Heredity of endothelin secretion - Human twin studies reveal the influence of polymorphism at the chromogranin a locus, a novel determinant of endothelial function

Article

关键词: TRAIT LINKAGE ANALYSIS;    BLOOD-PRESSURE;    GENE;    HYPERTENSION;    ANTAGONIST;    EXPRESSION;    DISEASE;    PLASMA;   

DOI  :  10.1161/CIRCULATIONAHA.106.648345

来源: SCIE

【 摘 要 】

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 (n = 238 pairs), plasma ET-1 was 58 +/- 5% (P < 0.0001) heritable. Plasma ET-1 was both correlated and associated with chromogranin fragment levels, and the 2 were influenced by shared genetic determination ( pleiotropy [rho(G)]; for the CHGA precursor, rho(G) = 0.318 +/- 0.105; P = 0.0032). We therefore hypothesized that variation in the CHGA gene may influence ET-1 secretion. Carriers of the CHGA promoter -988G, -462A, and -89A minor alleles showed significantly higher mean plasma ET-1 than their major allele homozygote counterparts (P = 0.02, P = 0.006, P = 0.03, 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 (P = 0.0075). In cultured human umbilical vein endothelial cells, CHGA caused dose-dependent secretion of ET-1 over a brief (< 1 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.

【 授权许可】

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