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

Abstract

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 ϩ -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 ϩ -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. (Circulation. 2008;118:247-257.)

Natural Variation within the Neuronal Nicotinic Acetylcholine Receptor Cluster on Human Chromosome 15q24: Influence on Heritable Autonomic Traits in Twin Pairs

“…Murine Chrna3 overexpression increased CHGA/EAP chimera secretion, and the nicotinic-agonist evoked increase in chimera release was inhibited by catestatin. Although we have not yet determined the precise causal variant in the Chrna3 region, these cellular results suggest a hypothesis unifying our experimental observations as reported previously (O'Connor et al, 2008): Nicotinic agonist stimulation of nAChRs on chromaffin cells releases catestatin, which in negative feedback manner blocks nicotinic secretion. Augmented expression of the crucial ␣3 subunit of the nAChR affecting autonomic function (CHRNA3) may increase the gain of the system, thereby changing the coupling between catestatin modulation of nAChRs and BP.…”

Twin methodology in epigenetic studies

“…Non-paternity can result in a biased estimation of IBD probability, leading to incorrect linkage results in non-parametric linkage analysis (MacGregor et al, 2000). In fact, DZ twins have been used in linkage mapping of gene expression QTLs (De Moor et al, 2007;Livshits et al, 2007;Perola et al, 2007;O'Connor et al, 2008). Similarly, methods using sib-pairs (i.e.…”

Chromogranin A Regulates Renal Function by Triggering Weibel–Palade Body Exocytosis

“…6 Might such variation also change processing of CHGA to its bioactive peptide? We 13 and Stridsberg et al 14 have observed a reciprocal relationship between the circulating concentrations of CHGA and its fragments, likely reflecting processing of the prohormone to its active fragments in plasma.…”