Vol.2, No.7, 682-684 (2010)
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/jo urna l/HEALTH/
Association of the CLC-Kb T481S polymorphism with
childhood hypertension
Rainer Büscher
University of Duisburg-Essen, Children’s Hospital, Pediatrics II, Essen, Germany;
Received 17 March 2010; revised 29 March 2010; accepted 31 March 2010.
Essential hypertension is a difficul t diagnosis in
children and the gene of the renal-epithelial
chloride channel ClC-Kb is potentially predis-
posing. In vitro studies have shown that a co-
mmon ClC-Kb threonine481serine (T481S) poly-
morphism leads to enhanced chloride channel
activity and may predispose for hypertension
(HT). We therefore analysed children at risk for
HT for the T481S polymorphism and associ-
ated genotype with blood pressure (BP) status.
A total of 48 children with essential hyperten-
sion (mean age 14.4 ± 2.7 years, 26 male; 22
female; mean BP 143.4 ± 7.5/88 ± 5.8 mmHg)
were compared with 78 children with white-coat
HT (WCHT), who showed occasionally hyper-
tensive BP values, which were not confirmed by
ambulatory blood pressure monitoring (mean
age 13.7 ± 2.5 years, 49 male, 29 female; mean
BP 122.4 ± 4.3/68.2 ± 3.5 mmHg). Other causes
of HT were excluded. Allelic frequencies of hy-
pertensive patients were not significantly dif-
ferent from those w ith WCHT (HT: A 0.84; T 0.16
vs. WCHT: A 0.85; T 0.15). However, the T-allele
was observed more frequently in WCHT sub-
jects with systolic and diastolic BP exceeding
the 90th percentile (A 0.71 ; T 0.29, n = 34, p < 0.05,
considered as borderline hypertensive). The
preliminary data suggest that children with
WCHT carry the ClC-Kb T481S polymorphism
more often and that this variant may predispose
for development of arterial HT.
Keywords: Essential Hypertension;
White-Coat Hypertension;
Ambulatory Blood Pressure Monitoring (Abpm);
Clc-Kb T481s Polymorphism;
Renal-Epithelial Chloride Channel
Essential hypertension in childhood is rare and in most
cases, diagnosis can only be confirmed by exclusion of
other causes of hypertension (HT) such as renovascular
disease, endocrine or cardiovascular disorders 1,2. In
childhood, HT is defined as blood pressure (BP) ex-
ceeding the 95th percentile for healthy children and Am-
bulatory Blood Pressure Monitoring (ABPM) is an im-
portant method for the detection and therapeutic moni-
toring of children and adolescents with HT 3-5. White
Coat Hypertension (WCHT) is the most common diag-
nosis in children referred for evaluation of HT (> 50%)
but there is doubt whether occasionally occurring hyper-
tensive episodes predispose for end-organ damage as
adult patient 6.
There is increasing evidence that disturbances in the
renal tubular sodium chloride (NaCl) reabsorption are
predisposing for the development of HT. The renal-
epithelial chloride channel ClC-Kb is expressed in the
baso-lateral cell membrane of the distal nephron and is
involved in NaCl reabsorption, therefore, the ClC-Kb
gene might influence development of HT. Recently, a
frequent polymorphism has been detected in the ClC-Kb
gene (threonine to serine amino acid change, T481S) and
in vitro data confirmed that the ClC-Kb T481S poly-
morphism leads to enhanced activation of the chloride
channel 7,8. Carriers of the ClC-Kb T481S polymor-
phism might therefore be at risk for elevated BP. How-
ever, this hypothesis has not been verified in a cohort of
hypertensive adult or paediatric patients so far.
The aim of our study is to geno type children and ado-
lescents at risk for development of essential hyperten-
sion for the ClC-Kb T481S polymorphism and associate
the presence of the polymorphism with elevated BP.
Over the past 15 years ABPM has been performed in
more than 3000 children in our department. Among th-
R. Büscher / HEALTH 2 (2010) 682-684
Copyright © 2010 SciRes. Openly accessible at http://www. scirp.org/journal/HEALTH/
ose, 126 Caucasian patients, who were seen at least three
times in our clinic, were diagnosed as WCHT. ABPM
(SpaceLabs 90217 oscillometric device, Redmond, Was-
hington, USA) confirmed hypertensive BP values ac-
cording to the percentiles o f Soergel et al. 3 in only 48
patients, while diagnosis was not confirmed in 78 pa-
tients. Organic reasons for HT like renovascular or car-
diovascular pathology or endocrine disorders were ex-
cluded and extended diagnostic analysis did not reveal
other feasible reasons for HT in 48 children. All 126
patients (48 HT, 22 female; 78 WCHT, 29 female) were
included in our study and EDTA blood samples or buccal
swabs were taken during a routine visit in order to gen-
erate genomic DNA. Patients were not significantly dif-
ferent regarding age (HT 14.4 ± 2.7 vs. WCHT 13.7 ±
2.5 years), height (HT 153.6 ± 22.6 vs. WCHT 151.5 ±
25.7 cm), weight (HT 57.1 ± 20.4 kg vs. WCHT 56.5 ±
23.9 kg) and BMI (HT 23.17 ± 5.0 vs. WCHT 23.75 ±
5.4 kg/m 2).
Genotyping f or th e ClC-Kb T4 81S polymorp hism was
performed using SSCP and direct sequencing as de-
scribed before 7,8. Results are expressed as mean ±
SEM. Comparison between the distribution of alleles
was performed using a 2-test. A p < 0.05 was consid-
ered statistically significant. The study was approved by
the board of ethics of the University of Duisburg-Essen
and all patients and their parents gave their written con-
A total of 126 patients were diagnosed as WCHT but
diagnosis was confirmed by ABPM in only 48 patients.
HT and WCHT patients were not different regarding
height, weight, and BMI. Systolic and diastolic BP was
significantly increased in hypertensive patients (systolic
daytime141 10 mmHg, diastolic daytime 83 11
mmHg; systolic nighttime 127 8, diastolic nighttime
67 13 mmHg) when compared to 78 WCHT patients
(systolic daytime 115 14 mmHg, diastolic daytime 71
10 mmHg; systolic nighttime 105 14, diastolic night-
time 60 8 mmHg).
A total of 126 patients were genotyped for the pres-
ence of the ClC-Kb T481S polymorphism (Table 1).
Allelic frequencies for the A- and T-allele in hyperten-
sive and WCHT patients were not significantly different
between both groups (A-allele: HT 0.84 vs. WCHT 0.85;
T-allele: HT 0.16 vs. WCHT 0.15) and did not differ
from data obtained from population studies in the litera-
ture 8 (Table 1). The distribution of all genotypes was
in Hardy-Weinberg equilibrium. When looking more de-
tailed in the group of WCHT patients whose BP exceeds
the 90th percentile, we identified 34 out of 78 patients
Table 1. Allele and genotype frequency distribution of ClC-Kb
Genotype HT (n = 48) WCHT (n = 78)
(homozygous noncarriers) 6 (75%) 58 (74.4%)
(heterozygote carriers) 9 (18.8%) 17 (21.8%)
(homozygous carr iers) 3 (6.2%) 3 (3.8%)
A-allele (n = 81) 0.84 (n = 133) 0.85
T-allele (n = 15) 0.16 (n = 23) 0.15
Allelic frequency of ClC-Kb T481S in WCHTchildren (RR >
90th percentile, n = 34)
A-allele (n = 48) 0.71
T-allele (n = 20) 0.29* vs. 0.15
*p < 0.05, Fisher exa ct te st a nd 2-test
(44%) fulfilling criteria of a borderline HT. In this sub-
group, the allelic frequency was significantly shifted
towards the T-allele (A-allele 0.71 vs. T-allele 0.29; p <
0.05 when compared to 0.15 in all other patients of this
group), suggesting that patients at risk for the develop-
ment of HT express the T-allele more often (Table 1).
Hypertension is a major risk factor for the development
of cardiovascular and cerebrovascular complications such
as heart attack and stroke 9. Hypertensive end-organ
damage has also been demonstrated in children and there
is a huge scientific and economic interest in identifying
children and adolescents at risk for developing HT in
order to initiate preventive treatment 10. Therefore,
even if HT does not appear to be significant initially,
children with borderline HT should have continuing fol-
low-up of their BP and monitoring for the complications
of HT. Our preliminary data suggest that children with
borderline HT carry the ClC-Kb T481S polymorphism
more often. The T481S polymorphism has been descri-
bed to be the first mutation that leads to a pronounced
gain of channel function and might therefore contribute
to elevated BP 7,8.
We are aware of the limitations of our retrospective
study such as small patients number and single center
design. However, this is the first study to support the in
vitro findings by Jeck and co-workers 7,8 that the
R. Büscher / HEALTH 2 (2010) 682-684
Copyright © 2010 SciRes. http://www.scirp.org/journal/HEALTH/
ClC-Kb T481S polymorphism detects children at risk for
development of HT while few other studies in adult hy-
pertensive patients d id not identify a positive correlation
so far 11 . Extended analysis and a larger population of
children with marginal elevated BP values are required
to clearly answer this question.
Openly accessible at
It is well known that renal tubular Na+ and Cl- trans-
port mediate BP control by influencing the extracellular
fluid volume 12. Therefore, genes involved in the
regulation of renal salt absorption are of potential inter-
est as candidate genes for the development of renal HT.
Jeck et al. 7,8 demonstrated that the ClC-Kb gene
T481S polymorphism leads to activation of the chloride
channel in the kidney. It is therefore feasible to hypo the-
size that also minor changes in th e handling of renal salt
absorption might lead to elevated BP. Proof of concept
using chloride absorption would be interesting to study.
However, due to the retrospective design of this study
and the lack of established standards in renal tubular
chloride handling in children, we are unable to test this
hypothesis in our study population.
It is important to know that all patients investigated
are European Caucasians which makes the possibility
unlikely that a subpopulation with a different ethnical
background exists Therefore, we can speculate that the
increased prevalence of the T-a llele in patients with bor-
derline HT is feasible and not biased by their genetic
background. However, other co-factors predisposing for
HT such as obesity or metabolic syndrome cannot be
ruled out 13. In this respect i t is interest ing t o no tice that
both, hypertensive and WCHT patients had an increased
BMI exceeding 23 kg/m2 making obesity a likely risk
fac t o r fo r de v e l o p m e n t o f H T in ou r s t u dy population.
In conclusion, children and adolescents with border-
line HT carry the ClC-Kb T481S polymorphism more
often and this genetic variant might predispose for the
development of arterial HT. Larger scale studies in ge-
netically diverse popu lations exclud ing other predispo se-
ing factors of HT a re needed to prove these observations.
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