Catecholamine release-inhibitory peptide catestatin (chromogranin A(352-372)): naturally occurring amino acid variant Gly364Ser causes profound changes in human autonomic activity and alters risk for hypertension.
BACKGROUND
Chromogranin A, coreleased with catecholamines by exocytosis, is cleaved to the catecholamine release-inhibitory fragment catestatin. We identified a natural nonsynonymous variant of catestatin, Gly364Ser, that alters human autonomic function and blood pressure.


RESULTS
Gly364Ser heterozygotes and controls underwent physiological and biochemical phenotyping, including catecholamine production, chromogranin A precursor, and its catestatin product. Case-control studies replicated effects of the gene on blood pressure in the population. Gly364Ser displayed diminished inhibition of catecholamine secretion from cultured neurons. Gly/Ser heterozygotes displayed increased baroreceptor slope during upward deflections (by approximately 47%) and downward deflections (by approximately 44%), increased cardiac parasympathetic index (by approximately 2.4-fold), and decreased cardiac sympathetic index (by approximately 26%). Renal norepinephrine excretion was diminished by approximately 26% and epinephrine excretion by approximately 34% in Gly/Ser heterozygotes. The coalescent dated emergence of the variant to approximately 70,000 years ago. Gly364Ser was in linkage disequilibrium with 1 major Chromogranin A promoter haplotype, although promoter haplotypes did not predict autonomic phenotypes. The 364Ser variant was associated with lower diastolic blood pressure in 2 independent/confirmatory groups of patients with hypertension; genotype groups differed by approximately 5 to 6 mm Hg, and the polymorphism accounted for approximately 1.8% of population diastolic blood pressure variance, although a significant gene-by-sex interaction existed, with an enhanced effect in men.


CONCLUSIONS
The catestatin Gly364Ser variant causes profound changes in human autonomic activity, both parasympathetic and sympathetic, and seems to reduce risk of developing hypertension, especially in men. A model for catestatin action in the baroreceptor center of the nucleus of the tractus solitarius accounts for these actions.
Rao
Fangwen
F
Department of Medicine, University of California at San Diego, USA.
Wen
Gen
G
Gayen
Jiaur R
JR
Das
Madhusudan
M
Vaingankar
Sucheta M
SM
Rana
Brinda K
BK
Mahata
Manjula
M
Kennedy
Brian P
BP
Salem
Rany M
RM
Stridsberg
Mats
M
Abel
Kenneth
K
Smith
Douglas W
DW
Eskin
Eleazar
E
Schork
Nicholas J
NJ
Hamilton
Bruce A
BA
Ziegler
Michael G
MG
Mahata
Sushil K
SK
O'Connor
Daniel T
DT
D000595:Amino Acid Sequence; D001341:Autonomic Nervous System / Q000502:physiology*; D001794:Blood Pressure / Q000235:genetics; D002395:Catecholamines / Q000378:metabolism*; D053379:Chromogranin A / Q000097:blood / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D014644:Genetic Variation; D023281:Genomics; D006239:Haplotypes; D006339:Heart Rate / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006973:Hypertension / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000097:blood / Q000235:genetics*; D010641:Phenotype; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000378:metabolism; D012307:Risk Factors; D017678:Sex Distribution
D002395:Catecholamines; D053379:Chromogranin A; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; C109084:chromogranin A (344-364)