title: Analysis and validation of traits associated with a single nucleotide polymorphism Gly364Ser in catestatin using humanized chromogranin A mouse models.
abstract: OBJECTIVE
  The human prohormone chromogranin A (CHGA), an index member of the granin family is processed to generate catestatin, a peptide that is hypotensive in action and modulates catecholamine release within the sympathoadrenal system. Hypertensive patients with excess sympathetic activity have diminished catestatin. Often the study of physiological consequences of human genetic variation is confounded by elements such as other variations in obligatory linkage disequilibrium with the variant being studied. Also the phenotype of the variant may be influenced by genetic background that varies amongst individuals. This study addresses the effects of a human catestatin polymorphism (rs9658667) using humanized CHGA mouse models.
  
  
  METHODS
  We created pertinent humanized mouse models wherein the mouse Chga gene locus was replaced by the human ortholog wild-type and the variant versions. This allowed for probing of the effects of catestatin variation in vivo with controls for other variations and global genetic background.
  
  
  RESULTS
  Both the wild-type and variant human catestatin expressing mouse models were normotensive. The variant catestatin mouse model recapitulated physiological influence of the polymorphism on autonomic traits. These mice had diminished catecholamine, attenuated stress response and increased baroreceptor slopes that would suggest reduced risk of developing hypertension. Elevated plasma glucose, a trait observed in humans was not observed in mice expressing the variant catestatin.
  
  
  CONCLUSIONS
  This functional genomics approach of creating humanized mouse models to study rs9658667 polymorphism recapitulated and validated many of the human trait associations. This approach can also be applied in the study of other human gene polymorphisms.
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California, USA.
authors.forename: Saiful A
authors.initials: SA
authors.lastname: Mir
authors.forename: Kuixing
authors.initials: K
authors.lastname: Zhang
authors.forename: Milos
authors.initials: M
authors.lastname: Milic
authors.forename: Yusu
authors.initials: Y
authors.lastname: Gu
authors.forename: Timo
authors.initials: T
authors.lastname: Rieg
authors.forename: Michael
authors.initials: M
authors.lastname: Ziegler
authors.forename: Sucheta M
authors.initials: SM
authors.lastname: Vaingankar
mesh_terms: D000818:Animals; D001341:Autonomic Nervous System / Q000502:physiology*; D001794:Blood Pressure; D002395:Catecholamines / Q000097:blood*; D053379:Chromogranin A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D023421:Models, Animal; D010446:Peptide Fragments / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011311:Pressoreceptors / Q000502:physiology; D013312:Stress, Physiological / Q000235:genetics
chemical_list: C506150:CHGA protein, human; D002395:Catecholamines; D053379:Chromogranin A; D010446:Peptide Fragments; C109084:chromogranin A (344-364)