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(Hypertension. 2000;35:699.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Lys173Arg and -344T/C Variants of CYP11B2 in Japanese Patients With Low-Renin Hypertension
From the Second Department of Internal Medicine (I.K., M.T., T.A., M.S., N.T.), University of the Ryukyus School of Medicine, Nishihara, Okinawa, Japan; and Kashiwa City Hospital (T.Y., T.N.), Kashiwa, Chiba, Japan.
Correspondence to Ichiro Komiya, MD, Second Department of Internal Medicine, University of the Ryukyus School of Medicine, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. E-mail cnoguchi{at}2naidomon.naha.okinawa.jp
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Abstract |
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Abstract—We analyzed the association of 2 biallelic polymorphisms of CYP11B2 (P450c11AS) gene (1 in the Lys173Arg of exon 3 and the other in the promoter at position -344T/C) with hypertension in 73 hypertensive patients and 134 normotensive subjects. The association between low-renin hypertension and angiotensin I–converting enzyme (ACE) gene was also analyzed. An elevated ratio of plasma aldosterone concentration to plasma renin activity was used to identify low-renin hypertension. Genotypes for CYP11B2 and ACE were determined through polymerase chain reactions. The Arg173 allele frequency did not differ between hypertensive patients considered as 1 group (34%) and normotensive control subjects (37%). However, only 22% of 58 CYP11B2 alleles studied in 29 patients with low-renin hypertension were Arg173 alleles, whereas the frequency of this allele was 41% in patients with normal- or high-renin hypertension (P=0.033). An analysis of the distribution of -344C and Arg173 genotypes indicated that these 2 variants were in complete linkage disequilibrium: -344C was present in a subset of chromosomes carrying the Arg173 (P<0.001 in low-renin hypertension). Therefore, the frequency of the -344C allele was low in the patients with low-renin hypertension compared with those with normal- or high-renin hypertension. Deletion (D) allele frequencies of the ACE gene were 31% in the patients with low-renin hypertension, 39% in the patients with normal- or high-renin hypertension, and 29% in normotensive control subjects. We detected an association between the CYP11B2 gene polymorphisms and low-renin hypertension with inappropriate elevation of aldosterone. The decreased frequencies of the Arg173 and -344C variants in the CYP11B2 appear to be genetically linked to low-renin hypertension in the Japanese population studied.
Key Words: hypertension, essential • cytochrome P-450 • polymorphism • aldosterone • renin-angiotensin system
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Introduction |
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Essential hypertension is thought to be a polygenic disease. Many gene polymorphisms have been proposed as possible markers for hypertension, including insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene,1 A1161C polymorphism of the angiotensin II type I receptor gene,2 and M235T angiotensinogen polymorphism.3 4 The renin-angiotensin-aldosterone system (RAS) is a key mechanism in the regulation of blood pressure. In addition to the vasoactive action, angiotensin II is a potent stimulus of aldosterone synthesis, which results in sodium and water retention.
We have reported that 12.4% of 436 Japanese hypertensive patients had low plasma renin activity (PRA) combined with a normal plasma aldosterone concentration (PAC), resulting in an elevated ratio of PAC to PRA (PAC/PRA),5 6 and we found that so-called pressure natriuresis was incomplete in this subgroup of patients.6 7 The inappropriate elevation of aldosterone in such hypertensive individuals suggests persistent mineralocorticoid synthesis despite minimal stimulation of RAS. The biosynthesis of aldosterone is controlled by P450c11AS, an enzyme encoded by the CYP11B2 gene, and is regulated by concentrations of angiotensin II and potassium.8 9 One mutation in the CYP11B2 gene causes corticosterone methyl oxidase deficiency.10 Gain-function mutations affecting P450c11AS could be the basis of some forms of low-renin essential hypertension in humans9 ; for 2 mutations in this gene, higher Vmax and lower Km values of enzyme activity were reported in Dahl R rats.11 Recently, Fardella et al12 reported genetic variation in CYP11B2 in Chilean patients with low-renin hypertension, with Arg173 alleles being found in patients with a PAC/PRA ratio of <830 rather than in the low-renin group. Davies et al13 found that the -344T allele in CYP11B2 was associated with higher aldosterone excretion in white patients with hypertension. In the present study, we sought to confirm this association between low-renin hypertension and the Lys173Arg allele or -344T/C polymorphisms of the CYP11B2 gene in sample patient populations of different ethnicity. For comparison, we also investigated insertion/deletion (I/D) polymorphism of intron 16 of the ACE gene.
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Methods |
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Patient Population
Seventy-three consecutive outpatients at Ryukyu University Hospital and Kashiwa City Hospital (29 men and 44 women, age range 46 to 64 years) who had well documented histories of essential hypertension were recruited for this study. Patients with a systolic blood pressure of >160 mm Hg, a diastolic blood pressure >95 mm Hg, or both on each of 3 clinic visits were deemed to have hypertension. All patients were Japanese, and their families had lived in Japan for at least 3 generations. Causes of secondary hypertension such as Cushing’s disease, primary aldosteronism, pheochromocytoma, and renovascular disease were excluded in all patients through appropriate clinical and biochemical examinations. None of patients had a history of diabetes, hyperlipidemia, peripheral vascular disease, or coagulopathy. The body mass index ranged from 21 to 26 kg/m2.
Control Subjects
We also studied 134 normotensive subjects (44 men and 90 women,
age range 44 to 65 years) who had systolic and
diastolic blood pressures of <140/80 mm Hg. Subjects
with renal failure were excluded from the study. The study was approved
by a review committee of the University of the Ryukyus School of
Medicine, and recruited subjects gave informed consent.
PAC/PRA Ratio
Peripheral blood samples were obtained with
participants in the supine position in the morning in the outpatient
department after the participants had rested for 30 minutes. None of
the patients were receiving antihypertensive medications. PRA and PAC
values were determined with radioimmunoassays. The PAC/PRA ratio was
calculated as described previously.14 Under normal
conditions, the PAC was 110 to 555 pmol/L, and the PAC/PRA ratio was
<830 pmol/L per ng · mL-1 ·
h-1.5 6 14 To facilitate
analysis, hypertensive patients were divided into groups with
elevated PAC/PRA ratios (low-renin hypertension) or normal to low
PAC/PRA ratios (normal- or high-renin
hypertension).5 6
Detection of CYP11B2 Gene Polymorphisms
Genomic DNA was prepared from peripheral white blood
cells according to a standard column extraction technique (Qiagen). Two
genotypes of CYP11B2 were determined through
polymerase chain reaction (PCR) amplification according to methods
described by Fardella et al12 and Hautanena et
al,15 respectively. The sequence of the sense
oligonucleotide primer for CYP11B2 gene was
5'-AGGCAGCTTCTACCAGGGCCCCAGTCACTC-3', and that of the antisense primer
was 5'-CCCCTCCCCTGCAAATCTCATCCC-TTA-3'.12 These 2
primers designed to flank the polymorphic region of the exon 3 in
the CYP11B2 gene allowed the detection of a 1286-bp fragment
as the Lys allele and of 1037- and 249-bp fragments as the Arg
allele after Bsu36I digestion.12
Another sequence of the sense oligonucleotide primer
for CYP11B2 gene was 5'-CAGGAGGAGACCCCATGTGAC-3', and that
of the antisense primer was 5'-CCACCACCCTGTTCAGCCC-3'.15
These 2 primers designed to flank the polymorphism of promoter
region in the CYP11B2 gene allowed the detection of 273-bp
and small fragments as the -344T allele and of 202-bp and small
fragments as the -344C allele after HaeIII
digestion.15
Detection of ACE I/D Polymorphism
The sequence of the sense oligonucleotide primer
for ACE gene I/D polymorphism was
5'-CTGGAGACCACTCCCATCCTTTCT-3', and that of the antisense primer was
5'-GATGTGGCCATCAC-TTTCGTCAGAT-3'.1 16 These 2 primers
designed to flank the polymorphic region of the ACE gene
allowed the detection of a 390-bp fragment as the insertion allele
and of a 190-bp fragment as the deletion allele.1 16
To avoid mistyping of the ACE D/D allele, PCR was
repeated with the use of allele-specific primers.17
PCR products were detected through electrophoresis in an agarose
gel and stained with ethidium bromide.12
Statistical Analysis
All data in the text and tables are reported as mean±SD.
Statistical analysis of the differences between groups was
performed with the use of ANOVAs, 
2 tests with
Yates’ correction, or Fisher’s exact probability test. Either 2x2 or
3x3 contingency tables were used with analysis by allele
or genotype, respectively. P<0.05 was considered
statistically significant.
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Results |
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PAC/PRA Ratio
Table 1 summarizes clinical and laboratory findings in hypertensive patients with or without an elevated PAC/PRA ratio and in the normotensive subjects. None of the participants had a PAC of >555 pmol/L. Blood pressures were significantly higher in the hypertensive groups than in the normotensive subjects. The ages of hypertensive and normotensive subjects did not differ significantly. Serum sodium concentrations were significantly higher in patients with low-renin hypertension than in those with normal- or high-renin hypertension (P=0.011) or the normotensive control subjects (P<0.001) (Table 1). A negative correlation between PAC/PRA ratio and serum potassium concentration existed in the patients with low-renin hypertension (P=0.011) (Figure 1), but there was no relationship between PAC/PRA ratio and serum potassium concentration in the patients with normal- or high-renin hypertension (data not shown).
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Association Between Low-Renin Hypertension and Polymorphisms in
CYP11B2 and ACE I/D Genes
We determined the presence of Arg173
alleles in all subjects through PCR amplification of
CYP11B2 gene exon 3 to 5, followed by digestion with
Bsu36I, which cleaves the Arg173
variant but not the Lys173 variant (Figure 2). No difference in
Arg173 allele frequency was evident between
hypertensive patients considered as 1 group (34%) and normotensive
control subjects (37%). However, of the 58 CYP11B2
alleles determined in 29 patients with low-renin hypertension, only
13 (22%) were Arg173 alleles compared with
36 of 88 alleles (41%) in patients with a normal- or high-renin
hypertension and 100 of 268 alleles (37%) in normotensive control
subjects (Table 2). Because -344C and
Arg173 genotypes were in complete linkage
disequilibrium (2=58.0, P<0.001 in
low-renin hypertension) (Table 2 and Figure 2), the
frequency of the -344C allele was also low in the patients with
low-renin hypertension compared with those with normal- or high-renin
hypertension (P=0.033). D allele frequencies of
ACE gene were 31% in patients with low-renin hypertension,
39% in patients with normal- or high-renin hypertension, and 29% in
normotensive control subjects (Table 2). No relation between
PAC/PRA ratio and Lys173Arg (or -344T/C)
genotypes existed in the patients with low-renin hypertension
(data not shown). However, their serum sodium concentrations were
slightly higher in the
Lys173/Lys173
genotype group than in the
Lys173/Arg173
genotype group (146.6±2.4 versus 144.6±2.4 mmol/L).
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TNAGG), which digests
Arg173 variant but not Lys173 variant.
Amplified 537-bp fragment was digested with HaeIII
(recognition sequence GG
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Discussion |
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The identification of genes involved in the pathogenesis of primary hypertension remains a major challenge.2 3 4 Genes that affect the RAS are attractive candidate genes, and nearly all accessible genes have been analyzed extensively. Among these candidate genes, CYP11B2 gene variation has been studied by some investigators13 15 18 19 ; a positive association with essential hypertension was -344T polymorphism in CYP11B2.13 18 However, other investigators found a positive association of -344C polymorphism with essential hypertension.15 Although Davies et al13 and Hautanena et al15 suggested that the -344T genotype group had higher urinary aldosterone excretion, others reported that the -344C genotype group had a higher PAC.19 Indeed, the -344T/C polymorphism is associated with essential hypertension. However, it is impossible to conclude which polymorphism is responsible for high blood pressure or high aldosterone secretion. On the other hand, Fardella et al12 found that more alleles in hypertensive subjects were Arg173 than in their normotensive group. They also found amino acid polymorphism showing Lys173 rather than Arg173 in CYP11B2 among a large number of Chilean patients with low-renin hypertension.12 Because spurious associations sometimes appear in 1 population due to genetic heterogeneity, association studies must be repeated in different populations to ensure that any association of a gene with a disease is pathogenetically significant.
We detected an association between CYP11B2 gene polymorphisms and hypertension with inappropriate elevations of aldosterone. The use of the PAC/PRA ratio as an index of the relationship between the stimulus to aldosterone secretion and the response facilitates the separation of clinical subtypes in essential hypertension.20 21 22 In an association study, subclassification of essential hypertension in this manner may be very important. Our results partly diverge from those of Fardella et al12 in allele frequencies among hypertensive patients. However, the low Arg173 allele frequency among patients with low-renin hypertension did not differ between their Chilean subjects (Arg173 allele frequency 21%) and our Japanese subjects (Arg173 allele frequency 22%).
No association between ACE I/D polymorphism and low-renin hypertension was detected in the present study. Several reports have failed to show an association between cardiovascular disease and ACE I/D polymorphism.23 24 25 26 Because the concentration of ACE is higher in individuals with D alleles,23 PAC may increase under low-renin conditions in such subjects. However, no relation between PAC/PRA ratio and ACE I/D genotypes existed in the patients with low-renin hypertension in the present study.
Although some mutations in human CYP11B2 may result in increases in aldosterone and 18-OH-corticosterone, the Arg173 and Lys173 variants are associated with similar levels of aldosterone secretion.12 This observation argues against autonomous production of aldosterone or other mineralocorticoids by 1 of these variant enzymes as a cause of PRA suppression or increased blood pressure. However, the decreased potassium concentration in the patients with low-renin hypertension is similar in pathophysiology to that in the patients with primary aldosteronism. The -344T/C polymorphism in CYP11B2 promoter region, which is steroidogenic factor-1 binding site, was reported to be associated with blood pressure13 15 18 or aldosterone secretion.13 15 19 The -344T/C and Lys173Arg polymorphisms proved to be in complete linkage disequilibrium in Japanese population. Although it is possible that the polymorphisms are in linkage with other causal mutations in neighboring genes, the decreased frequencies of Arg173 and -344C variants in CYP11B2 gene are genetically linked to low-renin hypertension in the Japanese population.
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Acknowledgments |
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This work was supported by Grant-in-Aid for Scientific Research 10671040 from the Ministry of Education, Science, and Culture.
Received September 10, 1999; first decision September 20, 1999; accepted October 15, 1999.
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