CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 5, September/October 2011
242
AFRICA
hence adjust for the facts that firstly, offspring inherit their genes
from their parents, with specific probabilities; and secondly,
observations between family members are often more similar
(correlated). Ignoring the similarity, relatives might yield spuri-
ously significant results. QTDT incorporates variance compo-
nents methodology to adjust for identity-by-descent probabilities
between relatives. In order to eliminate the effect that differences
in factors can have: gender, race and age between the R563Q
groups, we adjusted our tests for them.
Results
Overall 136 individuals (45 index cases and 91 family members)
were studied, of whom 89 were heterozygous for the R563Q
mutation and 47 homozygous RR. No subjects in this study
were found to be homozygous for the variant allele. All patients
and subjects were from either mixed ancestry (Cape Coloured)
or Xhosa origins, and 67 (49%) were male. The demograph-
ics and other characteristics of the subjects are summarised in
Table 1. The
p
-values in Table 1 are for a test of association with
mutation status, after adjusting for gender, race, age and kindred
membership. Effect estimates were not done because tests were
performed on quantile-normalised variables, therefore only
p
-values are presented.
Forty-four index cases had hypertension and one was a
normotensive control identified in our previous study.
4
Twenty-
two index cases had at least one relative willing to participate in
the study. Of the relatives, 72 were first-degree relatives (brother,
sister, son, daughter, mother or father), 11 were nephew or niece,
two were half brothers, two half sisters and four were grandchil-
dren, in relation to the index cases.
There was a significant association between age and R563Q
mutation status (
p
<
0.001), confirming the necessity of adjust-
ing for age in all models. Heterozygous subjects were older than
than the homozygous RR subjects, with a median difference of
nine years.
More R563Q heterozygous subjects, compared with homozy-
gous RR, were receiving antihypertensive therapy, 66/89 (74%)
versus 14/46 (30%) respectively. Of the R563Q heterozygous
subjects, 71 (80%) had hypertension, while 17 (36%) of the
R563Q homozygous RR subjects were hypertensive (
p
<
0.005).
Only nine (14%) of the 71 heterozygous hypertensives were
controlled on their antihypertensive therapy, versus two (12%) of
the hypertensive homozygous RR subjects. Both mean systolic
(
p
=
0.039) and MAP (
p
=
0.049) were significantly higher in
the R563Q heterozygous subjects, despite antihypertensive treat-
ment not being removed prior to examination.
Six R563Q heterozygous subjects had hypokalaemia. Two
displayed the full Liddle’s syndrome phenotype during preg-
nancy, with severe unprovoked hypokalaemia (K
+
=
2.1 and
2.2 mmol/l), marked suppression of aldosterone and renin, and
hypertension. Three patients had hypertension and hypokalaemia
associated with the use of diuretics, and another was normoten-
sive with unprovoked hypokalaemia (K
+
=
3.3 mmol/l). A R563Q
homozygous RR family member had mild unprovoked hypoka-
laemia (3.4 mmol/l) and normal BP. However, the observed
difference in the mean serum potassium between the R563Q
heterozygous and homozygous RR groups was not significant
(
p
=
0.224).
Discussion
Historically, the genetic basis of hypertension has been a contro-
versial issue. Platt (1947)
8
proposed that essential hypertension
is a Mendelian dominant trait with a distinct division between
normotension and hypertension. On the other hand, Pickering
(1955)
9
proposed that hypertension was the extreme of the
normal distribution of blood pressure and argued against having
an arbitrary division between normotension and hypertension.
He believed that hypertension has a multifactorial genetic and
environmental basis with each individual trait having a small
effect on blood pressure. The multifactorial nature of inheritance
of blood pressure is now the accepted relationship between BP
and genetics.
The
b
-ENaC, however, has always been an attractive candidate
gene for a dominant form of hypertension since the discovery
that Liddle’s syndrome was caused by an activating mutation in
the
β
-subunit of the ENaC.
10
However, the prevalence of Liddle’s
syndrome was extremely rare, and, although several other more
common mutations have been found, their causal relationship to
TABLE 1. CHARACTERISTICS OF THE R563Q HETEROZYGOUSAND HOMOZYGOUS RR GROUPS.
QUANTITATIVEVARIABLESARE SHOWNAS MEDIANAND INTERQUARTILE (IQ) RANGE
R563Q heterozygous
R563Q normal
Index cases
Relatives
Relatives
Number Percentage
Number Percentage
Number Percentage
Male
19/45
42
24/44
55
24/47
51
Xhosa
14/45
31
8/44
18
7/47
15
Mixed ancestry
31/45
69
36/44
82
40/47
85
Hypertensive
44/45
98
27/44
61
17/47
36
Number Median IQ range Number Median IQ range Number Median IQ range
p
-value
Age (years)
45
54
(24, 78)
44
39
(14, 39)
46
34
(26, 44)
Systolic BP (mmHg)
45
159 (90, 270)
44
140 (92, 250)
47
132 (123, 149) 0.003
Diastolic BP (mmHg)
45
99 (60, 190)
44
82 (67, 155)
47
84
(73, 91)
0.01
MAP (mmHg)
45
121 (70, 217)
44
103 (77, 187)
47
101 (90, 110)
0.005
Serum potassium (mmol/l)
45
4.1 (2.1, 5.2)
39
4.2 (3.3, 4.9)
45
4.2 (4.0, 4.4)
0.224
p
-values are for tests of association between the transformed variable and R563Q mutation status, after adjusting for covariates: gender, race, age
and kindred membership, using QTDT. The number column for quantitative variables indicates the total number of individuals analysed for that
variable.
