogranina A e a sua correlação com os aspectos salivar, dental e status periodontal : um estudo transversal em portadores de diabetes mellitus tipo 2

Kogawa¹

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Pancreastatin: Multiple Actions on Human Intermediary Metabolismin Vivo, Variation in Disease, and Naturally Occurring Functional Genetic Polymorphism

Cited by 80 publications

References 46 publications

Renal Albumin Excretion

Renal Albumin Excretion

Heredity of Endothelin Secretion

Concentração e perfil genético da Cromogranina A e a sua correlação com os aspectos salivar, dental e status periodontal : um estudo transversal em portadores de diabetes mellitus tipo 2

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