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(Circulation. 2008;118:247-257.)
© 2008 American Heart Association, Inc.

Genetics

Heritability and Genome-Wide Linkage in US and Australian Twins Identify Novel Genomic Regions Controlling Chromogranin A

Implications for Secretion and Blood Pressure

Daniel T. O'Connor, MD^*; Gu Zhu, MD^*; Fangwen Rao, MM^*; Laurent Taupenot, PhD^*; Maple M. Fung, MD; Madhusudan Das, PhD; Sushil K. Mahata, PhD; Manjula Mahata, PhD; Lei Wang, BS; Kuixing Zhang, MD, PhD; Tiffany A. Greenwood, PhD; Pei-an Betty Shih, PhD; Myles G. Cockburn, PhD; Michael G. Ziegler, MD; Mats Stridsberg, PhD; Nicholas G. Martin, PhD; John B. Whitfield, PhD

From the Departments of Medicine and Pharmacology and Center for Human Genetics and Genomics, University of California at San Diego School of Medicine, and Veterans Affairs San Diego Healthcare System, La Jolla, Calif (D.T.O., F.R., L.T., M.M.F., M.D., S.K.M., M.M., L.W., K.Z., T.A.G., P.B.S., M.G.Z.); Queensland Institute of Medical Research, Brisbane, Queensland, Australia (G.Z., N.G.M., J.B.W.); Department of Medical Science, University of Uppsala, Uppsala, Sweden (M.S.); and Department of Preventive Medicine, University of Southern California, Los Angeles (M.G.C.).

Correspondence to Daniel T. O'Connor, MD, Laurent Taupenot, PhD, or John B. Whitfield, PhD, Department of Medicine and Center for Human Genetics and Genomics, University of California at San Diego School of Medicine, 9500 Gilman Dr, La Jolla, CA 92093-0838. E-mail doconnor{at}ucsd.edu, ltaupenot@ucsd.edu, or john.whitfield@qimr.edu.au

Received April 12, 2007; accepted March 20, 2008.

Background— 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.

Methods and Results— 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.

Conclusions— 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.

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