Measured haplotype analysis of the aldosterone synthase gene and heart size.
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Gene-association studies of heart size and the aldosterone synthase (CYP11B2) gene have produced inconsistent results, possibly because of limitations in the sample size and/or the number and location of the polymorphisms. An analysis of six polymorphisms spanning 6 kb of the CYP11B2 gene in Caucasian British families revealed a limited number of haplotypes because of strong linkage disequilibrium over this small region. The genotype and haplotype information was used in an association study involving 955 members of 229 families phenotyped for echocardiographic measures of heart size. In a mixed effects linear modelling analysis, the G5937C polymorphism was associated with cardiac wall thickness (P=0.02), and the intron conversion and A4550C polymorphisms were associated with left ventricular cavity size (P=0.02 and 0.002, respectively). Measured haplotype analyses confirmed the association of alleles at the intron conversion and G5937C polymorphisms with cardiac wall thickness (P=0.02), and alleles at the intron conversion polymorphism with left ventricular cavity size (P=0.04). The polymorphisms contributed to 2.0-3.4% of the variability in these traits. In summary, genetic polymorphisms at the CYP11B2 gene make a small contribution to quantitative variation in echocardiographic measures of heart size. These results point to the importance of analysing the full extent of genetic variation that captures the haplotype structure of a locus in gene association studies. (+info)
Salt sensitivity of Japanese from the viewpoint of gene polymorphism.
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Excess salt intake is an important environmental risk for the predisposition to essential hypertension. Previous physiological studies have shown that salt sensitivity is associated with insulin resistance, enhancement of sympathetic nerve activity and decrease of blood pressure decline at night. We have been examining the genetic importance of candidate gene polymorphisms of salt-sensitive hypertension using several populations. The angiotensinogen gene (AGT) is a thrifty gene which increases the risk for common disease with growth of civilization via sodium and body fluid retention. The CC genotype of the AGT/T+31C polymorphism, which is in complete linkage disequilibrium with the TT genotype of the M235T polymorphism, was associated with a decrease of blood pressure decline at night in the Ohasama Study. On the other hand, the Gly460Trp genotype of the alpha-adducin gene (ADD1) is associated with erythrocyte sodium transport and increases tubular sodium reabsorption and risk for hypertension. We also revealed in the Ohasama Study that the Trp460 allele of ADD1 is associated with hypertension in young subjects with low renin activity. In addition to these polymorphisms, the T(-344)C polymorphism in the promoter of the aldosterone synthase gene (CYP11B2) and the C825T polymorphism of the G-protein beta3 subunit gene (GNB3) are considered candidates for the genetic risk of salt-sensitive hypertension. We compared the allele frequency of five candidate genes between Japanese and Caucasians; the results showed that the frequencies of all alleles were significantly higher in Japanese than in Caucasians. This interesting finding might suggest a feasible explanation for the huge interracial differences in the frequency of salt-sensitive hypertension. (+info)
Association between aldosterone synthase (CYP11B2) polymorphism and left ventricular mass in human essential hypertension.
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OBJECTIVES: The aim of our study was to evaluate the relationship between aldosterone synthase gene polymorphism and cardiac dimensions in essential hypertension. BACKGROUND: Higher aldosterone synthase messenger ribonucleic acid levels in the human heart are accompanied by increased intracardiac aldosterone production, a phenomenon that is associated with cardiac fibrosis and hypertrophy. Recent evidence suggests that a polymorphism (-344C/T) in the promoter region of the aldosterone synthase gene is associated with increased constitutive aldosterone production. METHOD: Relationships between M-mode echocardiographic cardiac dimensions and aldosterone synthase -344C/T polymorphism were studied in 210 never-treated, middle-aged patients (age 41.6 +/- 1.4 years) affected by mild to moderate essential hypertension. Among these patients, 48 had the genotype -C344C, 97 had -C344T, and 65 had -T344T. Patients in the three groups were similar in terms of age, gender, body mass index, and blood pressure. RESULTS: Left ventricular (LV) mass and thickness were positively correlated with the number of T alleles: LV mass (CC, CT, and TT, respectively: 168 +/- 6.9, 179 +/- 5.2, and 193 +/- 6.9 g; p = 0.03), LV septal thickness (0.99 +/- 0.02, 1.03 +/- 0.02, and 11.08 +/- 0.03 cm, p = 0.04), PWT (0.93 +/- 0.03, 0.95 +/- 0.01, and 1.03 +/- 0.02 cm; p = 0.002), and relative wall thickness (38.3 +/- 1.2%, 38.8 +/- 0.8%, and 42.8 +/- 1.1%; p = 0.004). This trend was confirmed by linear regression, suggesting a "major gene" behavior for the T allele. Multiple regression analysis showed that this effect was independent of anthropometric and clinical factors, including adrenal aldosterone. CONCLUSIONS: Our data suggest that -344C/T polymorphism affects LV mass and thickness in essential hypertension, independent of adrenal aldosterone. A role for intracardiac aldosterone synthesis is hypothesized. (+info)
Similarity by state/descent and genetic vector spaces: analysis of a longitudinal family study.
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Using the genome-wide screening data of the Framingham Heart Study (394 nuclear families, 1328 genotyped subjects, 397 marker loci) we have quantified the underlying genetic diversity through high-dimensional genetic feature vectors and constructed a genetic vector space for the analysis of population substructure. Adaptive clustering procedures led to three major subgroups that were regarded as being related to "biological" ethnicity and that included more than 70% of the subjects. Based on these subgroups we addressed the question of ethnicity-related and ethnicity-independent risk factors for coronary heart disease (CHD). To this end, we relied upon hypertension as an endophenotype of CHD and applied a multivariate sib-pair method in order to search for oligogenic marker configurations for which the sib-sib similarities deviated from the parent-offspring similarities. Indeed, the latter similarities are always "0.5" irrespective of the affection status of parents and offspring. Loci with significant contributions to the oligogenic marker configuration constituted a CHD-specific genetic vector space. We found several ethnicity-independent signals. One signal on chromosome 8 may relate to the CYP11B1/CYP11B2 genes. (+info)
Aldosterone, through novel signaling proteins, is a fundamental molecular bridge between the genetic defect and the cardiac phenotype of hypertrophic cardiomyopathy.
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BACKGROUND: Human hypertrophic cardiomyopathy (HCM), the most common cause of sudden cardiac death in the young, is characterized by cardiac hypertrophy, myocyte disarray, and interstitial fibrosis. The genetic basis of HCM is largely known; however, the molecular mediators of cardiac phenotypes are unknown. METHODS AND RESULTS: We show myocardial aldosterone and aldosterone synthase mRNA levels were elevated by 4- to 6-fold in humans with HCM, whereas cAMP levels were normal. Aldosterone provoked expression of hypertrophic markers (NPPA, NPPB, and ACTA1) in rat cardiac myocytes by phosphorylation of protein kinase D (PKD) and expression of collagens (COL1A1, COL1A2, and COL3A1) and transforming growth factor-beta1 in rat cardiac fibroblasts by upregulation of phosphoinositide 3-kinase (PI3K)-p100delta. Inhibition of PKD and PI3K-p110delta abrogated the hypertrophic and profibrotic effects, respectively, as did the mineralocorticoid receptor (MR) antagonist spironolactone. Spironolactone reversed interstitial fibrosis, attenuated myocyte disarray by 50%, and improved diastolic function in the cardiac troponin T (cTnT)-Q92 transgenic mouse model of human HCM. Myocyte disarray was associated with increased levels of phosphorylated beta-catenin (serine 38) and reduced beta-catenin-N-cadherin complexing in the heart of cTnT-Q92 mice. Concordantly, distribution of N-cadherin, predominantly localized to cell membrane in normal myocardium, was diffuse in disarrayed myocardium. Spironolactone restored beta-catenin-N-cadherin complexing and cellular distribution of N-cadherin and reduced myocyte disarray in 2 independent randomized studies. CONCLUSIONS: The results implicate aldosterone as a major link between sarcomeric mutations and cardiac phenotype in HCM and, if confirmed in additional models, signal the need for clinical studies to determine the potential beneficial effects of MR blockade in human HCM. (+info)
CYP11B2 polymorphisms and home blood pressure in a population-based cohort in Japanese: the Ohasama study.
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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. (+info)
The transcriptional regulating protein of 132 kDa (TReP-132) differentially influences steroidogenic pathways in human adrenal NCI-H295 cells.
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Steroid hormones synthesized from cholesterol in the adrenal gland are important regulators of many physiological processes. It is now well documented that the expression of many genes required for steroid biosynthesis is dependent on the coordinated expression of the nuclear receptor steroidogenic factor-1 (SF-1). However, transcriptional mechanisms underlying the species-specific, developmentally programmed and hormone-dependent modulation of the adrenal steroid pathways remain to be elucidated. Recently, we demonstrated that the transcriptional regulating protein of 132 kDa (TReP-132) acts as a coactivator of SF-1 to regulate human P450scc gene transcription in human adrenal NCI-H295 cells. The present study shows that overexpression of TReP-132 increases the level of active steroids produced in NCI-H295 cells. The conversion of pregnenolone to downstream steroids following TReP-132 expression showed increased levels of glucocorticoids, C(19) steroids and estrogens. Correlating with these data, TReP-132 increases P450c17 activities via the induction of transcript levels and promoter activity of the P450c17 gene, an effect that is enhanced in the presence of cAMP or SF-1. In addition, P450aro activity and mRNA levels are highly induced by TReP-132, whereas 3beta-hydroxysteroid dehydrogenase type II and P450c11aldo transcript levels are only slightly modulated. Taken together, these results demonstrate that TReP-132 is a trans-acting factor of genes involved in adrenal glucocorticoid, C(19) steroid and estrogen production. (+info)
Predictive models for breast cancer susceptibility from multiple single nucleotide polymorphisms.
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Hereditary predisposition and causative environmental exposures have long been recognized in human malignancies. In most instances, cancer cases occur sporadically, suggesting that environmental influences are critical in determining cancer risk. To test the influence of genetic polymorphisms on breast cancer risk, we have measured 98 single nucleotide polymorphisms (SNPs) distributed over 45 genes of potential relevance to breast cancer etiology in 174 patients and have compared these with matched normal controls. Using machine learning techniques such as support vector machines (SVMs), decision trees, and naive Bayes, we identified a subset of three SNPs as key discriminators between breast cancer and controls. The SVMs performed maximally among predictive models, achieving 69% predictive power in distinguishing between the two groups, compared with a 50% baseline predictive power obtained from the data after repeated random permutation of class labels (individuals with cancer or controls). However, the simpler naive Bayes model as well as the decision tree model performed quite similarly to the SVM. The three SNP sites most useful in this model were (a) the +4536T/C site of the aldosterone synthase gene CYP11B2 at amino acid residue 386 Val/Ala (T/C) (rs4541); (b) the +4328C/G site of the aryl hydrocarbon hydroxylase CYP1B1 at amino acid residue 293 Leu/Val (C/G) (rs5292); and (c) the +4449C/T site of the transcription factor BCL6 at amino acid 387 Asp/Asp (rs1056932). No single SNP site on its own could achieve more than 60% in predictive accuracy. We have shown that multiple SNP sites from different genes over distant parts of the genome are better at identifying breast cancer patients than any one SNP alone. As high-throughput technology for SNPs improves and as more SNPs are identified, it is likely that much higher predictive accuracy will be achieved and a useful clinical tool developed. (+info)