Angiotensin ii type 1 receptor gene a1166c polymorphism in hypertension; a study on its influence on aortic stiffness and response to antihypertensive therapy among malays
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Date
2005
Authors
Rehman, Asia
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Abstract
Hypertension is a major contributor to cardiovascular disease (CVD) which is
the leading cause of death in Malaysia. Aortic stiffness (AS) is an independent
marker of cardiovascular (CV) morbidity and mortality in these patients.
Angiotensin II type 1 receptor (AT1 R) gene A 1166C polymorphism has been
shown to be associated both with essential hypertension and AS measured as
pulse wave velocity (PWV). Treatment with angiotensin converting enzyme
inhibitor (ACEI) perindopril has been shown to reduce PWV among
hypertensive patients carrying C1166 allele. Data on association of AT1 R gene
A1166C allele with hypertension among Asians is controversial, while little is
known about its association with PWV and its influence on response to
antihypertensive treatment. Studies in this thesis were done to determine (1) the
association between C1166 poiymorphism of AT1 R gene with hypertension and
PWV among Malay hypertensive and normotensive subjects and (2) to study its
influence on reduction in PWV comparing two blockers of the renin angiotensin
aldosterone system.
Two hundred and one hypertensive without evidence of CV complication and
201 age and sex matched normotensive subjects were studied in a cross
sectional design. Blood pressure (BP), PWV, anthropometric measurements
(height, weight, hip and waist circumference) , were recorded and waist hip ratio
and body mass index (BMI) were calculated . Venous blood samples were
obtained for routine laboratory investigations and genetic analysis. A 11 66C
polymorphism was detected by polymerase chain reaction followed by
restriction endonuclease digestion. In a second study 46 hypertensive subjects
without C1166 polymorphism of AT1R gene and withouf evidence of target organ
damage, were randomly assigned to receive either perindopril or losartan in a
double blind parallel fashion for 4 months after a washout period of two weeks.
During the study, dose was adjusted to achieve target blood pressure «140/90
mmHg) and if required indapamide 1.5 mg was added to the study medication.
Heart rate, systolic and diastolic blood pressure (SSP and DSP) and PWV were
measured at the baseline, one month and 4 months after treatment. In both
studies PWV was measured using automated Complior® machine. Data from
both studies was analyzed using statistical software (SPSS 11.0) using
appropriate tests·.
Results from study I showed that C1166 allele frequency was 7.96% among
hypertensive patients and 7.73% among the normotensive subjects. There was
therefore a slightly higher C1166 allele frequency in the hypertensive population
which was of borderline Significance (p = 0.091). There was no significant
difference in SSP and DSP between carriers and non carriers of C11 66 allele in
hypertensive group (p=0.09 and p=0.161, respectively). Likewise there was not
significant difference in SBP and DBP in the normotensive group (p=0.708 and
p=0.838, respectively) and in the overall study population (p=0.174 and
p=0.431, fer SSP and DBP respectively). Subjects carrying (:1166 allele had
slightly higher PWV as compared to non carriers in the hypertensive group
(11 .09 ± 2.08 vs. 10.72 ± 1.80; p = 0.093) which was also of borderline
significance. No difference in PWV was seen among carriers and non carriers in
the normotensive group (9.86 ± 1.18 vs. 9.53 ± 1.54, P = 0.440) . However
when both normotensives and hypertensives were analyzed together, C
1166
polymorphism carriers had significantly higher PWV as compared to those
without this polymorphism (10.52±1 .82 vs. 10.15±1 .80, p= 0.040). In study II, a
total of 19 hypertensive patients on losartan and 20 on perindopril completed
the study. In both the groups patients had similar age, anthropometric
measurements and sex distribution. There was no significant difference in
baseline BP (150.89 ± 13.91/93.68 ± 10.37 vs. 151 .85 ± 12.21/91 .65 ± 7.54, P
= 0.821 and 0.486) and PWV (11 .63 ± 1.75 vs.10.97 ± 1.69, P =0.293) between
the groups. After 4 months treatment there was a significant reduction from
baseline in SBP (13.57 ± 15.97, P = 0.002), DBP (8.26 ± 8.54, P = 0.001) and
PWV (0.83 ± 1.19, p=0.007) in the losartan group and SBP (17 .95 ± 12.26, P
<0.001), DBP (9.25 ± 6.23, P <0.001) and PWV (0.57 ± 1.22, p = 0.047) in the
perindopril group. However there was no Significant difference in reduction in
SBP (p=0.342), DBP (p = 0.681) and PWV (p = 0.521) between the two groups
among Malay hypertensive subjects without C1166 polymorphism. Regression
analysis showed that reduction in RWV by losartan and perindopril group was
independent of reduction in BP by these drugs and reduction in BP explained
about 22 % (~ = 0.221) in losartan group and 21 % (~ = 0.209) in perindopril
groups, of the total change in PWV.
among Malay hypertensive and normotensive subjects and it is not associated
with hypertension. A 11 66C polymorphism is not associated with PWV in
hypertensive patients and normotensive subjects but is Significantly associated
with PWV in the overall Malay population. Among Malay hypertensive subjects