title: CLCNKB-T481S and essential hypertension in a   Ghanaian population.
abstract: OBJECTIVE
  Prior to the discovery of chloride channel Kb with a variant threonine change to serine at position 481 (CLCNKB-T481S) there were no variants or clinical disorders associated with gain-of-function defects in thick ascending limb of the kidney channels or transporters. CLCNKB-T481S is a novel gain-of-function variant that has been associated with essential hypertension. This finding has not been replicated until our current study. In this study, we re-examined CLCNKB-T481S using a large homogenous population from Ghana, and coupled genetic analyses with the functional characterization of this polymorphism using a mammalian expression system.
  
  
  METHODS
  We genotyped CLCNKB-T481S in four ethnically defined control populations and a homogenous cohort of normotensive and hypertensive Ghanaians. Functional analysis was performed by whole-cell patch-clamp recording of tsA201 cells (a cell line derived from the human renal cell line, HEK-293) transiently transfected with ClC-Kb and barttin.
  
  
  RESULTS
  CLCNKB-T481S was found more commonly in the African and Caucasian-Americans when compared with the Asian and Hispanic American populations, having minor allele frequencies of 0.20, 0.15, 0.06 and 0.01 respectively. Additionally, CLCNKB-T481S was significantly associated with hypertension in Ghanaian males. In stratified logistic regression analysis with Ghanaian males, we observed a significant odds ratio of 3.29 (1.17-9.20 95% confidence interval, P=0.024) in the recessive model (TT versus AT&TT). Unlike previous results obtained in Xenopus oocytes, coexpression of CLCNKB-T481S with the obligatory accessory subunit barttin in tsA201 cells did not generate larger currents than coexpression of the wild-type allele.
  
  
  CONCLUSIONS
  We conclude that CLCNKB-T481S is associated with essential hypertension in males within the Ghanaian population; however, further studies are needed to understand its sex and ethnic segregation as well as to identify cellular factors that account for the divergent functional expression of ClC-Kb-T481S plus barttin in Xenopus oocytes and mammalian cells.
authors.affiliation: Department of Medicine, Division of Genetic Medicine, Vanderbilt University, Nashville, Tennessee 37232-0275, USA. saba.sile@vanderbilt.edu
authors.forename: Saba
authors.initials: S
authors.lastname: Sile
authors.forename: Digna R
authors.initials: DR
authors.lastname: Velez
authors.forename: Niloufar B
authors.initials: NB
authors.lastname: Gillani
authors.forename: Tinatin
authors.initials: T
authors.lastname: Narsia
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Vanoye
authors.forename: Scott M
authors.initials: SM
authors.lastname: Williams
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D044383:Black People / Q000235:genetics; D002460:Cell Line; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism; D004594:Electrophysiology; D005260:Female; D005838:Genotype; D005869:Ghana; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D044465:White People / Q000235:genetics
chemical_list: C412733:CLCNKB protein, human; D018118:Chloride Channels