CLCNKB-T481S and essential hypertension in a Ghanaian population

Abstract

Objective Prior to the discovery of CLCNKB-T481S there were no variants or clinical disorders associated with gain-of-function defects in thick ascending limb (TAL) 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-examine 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 to the Asian and Hispanic American populations having minor allele frequencies of 0.20, 0.15 and 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% CI, p=0.024) in the recessive model (TT v AT&TT). Unlike previous results obtained in Xenopus oocytes, co-expression of CLCNKB-T481S with the obligatory accessory subunit barttin in tsA201 cells did not generate larger currents than co-expression 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 gender 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.

In-vivo administration of CLC-K kidney chloride channels inhibitors increases water diuresis in rats

“…Indeed, although with a large variation between ethnic populations [7][8][9][10], CLCNKA, CLCNKB and BSND are today proposed as candidate genes for hypertension [11,12]. Particularly, the common variant of ClC-Kb, T481S, shows greater chloride channel function than does wild-type ClC-Kb [13] and carriers of this variant show an increased systolic and diastolic pressure and increased likelihood of developing hypertension [14,15]. Four single-nucleotide polymorphisms within CLCNKA have been associated with salt-sensitive hypertension [16].…”

Lack of association of variants of the renal salt reabsorption-related genes SLC12A3 and ClC-Kb and hypertension in Mongolian and Han populations in Inner Mongolia

“…Subsequent studies performed on Australian, Swedish, Italian, and Japanese populations have failed to demonstrate a correlation between the ClC-Kb-T481S polymorphism and hypertension (Speirs et al, 2005;Kokubo et al, 2005;Fava et al, 2007;Barlassina et al, 2007). In contrast, Sile et al (2009) observed that ClC-Kb-T481S was associated with EH in males within the Ghanaian population; however, cultured mammalian cells that heterologously expressed ClC-Kb-T481S and the Barttin subunit did not perform significantly differently from the wild-type cells. In our study, we did not find an association between the ClC-Kb-T481S variant and essential hypertension in the Mongolian and Han populations.…”

Novel diuretic targets

“…The low blood pressure associated with defective ClC-Kb function suggests ClC-Kb is a target for antihypertensive drugs (41,81). This suggestion is further supported by the observation of an association between a common ClC-Kb polymorphism that increases channel activity and a predisposition to hypertension (7,37,62,73,126). However, it should be noted that such a predisposition has not been detected in all studies (17,37,73,132).…”

“…However, it should be noted that such a predisposition has not been detected in all studies (17,37,73,132). It has been suggested that salt-loading conditions as well as sex and ethic segregation need to be considered, and that larger studies are necessary to resolve the issue (73,126,150).…”