TY - JOUR
T1 - Functional BSND Variants in Essential Hypertension
AU - Sile, Saba
AU - Gillani, Niloufar B.
AU - Velez, Digna R.
AU - Vanoye, Carlos G.
AU - Yu, Chang
AU - Byrne, Loretta M.
AU - Gainer, James V.
AU - Brown, Nancy J.
AU - Williams, Scott M.
AU - George, Alfred L.
N1 - Funding Information:
Supported by the National Institutes of Health, Bethesda, Maryland (DK071742, to S.S.), and the Robert Wood Johnson Foundation (Amos Medical Faculty Development Program, to S.S.), Silver Spring, MD.
PY - 2007/11
Y1 - 2007/11
N2 - Background: Defects in the handling of renal salt reabsorption may contribute to interindividual differences in blood-pressure regulation and susceptibility to hypertension. Sodium chloride reabsorption in the thick ascending limb (TAL) is dependent in part on the chloride channel, ClC-Kb (encoded by CLCNKB), and its accessory subunit, barttin (encoded by BSND). Methods: We investigated genetic variations in BSND in a screening population, and genotyped a homogenous cohort of normotensive and hypertensive Ghanaian subjects, in addition to four ethnically defined control populations. Functional consequences of the identified BSND variants were examined using a heterologous expression system. Results: Three novel, nonsynonymous coding-sequence single-nucleotide polymorphisms were identified (V43I, E255Q, and G284D) in the screening population. BSND-V43I was identified in African American, Asian, and Hispanic subjects, with minor allele frequencies of 0.14, 0.18, and 0.01, respectively, but it was absent in the Caucasian population. BSND-E225Q and BSND-G284D were rare variants. Two of these variants (V43I and G284D) exhibited partial loss-of-function phenotypes when heterologously expressed with ClC-Kb chloride channels in cultured cells. In logistic regression analyses, we observed no association between hypertension and BSND-I43 in our study population. However, we did observe significant deviation from Hardy-Weinberg equilibrium in the normotensive population. Conclusions: We conclude that BSND-V43I, a common variant conferring partial loss of function, exhibits significant deviation from Hardy-Weinberg equilibrium in the Ghanaian normotensive control population. However, it does not independently confer protection against hypertension.
AB - Background: Defects in the handling of renal salt reabsorption may contribute to interindividual differences in blood-pressure regulation and susceptibility to hypertension. Sodium chloride reabsorption in the thick ascending limb (TAL) is dependent in part on the chloride channel, ClC-Kb (encoded by CLCNKB), and its accessory subunit, barttin (encoded by BSND). Methods: We investigated genetic variations in BSND in a screening population, and genotyped a homogenous cohort of normotensive and hypertensive Ghanaian subjects, in addition to four ethnically defined control populations. Functional consequences of the identified BSND variants were examined using a heterologous expression system. Results: Three novel, nonsynonymous coding-sequence single-nucleotide polymorphisms were identified (V43I, E255Q, and G284D) in the screening population. BSND-V43I was identified in African American, Asian, and Hispanic subjects, with minor allele frequencies of 0.14, 0.18, and 0.01, respectively, but it was absent in the Caucasian population. BSND-E225Q and BSND-G284D were rare variants. Two of these variants (V43I and G284D) exhibited partial loss-of-function phenotypes when heterologously expressed with ClC-Kb chloride channels in cultured cells. In logistic regression analyses, we observed no association between hypertension and BSND-I43 in our study population. However, we did observe significant deviation from Hardy-Weinberg equilibrium in the normotensive population. Conclusions: We conclude that BSND-V43I, a common variant conferring partial loss of function, exhibits significant deviation from Hardy-Weinberg equilibrium in the Ghanaian normotensive control population. However, it does not independently confer protection against hypertension.
KW - BSND
KW - hypertension
KW - modifier gene
KW - protective alleles
KW - renal chloride channel
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U2 - 10.1016/j.amjhyper.2007.07.003
DO - 10.1016/j.amjhyper.2007.07.003
M3 - Article
C2 - 17954364
AN - SCOPUS:35348897136
VL - 20
SP - 1176-1182.e1
JO - American Journal of Hypertension
JF - American Journal of Hypertension
SN - 0895-7061
IS - 11
ER -