CYP11B2 Polymorphism Research Articles

Association between Aldosterone Production and Variation in the 11β-Hydroxylase (CYP11B1) Gene

Variation in the region of chromosome 8 including the genes steroid 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) influences mineralocorticoid and glucocorticoid metabolism. However, the relative importance of polymorphisms in CYP11B1 and CYP11B2 in determining these phenotypes is unknown. Our objective was to investigate genetic influences of the CYP11B1 and CYP11B2 genes on mineralocorticoid metabolism. We measured 24-h urinary excretion of the key metabolites of the principal mineralocorticoids, glucocorticoids and androgens secreted by the adrenal cortex. We genotyped polymorphisms spanning the CYP11B1 and CYP11B2 genes, which together capture all common variations at the locus. Participants included 573 members of 105 British Caucasian families ascertained on a hypertensive proband. We assessed heritability of urinary tetrahydroaldosterone (THAldo) excretion and association of THAldo excretion with genotype. The heritability of THAldo excretion was 52% (P < 10(-6)). There was significant association between THAldo and genotype at several of the CYP11B1/B2 polymorphisms. The strongest association was observed at the rs6387 (2803A/G) polymorphism in intron 3 of CYP11B1 (P = 0.0004). Association followed a codominant model with a 21% higher THAldo excretion per G allele. Genotype at rs6387 accounted for 2.1% of the total population variability of THAldo. We found significant association between THAldo excretion and urinary total androgen excretion, urinary tetrahydrodeoxycortisol level, and urinary cortisol metabolites (all P < 0.001). Aldosterone synthesis is highly heritable and is affected by genotype at CYP11B1. Our findings support the hypothesis that genetically determined differences in 11-hydroxylation efficiency can have downstream effects on mineralocorticoid synthesis. Such effects may be of relevance to the development of low-renin essential hypertension.

PI-31Genotype frequencies for ten polymorphisms of the renin-angiotensin-aldosterone system between healthy French-Canadians and other ethnic groups

BACKGROUND/AIMS Differences exist in frequencies of certain genotypes within different populations. We analysed the polymorphism frequency of ten polymorphisms of the RAAS in our population and compared them to other ethnic groups. METHODS This is an observational study performed on 18 to 25 years old 200 healthy males of French-Canadian origin. The Gen Elute Blood Genomic DNA kit (Sigma PC# NA2020) was used to extract DNA. The studied polymorphisms were: ACE I/D, ATR1 A1166C, AGT M235T, AGT T174M, CYP11B2 T-344C, α-adducin G460W, beta-2 adrenergic receptor Q27E, bradykinin β2R +9/-9, eNOS T-786C and eNOS E298D. They were analysed by the standard PCR/enzymatic digestion/electrophoresis method. RESULTS All polymorphisms tested were in Hardy-Weinberg equilibrium. When compared to other ethnic groups, our population's genotype frequencies differed from the Asian and the African-American populations with respect to every polymorphism, except for the bradykinin β2R gene (data was unavailable) and differed from the African population with respect to the polymorphism of ACE, AGT235, AGT174 and CYP11B2. When compared with other Caucasian populations, we obtained different genotype frequencies for the ATR1, AGT235, beta-2 adrenergic receptor, eNOS-786 and eNOS298 genes. CONCLUSION Our study depicts the genetic profile of ten polymorphisms of the RAAS in French-Canadian healthy man. We noted differences in that profile when compared to Africans, African-Americans, Asians and other Caucasians. Clinical Pharmacology & Therapeutics (2005) 79, P15–P15; doi: 10.1016/j.clpt.2005.12.052

Lack of association between the CYP11B2 gene polymorphism and preeclampsia, eclampsia, and the HELLP syndrome in Turkish women

Objectives It is possible that altered control of aldosterone synthase gene (CYP11B2) expression or translation may be responsible for hypertension. Hypertension is one of the major components of preeclampsia. We present here a study investigating the association between the CYP11B2 gene polymorphism in the promoter region at the position of −344 and preeclampsia. Study design We analyzed a group of Turkish women for preeclampsia ( n = 143), eclampsia ( n = 36), and the HELLP syndrome ( n = 55) and compared them with controls ( n = 147). Genotypes for CYP11B2 were determined by polymerase chain reaction followed by digestion with BsuRI restriction enzyme. Results The −344T/T, −344C/T, and −344C/C genotypes were found at comparable frequencies among the study groups, between the study and control groups, and between the study groups combined and the control group ( p > 0.05). We combined the genotypes of TC and CC (polymorphic) and compared them with the TT (wild-type) genotype. There was no significant difference in the frequency of the TC plus CC genotypes among the study groups, between the study and control groups, and between the study groups combined and the control group ( p > 0.05). There was no association of the CYP11B2 polymorphism among the preeclampsia, eclampsia, and HELLP groups and controls. Conclusions The CYP11B2 gene polymorphism is not directly associated with preeclampsia, eclampsia, and the HELLP syndrome in women with these conditions. Therefore, this polymorphism may not be a risk factor for these disorders, at least not in the Turkish population.

319 Can genetic polymorphism of CYP11B2 be used as a marker of left ventricular remodeling in aortic stenosis?

319 Can genetic polymorphism of CYP11B2 be used as a marker of left ventricular remodeling in aortic stenosis?

No association between primary aldosteronism and two CYP11B2 polymorphisms in a well-characterized Australian sample

Two aldosterone (aldo) synthase gene (CYP11B2) polymorphisms have been reported to be associated with undifferentiated hypertension (HT), low renin HT and HT due to primary aldosteronism (PAL); (i) a C-344T substitution at a steroidogenic factor-1 binding site in the promoter and (ii) a conversion involving transfer of intron 2 from 11β-hydroxylase (CYP11B1). However, other studies have reported no association or implicated the other allele. So far, reported studies examining these polymorphisms have been confined to European or Japanese hypertensive populations. Using similar laboratory and statistical methods, we compared frequencies of these polymorphisms in 107 predominantly white Caucasian Australian patients with PAL (confirmed by fludrocortisone suppression testing after screening using aldo/renin ratio), with those in 99 normotensive controls. No differences in frequency were found for either polymorphism, whether comparing controls to all with PAL or to those with aldo producing adenoma [n=18] or bilateral adrenal hyperplasia [n=71] (differentiated by adrenal venous sampling). The two polymorphisms were in linkage disequilibrium, as previously reported. Reported associations with HT in several different populations could be due to linkage disequilibrium of these alleles with important functional polymorphisms. The conflicting association data may be a result of the CYP11B2 variants being present on multiple different risk haplotypes. Alternatively, ethnic background might be an important determinant of allele distribution for these polymorphisms. Given the current study's sample size, a direct effect of these polymorphisms in a small subset of our patients is possible, but it excludes overall relative risks greater than 1.9-fold. (See Table 1)

CYP11B2 gene polymorphisms and hypertension in highlanders accustomed to high salt intake

High salt intake is the main determinant of hypertension. The alleles, which once had adaptive value in the salt-poor environment, by promoting salt retention, now induce hypertension. It would be interesting to determine whether the variant alleles of the aldosterone synthase gene (CYP11B2), if related to exaggerated expression/altered activity, are associated with hypertension when combined with a salt-rich diet. To investigate the -344T/C, K173R and intron-2 conversion polymorphisms of CYP11B2 for an association with hypertension in highlanders accustomed to a high salt intake. Three CYP11B2 polymorphisms were compared with respect to frequencies and clinical characteristics in 190 normotensive highlanders (NHLs) and 100 hypertensive highlanders (HHLs). One-way ANOVA, chi2 test and logistic regression analysis were carried out to investigate the association of these polymorphisms with hypertension. The HHLs had significantly higher systolic blood pressure (SBP), diastolic blood pressure (DBP) (P < 0.0001), body mass index (BMI) (P = 0.0002), plasma aldosterone levels (P = 0.03) and aldosterone to plasma renin ratio (ARR) (P < 0.0001) and lower plasma renin activity (PRA) (P = 0.007). The -344T/C and K173R polymorphisms were in complete linkage disequilibrium with each other and the intron-2 conversion allele was in absolute association with the T allele. The TC/CC genotypes correlated with higher BMI when compared with TT genotype in the NHLs and the HHLs (P = 0.002 and 0.004, respectively). The intron-2 conversion heterozygotes/homozygotes correlated with higher SBP in the HHLs (P = 0.03) and significantly higher ARR when compared to IwIw (P = 0.02). Genotype combinations between the -344T/C and intron-2 conversion polymorphisms revealed that combinations with TC or CC genotypes inclined towards higher BMI in both the groups (P < 0.05). Our findings showed a correlation of C allele with high BMI, suggesting that -344T/C polymorphism is in linkage disequilibrium with a functional polymorphism on the adjacent 11-beta hydroxylase gene. The correlation of the intron-2 conversion allele with high SBP and ARR associates it with hypertension. The intron-2 conversion could be a functional variant, since it has been suggested to lead to overexpression of the gene; however, the presence of another functional variant in linkage disequilibrium within the gene cannot be ruled out.

Association of peripheral and central arterial wave reflections with the CYP11B2 ???344C allele and sodium excretion

Angiotensin II and aldosterone, generated by the angiotensin-converting enzyme (ACE) and aldosterone synthase (CYP11B2), respectively, not only regulate sodium and water homeostasis, but also influence vascular remodeling in response to high blood pressure. In the European Project on Genes in Hypertension (EPOGH), we therefore investigated whether the ACE I/D and CYP11B2 C-344T polymorphisms influence early arterial wave reflections, a measure of vascular stiffness. We measured the peripheral and central augmentation index of systolic blood pressure by applanation tonometry at the level of the radial artery in 622 subjects (160 families and 64 unrelated individuals) randomly recruited from three European populations, whose average urinary sodium excretion ranged from 196 to 245 mmol/day. In multivariate analyses, with sodium excretion analyzed as a continuous variable, we explored the phenotype-genotype associations by means of generalized estimating equations and the quantitative transmission disequilibrium test. The peripheral and central augmentation indexes were significantly higher in CYP11B2 -344C allele carriers than in -344T homozygotes. In offspring, early wave reflections increased with the transmission of the -344C allele. This effect of the CYP11B2 polymorphism occurred in subjects with a higher than median urinary sodium excretion (210 mmol/day). The ACE I/D polymorphism did not influence augmentation of systolic blood pressure. The CYP11B2 C-344T polymorphism affects arterial stiffness. However, sodium intake seems to modulate this genetic effect.

Genetic Variation at the Locus Encompassing 11-β Hydroxylase and Aldosterone Synthase Accounts for Heritability in Cortisol Precursor (11-Deoxycortisol) Urinary Metabolite Excretion

Genetic variation in the gene encoding aldosterone synthase (CYP11B2) has previously been shown to be associated with hypertension and left ventricular hypertrophy. The intermediate phenotype most consistently associated with variation at this locus is that of elevated plasma 11-deoxycortisol (S). However, in normal subjects, aldosterone synthase does not metabolize S, which is converted to cortisol (F) by the enzyme 11 beta hydroxylase, encoded by the gene CYP11B1, which lies adjacent to CYP11B2 on chromosome 8. It is possible that the quantitative trait locus for the phenotype is within CYP11B1 and that linkage disequilibrium across the extended locus could account for these observations. However, variation across the whole CYP11B1/B2 locus had not been extensively characterized with respect to these phenotypes. We genotyped six polymorphisms in the CYP11B2 gene and three polymorphisms in the CYP11B1 gene in 248 Caucasian nuclear families comprising 1428 individuals. We measured plasma levels of S and F in 460 individuals from 86 families and urinary excretion rates of tetrahydrodeoxycortisol (THS) and tetrahydrodeoxycorticosterone in 573 individuals from 105 families. We examined heritability of the phenotypes and their association with genotypes and haplotypes at this locus. All steroid phenotypes except urinary tetrahydrodeoxycorticosterone were highly heritable (P < 0.00001). There was strong linkage disequilibrium across the CYP11B1/B2 locus. There was modest evidence for association between polymorphisms of CYP11B2 and plasma levels of S (P = 0.02 for T4986C polymorphism) and the plasma S to F ratio, reflecting the activity of 11-beta hydroxylase (P = 0.01 for T4986C polymorphism). There was strong evidence for association between polymorphisms of both CYP11B1 and CYP11B2 and urinary THS, which was strongest for the CYP11B1 exon 1 polymorphism (P = 0.00002). Addition of other marker data to CYP11B1 exon 1 did not improve the fit of a log-linear model. Genotype at CYP11B1 explained approximately 5% of the variance in urinary THS excretion in the population. Thus, it is likely that linkage disequilibrium between causative CYP11B1 variants and CYP11B2 polymorphisms account for the previous observations. Further fine-mapping studies across the CYP11B1 locus are required to localize the causative variant(s) for the biochemical phenotype; this may also identify susceptibility alleles for hypertension and left ventricular hypertrophy.

Haplotypic analyses of the aldosterone synthase gene CYP11B2 associated with stage-2 hypertension in northern Han Chinese.

The objective of this study was to investigate the association of polymorphisms in the aldosterone synthase gene CYP11B2 (-344T/C, Lys173/Arg, and an intronic conversion [IC]) with stage-2 hypertension in northern Han Chinese. A total of 503 hypertensives and their age-, gender-, and area-matched controls were included in this study. The female hypertensives had significantly higher frequencies of the -344T, 173Lys, and IC-conversion alleles (p = 0.002, 0.002, and 0.014, respectively). The estimated frequency of haplotype composed of the -344T, 173Lys, and IC-conversion alleles (haplotype 4) was significantly higher in the female hypertensives compared with their controls (p = 0.007). Using a multivariate score test, we found that haplotype 4 remained associated with female hypertension after the adjustment for covariates (p = 0.003), while the haplotype 3 of T-Arg-WT showed a protective effect both in the males and in the females (p = 0.03 and 0.006, respectively). The odds ratio for haplotype phase of 4-4 was 2.60 (95% CI, 1.21-5.58) and for 3-3, 0.20 (95% CI, 0.03-0.77). These results indicate that the Lys173 and the IC-conversion allele of the CYP11B2 gene confer an increased risk for stage-2 hypertension in northern Han Chinese women.

CYP11B2 polymorphisms and home blood pressure in a population-based cohort in Japanese: the Ohasama study.

Genetic polymorphisms of the aldosterone synthase gene (CYP11B2) have been major targets of studies into the genetic factors involved in hypertension. We have identified three genetic variants of CYP11B2, -344C/T at the promoter region, a conversion in intron 2 from the CYP11B2 sequence to the CYP11B1 sequence, and R173K in exon 3, in the Japanese population. -344C/T and R173K were in complete linkage disequilibrium in CYP11B2, and -344C/T was in strong, but not complete, linkage disequilibrium with the polymorphism in intron 2. Thus, two genetic polymorphisms, -344C/T and the gene conversion in intron 2, were investigated in association with home blood pressure (BP) values and clinical parameters in 1,242 subjects aged 40 and over in Ohasama, a rural Japanese community. Hypertension was defined as being treated with antihypertensive medication and/or having home BP values of more than 135 mmHg in systole and/or 85 mmHg in diastole. The results demonstrated that the -344T allele was significantly associated with increased prevalence of hypertension (p=0.015 in multiple logistic regression analysis, adjusted by age, gender, BMI, and smoking status), though BP level was unaltered. This allele was also significantly related to the prevalence of cardiovascular diseases in the older population (60 < or = age, p=0.014). The resting polymorphism, a gene conversion in CYP11B2 intron 2, was not associated with any clinical parameters. Therefore, -344C/T polymorphism in CYP11B2 was considered an independent genetic factor possibly associated with hypertension or atherosclerotic diseases in the Japanese population.

The impact of polymorphisms in the gene encoding aldosterone synthase (CYP11B2) on steroid synthesis and blood pressure regulation

The terminal stages in the synthesis of aldosterone and cortisol are catalysed by the enzymes aldosterone synthase and 11β-hydroxylase respectively. We have previously reported that polymorphic variation in the 5′ promoter region (-344C/T) of the gene encoding aldosterone synthase (CYP11B2) is associated with increased aldosterone metabolite excretion and with hypertension associated with a raised aldosterone to renin ratio (ARR). Additionally, basal and ACTH-stimulated plasma levels of 11-deoxycortisol, the precursor of cortisol, are higher in subjects carrying the T-allelic variant. We have now identified in a family study (573 individuals from 105 extended families ascertained through a hypertensive proband) that excretion of the main metabolite of this steroid (tetrahydro-11-deoxycortisol, THS) is heritable (19.4%) and that the T-allele of CYP11B2 is more strongly associated with higher THS levels than the C-allele. Raised plasma and urinary levels of 11-deoxycortisol suggest that there is relative inefficiency of 11β-hydroxylation in the zona fasciculata; the P450 enzyme responsible for this step is encoded by the gene CYP11B1, which is highly homologous with and adjacent to CYP11B2. The association of genetic variation in the promoter of CYP11B2 which, in the adrenal cortex, is only expressed in zona glomerulosa, and zona fasciculata 11β-hydroxylation function is paradoxical. There may be linkage dys-equilibrium between this polymorphism and a quantitative trait locus (QTL) in CYP11B1. Chronic alteration of 11β-hydroxylase activity may increase ACTH drive to the adrenal cortex, altering the regulation of aldosterone synthesis. This may explain, at least partly, the association between CYP11B2 polymorphisms and hypertension.

CYP11B2 polymorphisms and cardiovascular risk factors

CYP11B2 polymorphisms and cardiovascular risk factors

Haplotype analysis of aldosterone synthase gene (CYP11B2) polymorphisms shows association with essential hypertension.

The CYP11B2 locus is an important candidate region in essential hypertension (HT). We therefore investigated CYP11B2 polymorphisms T-344C, T4986C and A6547G for association with essential HT. This included haplotype analysis and measurement of plasma aldosterone levels. The three single nucleotide polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis of genomic DNA from 146 HT and 291 normotensive (NT) white subjects of Anglo-Celtic descent, in whom parental blood pressure status was the same as the subjects'. Genotype and allele frequencies in HTs and NTs were compared by chi2 analysis. Linkage disequilibrium and haplotype frequencies were estimated by the program 'snphap'. Phenotype-genotype relationships were tested using one-way analysis of variance. The T-344C variant was associated with HT (chi2 = 7.4, P = 0.0064). This association was confined to female HTs (P = 0.0061 for genotypes, P = 0.0013 for alleles). A strong association with HT was also seen for the A6547G variant (P = 0.0015), being greatest in females (P < 0.0001). No association was seen for the T4986C variant. Haplotype analysis of the three single nucleotide polymorphisms across eight different haplotype combinations showed a significant association with HT (chi2 = 24, seven degrees of freedom, P < 0.001). No significant tracking of plasma aldosterone with genotype was observed. The T-344C and A6547G, but not the T4986C, variants of the aldosterone synthase gene are associated with HT in females of the Anglo-Celtic population studied. This was reinforced by haplotype analysis.

A biallelic gene polymorphism of CYP11B2 predicts increased aldosterone to renin ratio in selected hypertensive patients.

Altered control of aldosterone synthase (CYP11B2) gene expression may modulate aldosterone secretion, as suggested by a raised aldosterone to renin ratio (ARR) in some patients with essential hypertension. We compared the frequency of two linked CYP11B2 polymorphisms, one in the steroidogenic factor-1 (SF-1) binding site and the other an intronic conversion (Int2) in relation to ARR in 141 hypertensive patients. Patients were divided into groups with either normal or high supine ARR using a cut-off threshold of 145 pmol/liter per ng/liter. Supine ARR was normal in 104 patients and raised in 37 patients. The two polymorphisms were in strong linkage disequilibrium (chi(2) = 123.8; P < 0.0001). The SF-1 T and Int2 C alleles were more prevalent among patients with high ARR (46% and 43%, respectively) than with normal ARR (22% and 17%; P < 0.01 and P < 0.005, respectively). Odds ratios for raised ARR in subjects with a homozygous SF-1 T and Int2 C haplotype were 6.1 (95% confidence interval, 1.6-22.5; P < 0.005) when compared with the contrasting haplotype. Linear modeling of individual postural changes in renin and aldosterone showed a maximal achievable aldosterone increase of 110 pmol/liter with no mutated haplotype and 500 pmol/liter with two mutated haplotypes. These findings support the view of a molecular basis regulating aldosterone production.

Interaction between the C(-344)T polymorphism of CYP11B2 and age in the regulation of blood pressure and plasma aldosterone levels: cross-sectional and longitudinal findings of the Olivetti Prospective Heart Study.

To study the interaction between the C(-344)T polymorphism and known determinants (age, body mass and dietary sodium) of blood pressure and plasma aldosterone. Cross-sectional and longitudinal (1980-1995) survey of male workers in southern Italy. Medical centre of the Olivetti factories. In 1995, the C(-344)T polymorphism was characterized in 811 untreated men. A subgroup of 280 participants already seen in 1980 was the object of longitudinal analysis. Blood pressure, demographic, anthropometric and biochemical variables (serum and urinary electrolytes and plasma aldosterone) and frequency of the C(-344)T polymorphism. In the whole population, there was no difference among genotypes for any of the variables examined. However, multiple regression showed a significant interaction between age (but not body mass or sodium intake) and genotype with regard to systolic (P = 0.03) and diastolic ( P= 0.02) pressure variability independently of covariates. Diastolic pressure increased linearly with age in carriers of the T allele (TT, P<0.001 and TC, P= 0.005), but not in CC homozygotes ( P= 0.848). In T carriers - but not in CC homozygotes - blood pressure and serum potassium increased and plasma aldosterone and serum sodium decreased across quintiles of age (P< 0.001 for all trends). In the longitudinal study, diastolic pressure increased significantly over time only in T carriers (TC+TT: +2.6 +/- 0.6, versus CC: -0.4 +/- 1.5 mmHg, P= 0.04). Inter-individual variation of blood pressure and plasma aldosterone is affected by the interaction of C(-344)T polymorphism and ageing, thus supporting a role for this variant in mechanisms affecting blood pressure regulation.

Aldosterone synthase gene (CYP11B2) C-334T polymorphism, ambulatory blood pressure and nocturnal decline in blood pressure in the general Japanese population: the Ohasama Study.

The C-344T polymorphism in the 5'-flanking region of the aldosterone synthase (CYP11B2) gene has been suggested to be associated with hypertension and disturbed circadian blood pressure (BP) rhythm through its effect on aldosterone synthesis. However, previous findings on this topic have been inconsistent. A cross-sectional study. We investigated the CYP11B2 C-344T genotype in 802 subjects, aged 40 and over, in a Japanese community, who gave written informed consent and were monitored for 24 h ambulatory BP. The frequencies of the CC, CT, and TT genotypes in these Japanese subjects were 0.14, 0.44, and 0.42, showing a higher frequency of the T allele (0.64) than in Caucasians. Although there was no significant difference in 24 h ambulatory BP levels among the genotypes, the nocturnal decline in BP was significantly greater in the CC homozygous subjects than in other subjects (P = 0.0065 for systolic and P = 0.031 for diastolic decline in nocturnal BP). Detailed analyses demonstrated that this association was significant only in aged (60 years and over) or male subjects. The prevalence of previous cardiovascular disease was significantly less in these subjects with the CC genotype than in those with the TC and TT genotypes, although age, body mass index, male gender, smoking, use of alcohol and antihypertensive medication did not differ among the three genotypes. There was no significant difference among the three genotypes in biochemical and hormonal parameters. Although the C-344 T polymorphism of CYP11B2 did not directly influence the level of 24 h BP, the CC genotype was associated with decreased nocturnal BP in elderly or male Japanese. Since prevalence of previous cardiovascular disease was significantly less in homozygous CC subjects, greater nocturnal BP decline in this genotype appears to be beneficial in the circadian BP rhythm.

Lack of association between genetic polymorphism of CYP11B2 and hypertension in Japanese: the Suita Study.

Aldosterone synthase (CYP11B2) is a key enzyme in the biosynthesis of aldosterone. Recently, a polymorphism in the 5'-flanking region of the CYP11B2 gene [T(-344)C] has been reported to be associated with blood pressure and plasma aldosterone levels. We investigated the association between this polymorphism and hypertension in a large population-based sample of 4,000 Japanese. The genotype distribution in hypertensive subjects (n=1,535) was compared to that in normotensive subjects (n=2,514). In subjects not receiving antihypertensive medication, the influence of the genotype on blood pressure values adjusted for clinical covariates was analyzed. All analyses were performed separately for men and women. The genotype distribution did not differ between hypertensive and normotensive subjects in either men (frequency of C allele: 30.3% vs. 31.4%, p=0.48) or women (31.5% vs. 31.7%, p=0.93). There were no significant differences in systolic blood pressure, diastolic blood pressure, or pulse pressure among the three genotypes in either men or women who had not received hypertensive medication. Our data suggest that the T(-344)C polymorphism of CYP11B2 is unlikely to influence blood pressure status in the Japanese population.

HAPLOTYPES OF ALDOSTERONE SYNTHASE (CYP11B2) GENE IN THE GENERAL POPULATION OF JAPAN: THE OHASAMA STUDY

Since the identification of a chimeric aldosterone synthase which induces mendelian hypertension, polymorphisms in aldosterone synthase (CYP11B2) has been one of major targets for molecular analyses in association with hypertension. To date, four polymorphic variants of CYP11B2, −344T/C at promoter region, a gene conversion in intron 2, 2713A/G (in exon 3) which converts from Lys to Arg at codon 173 (K173R), and 4986T/C (in exon7) which converts from Val to Ala at codon 386 (V386A), have been identified in Caucasian population. Then, linkage disequilibrium between −344T/C polymorphism and a gene conversion in intron 2 or K173R mutation has been described, suggesting the presence of genetic haplotypes in Caucasians. Since the presence of a gene conversion in intron 2 or V386A mutation was still unknown in the Japanese population, all these polymorphisms were examined together to determine the CYP11B2 haplotypes of Japanese, using DNA samples from 1290 participants of the Ohasama study, who represent the general population of a rural community of northern Japan. Molecular analyses demonstrated the presence of a gene conversion of intron 2, but the absence of V386A mutation in Japanese population. The complete linkage disequilibrium between −344T/C polymorphism and K173R mutation was noted. Although −344T allele was linked either with a gene conversion in intron 2 or with normal intron 2, −344C allele was completely linked with normal intron 2. These results indicate the presence of 3 allelic haplotypes of CYP11B2, −344C with normal intron 2 and 173R, −344T with normal intron 2 and 173K, and −344T with converted intron 2 and 173K, in the general Japanese population. The frequency (total 1.0) was 0.35, 0.53, and 0.12, respectively. The presence of allelic haplotypes is considered to be an additional genetic information to individual polymorphism of CYP11B2 to determine the linkage between CYP11B2 polymorphisms and hypertension.

The Effects of an Aldosterone Synthase (CYP11B2) Gene Polymorphism on the Risk of Myocardial Infarction

Background and Objectives:Several polymorphisms of the renin-angiotensin-aldosterone system have been found to have pleiotropic effects on cardiovascular diseases. Polymorphism of the aldosterone synthase gene (CYP11B2, which may influence plasma aldosterone levels, has been reported to cause systemic hypertension, influence the left ventricular diameter and mass, and decrease baroreflex sensitivity of the cardiovascular syst- em. Through these mechanisms, it is thought to increase the risk of myocardial infarction (MI. Our study was designed to elucidate whether polymorphism of CYP11B2 increased the risk of MI. Subjects and Methods: We analyzed the genotypes of CYP11B2 and the classic risk factors of MI in 188 MI patients and 320 control subjects without history of MI. Results:There was no significant difference in the distribution of genotypes between the patient and control groups. Adjusting for the classical risk factors, multiple logistic regression an- alysis showed no significant effect of CYP11B2 gene polymorphism on the development of MI. However, the presence of the -344C allele is associated with a markedly increased MI risk conferred by classic risk factors including hypertension, smoking, and male sex. In particular, hypertension was not a significant risk factor as compared with non-hypertensive patients in subjects without -344C, but the relative risk was increased to 2.40 (95% CI:1.05-5.51, p<0.05 with -344C. The relative risks of smoking and male sex were also incre- ased with the presence of the -344C allele. Conclusion:CYP11B2 polymorphism is not an independent risk factor of MI, although hypertension, smoking, and male sex are more potent risk factors for MI in Koreans who possess the -344C allele. ( ( ( (Korean Circulation J 2001;31(12 :1261-1266

Lys 173 Arg and −344T/C Variants of CYP11B2 in Japanese Patients With Low-Renin Hypertension

We analyzed the association of 2 biallelic polymorphisms of CYP11B2 (P450c11AS) gene (1 in the Lys(173)Arg 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 Arg(173) 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 Arg(173) 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 Arg(173) genotypes indicated that these 2 variants were in complete linkage disequilibrium: -344C was present in a subset of chromosomes carrying the Arg(173) (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 Arg(173) and -344C variants in the CYP11B2 appear to be genetically linked to low-renin hypertension in the Japanese population studied.