Heritability and Genome-Wide Linkage in US and Australian Twins Identify Novel Genomic Regions Controlling Chromogranin A : Implications for Secretion and Blood Pressure

• Published in: Circulation (New York, N.Y.) N.Y.), 2008-07, Vol.118 (3), p.247-257
• Main Authors: O'CONNOR, Daniel T, GU ZHU, GREENWOOD, Tiffany A, SHIH, Pei-An Betty, COCKBURN, Myles G, ZIEGLER, Michael G, STRIDSBERG, Mats, MARTIN, Nicholas G, WHITFIELD, John B, FANGWEN RAO, TAUPENOT, Laurent, FUNG, Maple M, DAS, Madhusudan, MAHATA, Sushil K, MAHATA, Manjula, LEI WANG, KUIXING ZHANG
• Format: Article
• Language: English
• Subjects: Alleles; Australia; autonomic; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - genetics; Cardiology. Vascular system; Cardiovascular system; catecholamines; Chromaffin Cells - enzymology; Chromaffin Cells - secretion; Chromogranin A - blood; Chromogranin A - genetics; Chromogranin A - metabolism; Chromogranin A - secretion; Chromosome Mapping; Chromosomes, Human, Pair 17; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Environment; Exocytosis; Female; genes; Genetic Linkage; Genetic Variation; genetics; Genome, Human; Humans; hypertension; Hypertension - genetics; Male; Medical sciences; MEDICIN; MEDICINE; Middle Aged; Miscellaneous; nervous system; Peptide Fragments - blood; Peptide Fragments - genetics; Pharmacology. Drug treatments; Proton-Translocating ATPases - metabolism; Quantitative Trait, Heritable; Siblings; Twins - genetics; United States
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.107.709105

Chromogranin A (CHGA) triggers catecholamine secretory granule biogenesis, and its catestatin fragment inhibits catecholamine release. We approached catestatin heritability using twin pairs, coupled with genome-wide linkage, in a series of twin and sibling pairs from 2 continents. Hypertensive patients had elevated CHGA coupled with reduction in catestatin, suggesting diminished conversion of precursor to catestatin. Heritability for catestatin in twins was 44% to 60%. Six hundred fifteen nuclear families yielded 870 sib pairs for linkage, with significant logarithm of odds peaks on chromosomes 4p, 4q, and 17q. Because acidification of catecholamine secretory vesicles determines CHGA trafficking and processing to catestatin, we genotyped at positional candidate ATP6N1, bracketed by peak linkage markers on chromosome 17q, encoding a subunit of vesicular H(+)-translocating ATPase. The minor allele diminished CHGA secretion and processing to catestatin. The ATP6N1 variant also influenced blood pressure in 1178 individuals with the most extreme blood pressure values in the population. In chromaffin cells, inhibition of H(+)-ATPase diverted CHGA from regulated to constitutive secretory pathways. We established heritability of catestatin in twins from 2 continents. Linkage identified 3 regions contributing to catestatin, likely novel determinants of sympathochromaffin exocytosis. At 1 such positional candidate (ATP6N1), variation influenced CHGA secretion and processing to catestatin, confirming the mechanism of a novel trans-QTL for sympathochromaffin activity and blood pressure.