High frequency of SERPINA6 polymorphisms that reduce plasma corticosteroid-binding globulin activity in Chinese subjects.

Context: 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. Participants and Design: Blood samples from 2287 anonymous Chinese workers undergoing routine health tests were screened for the SERPINA6 coding sequence polymorphisms. Main Outcome Measures and 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. (J Clin Endocrinol Metab 97: E678-E686, 2012)