title: High frequency of SERPINA6 polymorphisms that reduce plasma corticosteroid-binding globulin activity in Chinese subjects.
abstract: BACKGROUND
  Cortisol is transported by corticosteroid-binding globulin (CBG) in blood. Single nucleotide polymorphisms (SNP) in the human CBG (SERPINA6) gene that disrupt CBG production or steroid binding are considered rare.
  
  
  OBJECTIVE
  The objective of the study was to identify and determine the frequency of SNP in SERPINA6 that influence the production or cortisol-binding properties of CBG in Chinese subjects.
  
  
  METHODS
  Blood samples from 2287 anonymous Chinese workers undergoing routine health tests were screened for the SERPINA6 coding sequence polymorphisms.
  
  
  RESULTS
  In a pilot study of 108 Chinese women, two nonsynonymous SNP were identified within SERPINA6 exon 2 encoding CBG A51V (n = 3) and CBG E102G (n = 1) variants. Sequence analysis of SERPINA6 exon 2 in a further 137 Chinese women revealed two other individuals with nonsynonymous SNP encoding CBGs R64Q and R64W as well as another CBG A51V carrier. The surprisingly high frequency of heterozygous CBG A51V carriers was confirmed in 1011 Chinese men (1:35) and 1031 other women (1:37). Individuals homozygous for these SNP were not identified. When expressed in Chinese hamster ovary cells, CBG A51V bound steroid normally, but its production/secretion was severely impaired; CBG E102G was produced normally, but its cortisol-binding capacity was abnormally low, whereas CBG R64Q and R64W were produced and bound cortisol normally.
  
  
  CONCLUSIONS
  Defects in CBG A51V production explain why plasma CBG levels in individuals heterozygous for this variant are approximately 50% lower than normal. The high frequency of CBG A51V will allow clinical consequences of CBG deficiencies to be assessed for the first time in large patient populations.
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Lin
authors.forename: Caroline
authors.initials: C
authors.lastname: Underhill
authors.forename: Jing-Hui
authors.initials: JH
authors.lastname: Lei
authors.forename: Anna
authors.initials: A
authors.lastname: Helander-Claesson
authors.forename: Hwa-Yong
authors.initials: HY
authors.lastname: Lee
authors.forename: Bernd R
authors.initials: BR
authors.lastname: Gardill
authors.forename: Yves A
authors.initials: YA
authors.lastname: Muller
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wang
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Hammond
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D016466:CHO Cells; D002681:China; D015331:Cohort Studies; D006224:Cricetinae; D003412:Cricetulus; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D008297:Male; D008958:Models, Molecular; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000378:metabolism; D014156:Transcortin / Q000032:analysis* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; C534935:SERPINA6 protein, human; D014156:Transcortin; D006854:Hydrocortisone