CLCNKB-T481S and essential hypertension in a Ghanaian population.

Sile S, Velez DR, Gillani NB, Narsia T, Moore JH, George AL, Vanoye CG, Williams SM
J Hypertens. 2009 27 (2): 298-304

PMID: 19226700 · PMCID: PMC3845205 · DOI:10.1097/hjh.0b013e3283140c9e

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.

MeSH Terms (16)

Adult African Continental Ancestry Group Amino Acid Substitution Cell Line Chloride Channels Electrophysiology European Continental Ancestry Group Female Genotype Ghana Humans Hypertension Logistic Models Male Middle Aged Polymorphism, Genetic

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