Subtype prediction in primary aldosteronism: measurement of circadian variation of adrenocortical hormones and 24-h urinary aldosterone.

OBJECTIVE: Currently, adrenal venous sampling (AVS) is the only reliable method to distinguish unilateral from bilateral hyperaldosteronism in primary aldosteronism (PA). However, AVS is costly and time-consuming compared with simple blood tests. In this study, we conducted a retrospective study to determine whether circadian variation in plasma adrenocortical hormone levels (i.e. aldosterone, cortisol and ACTH) and a 24-h urinary aldosterone could contribute to the clinical differentiation between unilateral hyperaldosteronism (UHA) and bilateral hyperaldosteronism (BHA). DESIGN: In 64 patients who were diagnosed with PA and underwent AVS, 32 and 22 patients were diagnosed with UHA and BHA, respectively. Plasma adrenocortical hormone levels at 0:00, 6:00, 12:00 and 18:00 and 24-h urinary aldosterone under a condition of 6 g daily dietary sodium chloride intake were measured. RESULTS: Baseline plasma aldosterone concentration (PAC) and 24-h urinary aldosterone level in patients with UHA were significantly higher than in patients with BHA, particularly at 6:00. The area under the ROC curve for PAC at 0:00, 6:00, 12:00 and 18:00 and 24-h urinary aldosterone to discriminate UHA and BHA was 0·839 [95% confidence interval (CI); 0·73-0·95], 0·922 (95% CI; 0·85-1·00), 0·875 (95% CI; 0·78-0·97), 0·811 (95% CI; 0·69-0·93), 0·898 (95% CI; 0·81-0·99), respectively. CONCLUSIONS: PAC at different blood sampling times and 24-h urinary aldosterone level may be diagnostically helpful in discriminating between UHA and BHA. We believe that these tests could reduce the number of unnecessary AVS procedures.

Association of the smoothelin (SMTN) gene with cerebral infarction in men: a haplotype-based case-control study.

Smoothelin is a specific type of cytoskeletal protein found in smooth muscle cells (SMCs). Several previous research studies have examined the relationship between smoothelin and atherosclerotic plaque. The aim of the present study was to further assess the association between the human SMTN gene and cerebral infarction (CI) using a haplotype-based case-control study. A total of 168 CI patients and 259 supercontrols were genotyped for the five single-nucleotide polymorphisms (SNPs) used as genetic markers for the human SMTN gene (rs2074738, rs5997872, rs56095120, rs9621187 and rs10304). Data were analyzed for three separate groups that included total subjects, men and women. The genotypic distribution of rs10304 for men showed a significant difference between the control and CI groups. In addition, the frequency of the C-T-T-A haplotype (established by rs5997872, rs56095120, rs9621187 and rs10304) was significantly higher in the CI versus the control group (p = 0.013), while the frequency of the C-A-T-G haplotype (established by rs5997872, rs56095120, rs9621187 and rs10304) in the CI group was significantly lower than that seen in the controls (p = 0.021). In conclusion, we confirmed that the haplotype constructed using rs5997872, rs56095120, rs9621187 and rs10304 was a useful genetic marker of CI in Japanese men.

The insulin-like growth factor-1 gene is associated with cerebral infarction in Japanese subjects.

Atherosclerosis leads to cerebral infarction (CI) and the insulin/insulin-like growth factor-1 (IGF1) signaling pathway plays an important role in this process during adult life. The purpose of this study was to investigate the relationship between the human IGF1 gene and CI in the Japanese population via a case-control study that also included a separate analysis of the two gender groups. A total of 155 CI patients and 316 controls were genotyped for six single nucleotide polymorphisms (SNPs) of the human IGF1 gene (rs2162679, rs7956547, rs2288378, rs2072592, rs978458 and rs6218). All data were analyzed for three separate groups: the total subjects, men and women. The logistic regression analysis revealed that the GG + AG variant of rs2162679 (P = 0.047), the AA + GA variant of rs2072592 (P = 0.005) and the CC + TC variant of rs6218 (P = 0.015) exhibited a protective effect for CI in the total subject group. For the women and the total subjects groups, the overall distribution of the haplotype established by rs7956547-rs978458 was significantly different between the CI patients and the non-CI subjects. For the total subjects, the frequency of the T-G haplotype (rs7956547-rs978458) was also significantly higher (P = 0.034), whereas the frequency of the T-A haplotype (rs7956547-rs978458) was significantly lower (P = 0.008) in the CI patients versus the non-CI subjects. For women, the frequency of the T-A haplotype (rs7956547-rs978458) was significantly lower (P = 0.021) in the CI patients as compared with the non-CI subjects. The specific SNPs and haplotypes can be utilized as genetic markers for CI resistance or CI risk.

Haplotype-based case-control study of CYP4A11 gene and myocardial infarction.

CYP4A11, which is a member of the cytochrome P450 family, acts mainly as an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite involved in the maintenance of cardiovascular health. Recently, it was reported that many subfamilies of CYP genes have an association with myocardial infarction (MI). The aim of the present study was to assess the association between the human CYP4A11 gene and MI, using a haplotype-based case-control study with a separate analysis of the gender groups. A total of 239 MI patients and 285 controls were genotyped for 3 single-nucleotide polymorphisms (SNPs) of the human CYP4A11 gene (rs2269231, rs1126742, rs9333025). The data obtained via haplotype-based case-control studies were assessed for 3 separate groups: total subjects, men, and women. For the total, men and women groups, the distribution of the genotypes and alleles of the 3 SNPs did not show any significant difference between the MI patients and the control subjects. For the total and the men groups, the overall distribution of the haplotypes constructed with the 3 SNPs significantly differed between the MI patients and control subjects (P < 0.001). Also, for the total and for the men, the frequency of the T-T-A haplotype constructed with the 3 SNPs was significantly lower for the MI patients than for the control subjects (both P < 0.001). The T-T-A haplotype constructed with the 3 SNPs appears to be a protective genetic marker for MI in Japanese men.

Haplotype of smoothelin gene associated with essential hypertension.

Smoothelin is a specific cytoskeletal protein that is associated with smooth muscle cells. The human SMTN gene encodes smoothelin-A and smoothelin-B, and studies using SMTN gene knockout mice have demonstrated that these animals develop hypertension. The aim of the present study was to investigate the association between the human SMTN gene and essential hypertension (EH) using a haplotype-based case-control study. This is the first study to assess the association between essential hypertension and this gene. A total of 255 EH patients and 225 controls were genotyped for the five single-nucleotide polymorphisms (rs2074738, rs5997872, rs56095120, rs9621187 and rs10304) used as genetic markers for the human SMTN gene. Data were analyzed for three separate groups: total subjects, men and women. Although there were no differences for genotype distributions, or the dominant and recessive model distributions noted for total subjects, men and women for all of the SNPs selected for the present study, for the total subjects group, the frequency of the G-C-A-C haplotype constructed with rs2074738-rs5997872-rs56095120-rs9621187 was significantly lower in the essential hypertension patients than in the controls (P = 0.002). The G-C-A-C haplotype appears to be a useful protective marker of essential hypertension in Japanese, and the SMTN gene might also be a genetic marker for essential hypertension.

Association of the insulin-like growth factor1 gene with myocardial infarction in Japanese subjects.

During adult life, the insulin/insulin-like growth factor1 (IGF1) signaling pathway plays an important role in cardiovascular function. Several reports have suggested that low baseline levels of IGF1 increase the risk of fatal ischemic heart disease. Thus, IGF1 may be involved in cardiovascular disease. The aim of the present study was to investigate the relationship between the human IGF1 gene and myocardial infarction (MI) in the Japanese population via the use of single nucleotide polymorphisms (SNPs). After selecting six SNPs in the human IGF1 gene (rs2162679, rs7956547, rs2288378, rs2072592, rs978458 and rs6218), we performed a case-control study using each of the SNPs and haplotypes in 320 MI patients and 307 non-MI controls. Multiple logistic regression analysis demonstrated that the GG+GA variant of rs2162679 (p=0.009) and the AA+GA variant of rs2072592 (p=0.026) exhibited a resistant effect for MI. The haplotype-based case-control study revealed that the frequency of the A-T-G-G haplotype for rs2162679-rs7956547-rs2072592-rs978458 was significantly higher in the MI group (47.3%) as compared to the non-MI group (41.4%) (p=0.037, odds ratio=1.270). The frequency of the A-T-G-T haplotype for rs2162679-rs7956547-rs978458-rs6218 was also significantly higher in the MI group (47.3%) as compared to the non-MI group (41.3%) (p=0.033, odds ratio=1.276). The current results suggest that specific SNPs and haplotypes can be utilized as genetic markers for MI risk or MI resistance. In addition, IGF1 or a neighboring gene might be associated with increased or decreased susceptibility to MI.

[Establishment of genetic testing for Gitelman's syndrome].

Gitelman's syndrome is an autosomal recessive disorder marked by salt wasting and hypokalaemia resulting from loss of-function mutations in the SLC12A3 gene that codes for the thiazide sensitive Na -Cl cotransporter. Gitelman's syndrome is usually distinguished from Bartter's syndrome by the presence of both hypomagnesaemia and hypocalciuria. The human SLC12A3 gene, which is located on chromosome 16, consists of 26 exons and encodes a protein that contains 12 putative transmembrane domains with long intracellular amino and carboxy termini. In the present study, we developed a method of genetic diagnosis for Gitelman's syndrome using DNA sequencing. A patient was found to be a compound heterozygote with a single base substitution at nucleotide 2552 (CTC-to-CAC, L849H) and a substitution at nucleotide 2561 (CGC-to-CAC, R852H) in exon 22. Familial linkage analysis confirmed that 849H was the paternal allele and 852H was the maternal allele. The method can save time and costs, and it should be useful for genetic testing in clinical laboratory of every hospital.

A haplotype of the CYP4F2 gene associated with myocardial infarction in Japanese men.

This study assessed associations between the CYP4F2 gene and myocardial infarction (MI), using a haplotype-based case-control study of 234 MI patients and 248 controls genotyped for 5 single-nucleotide polymorphisms (rs3093105, rs3093135, rs1558139, rs2108622, rs3093200). For men, G allele frequency of rs2108622 and frequency of the T-C-G haplotype were significantly higher, and frequency of the T-C-A haplotype was significantly lower for MI patients than for controls (P=0.006, P=0.001 and P=0.002, respectively).

Association of the purinergic receptor P2Y, G-protein coupled, 2 (P2RY2) gene with myocardial infarction in Japanese men.

BACKGROUND: Atherosclerosis leads to myocardial infarction (MI) and P2RY2 plays an important role in this process. The aim of the present study was to investigate the association between human P2RY2 and MI via a haplotype-based case-control study that additionally analyzed the group by sex. METHODS AND RESULTS: The 310 MI patients and 254 controls were genotyped for 5 single-nucleotide polymorphisms (SNPs) of the human P2RY2 gene (rs4944831, rs1783596, rs4944832, rs4382936, rs10898909). Data were separately analyzed for the total, male, and female subjects. For men, the GA+AA genotype of rs10898909 was significantly higher in MI patients as compared with controls (P=0.040). Logistic regression analysis found a significant difference for the genotype (P=0.016). As compared with controls, the frequencies of the C-A and T-C-A haplotypes were significantly higher (P=0.016, and P=0.045, respectively) in men, whereas the frequencies of the C-G and T-A-A haplotypes were significantly lower (P=0.023, and P=0.025, respectively) in MI patients. CONCLUSIONS: The GA+AA genotype, as well as the C-A and T-C-A haplotypes, of human P2RY2 could be genetic markers for MI in Japanese men.

A haplotype of the CYP4A11 gene associated with essential hypertension in Japanese men.

OBJECTIVE: CYP4A11, a member of the cytochrome P450 family, acts mainly as an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid, a metabolite involved in blood pressure regulation in humans. Disruption of the murine cyp4a14 and cyp4a10 genes, homologues of human CYP4A11, was reported recently to cause hypertension. The gene-disrupted male mice had higher blood pressure than the gene-disrupted female mice. The present study aimed to assess the association between the human CYP4A11 gene and essential hypertension, using a haplotype-based case-control study including separate analysis of the gender groups. METHODS: The 304 essential hypertension patients and 207 age-matched control individuals were genotyped for three single-nucleotide polymorphisms of the human CYP4A11 gene (rs2269231, rs1126742, rs9333025). Data were assessed for three separate groups: total participants, men and women. RESULTS: For total participants, the genotypic distribution of rs1126742 differed significantly between the two groups (P = 0.005). For total participants, men and women, the recessive model (CC versus TC + TT) of rs1126742 differed significantly between the two groups (P = 0.007, P = 0.043, and P = 0.045, respectively). Logistic regression analysis showed the TC + TT genotype was significantly higher in essential hypertension patients than in control individuals for total participants and men (P = 0.022 and P = 0.043, respectively). The A-T-G haplotype frequency (established by rs2269231, rs1126742, rs9333025) was significantly higher in essential hypertension men than in control men (P = 0.043). CONCLUSIONS: Essential hypertension is associated with the TC + TT genotype of rs1126742 in the human CYP4A11 gene. The A-T-G haplotype appears a useful genetic marker of essential hypertension in Japanese men.

A haplotype-based case-control study examining human extracellular superoxide dismutase gene and essential hypertension.

It has been reported that oxidative stress is involved in the pathophysiology of essential hypertension (EH), which is a multifactorial disorder. Extracellular superoxide dismutase (EC-SOD) protects the human body from oxidative stress by converting the toxic superoxide anion (O2-) into less toxic hydrogen peroxide (H2O2). In EC-SOD knockout mice, blood pressure was reported to be significantly higher than that seen in wild-type mice. The aim of this study was thus to investigate the relationship between EH and the human EC-SOD gene by using single-nucleotide polymorphisms (SNPs) in a haplotype-based case-control study. We selected 6 SNPs within the human EC-SOD gene (rs13306703, rs699473, rs699474, rs17881426, rs2536512 and rs1799895), and then performed case-control studies in 243 EH patients and 251 age-matched normotensive (NT) subjects. In Japanese subjects, no heterogeneity was found for rs699474, and no significant differences were observed between the EH and NT groups for the overall distribution of the genotypes or the alleles for each of the SNPs. However, in the haplotype-based case-control study that used rs13306703 and rs2536512, significant differences were observed in the overall distribution (chi2=14.26, p=0.003). The frequency of the T-A haplotype was significantly higher in the EH group than in the NT group (2.4% vs. 0.0%, p<0.001). Based on the results of our haplotype-based case-control study, the T-A haplotype may be a genetic marker for EH, and thus the EC-SOD gene might be a susceptibility gene for EH.

Haplotype-based case-control study of the human CYP4F2 gene and essential hypertension in Japanese subjects.

CYP4F2 acts primarily as an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite involved in the regulation of blood pressure in humans. The aim of the present study was to assess the association between the human CYP4F2 gene and essential hypertension (EH) using a haplotype-based case-control study that included separate analysis of the two gender groups. The 249 EH patients and 238 age-matched controls were genotyped for 5 single-nucleotide polymorphisms (SNPs) of the human CYP4F2 gene (rs3093105, rs3093135, rs1558139, rs2108622, rs3093200). Data were analyzed for 3 separate groups: all subjects, and men and women separately. For the total population and for male subjects, the distribution of the dominant model of rs1558139 (CC vs. CT+TT) differed significantly between the EH patients and control subjects (p=0.037 and p=0.005, respectively), with a higher percentage of EH patients showing the CC genotype. Logistic regression showed that, for men, the CC genotype of rs1558139 was more prevalent in the EH patients than in the control subjects (p=0.026), while, for the total population, the difference disappeared (p=0.247). For men, the overall distribution of the haplotypes was significantly different between the EH patients and the control subjects (p=0.042), and the frequency of the T-T-G haplotype was also significantly lower for EH patients than for control subjects (p=0.009). In conclusion, the present results indicate that rs1558139 might be a genetic marker for EH and the T-T-G haplotype might be a protective genetic marker for EH in Japanese men.

Case-control study of the role of the Gitelman's syndrome gene in essential hypertension.

BACKGROUND: Gitelman's syndrome is an inherited tubular disorder characterized by sodium wasting, low blood pressure, secondary hyperaldosteronism, metabolic alkalosis, hypokalemia, hypomagnesemia of renal origin, and hypocalciuria. The majority of patients with this syndrome carry inactivating mutations in the SLC12A3 gene encoding the thiazide-sensitive Na (+)-Cl (-) cotransporter (NCC) located in the distal convoluted tubule, which is involved in renal sodium reabsorption. This suggests that the SLC12A3 gene is involved in mediation of blood pressure levels. The aim of the present study was to investigate relationships between single nucleotide polymorphisms (SNPs) in the human SLC12A3 gene and essential hypertension (EH) in Japanese. METHOD: We selected 3 SNPs in the human SLC12A3 gene (T180K, A569V, L849H), and performed a case-control study of 315 EH patients and 305 normotensive (NT) individuals. RESULTS: There was no significant difference in overall distribution of genotypes or alleles of any of the SNPs between the EH and NT groups. CONCLUSION: We conclude that the causal gene of Gitelman's syndrome is not involved in determining blood pressure levels.

Association of extracellular superoxide dismutase gene with cerebral infarction in women: a haplotype-based case-control study.

It has been reported that oxidative stress is a factor in cerebral infarction (CI). Extracellular superoxide dismutase (EC-SOD) is important in preventing oxidative stress, and the cerebral infarct size of EC-SOD knockout mice is significantly larger than that in wild-type controls. The aim of this study was to investigate the relationship between CI and the human EC-SOD gene using single-nucleotide polymorphism (SNP) in Japanese individuals. We selected five single-nucleotide polymorphisms of the human EC-SOD gene (rs13306703, rs699473, rs17881426, rs2536512 and rs1799895) and performed a case-control study using each SNP and haplotype in 175 CI patients (103 men, 72 women) and 299 controls (144 men and 155 women). Among women, there were significant differences between the CI and control group in overall distribution of alleles for rs699473 (men: OR=1.031, 95% CI: 0.705-1.506, women: OR=1.916, 95% CI: 1.196-3.071) and rs2536512 (men: OR=0.774, 95% CI: 0.523-1.146, women: OR=2.107, 95% CI: 1.227-3.462). In a haplotype-based case control on rs13306703, rs699473 and rs1799895 in women, the frequency of the C-C-C haplotype was significantly higher in the CI group than in the control group (men; 51.5% vs 51.4% p=0.9865, women; 62.5% vs 49.7% p=0.0108). Multiple logistic regression analysis also revealed a significant difference in C-C-C haplotype in women, even after adjustment for confounding factors (OR=2.205, 95% CI: 1.069-4.552 p=0.032). The C-C-C haplotypes could be genetic markers for CI, and the EC-SOD gene may be a susceptibility gene for CI in women.

Haplotype-based case-control study of the association between the guanylate cyclase activator 2B (GUCA2B, Uroguanylin) gene and essential hypertension.

Uroguanylin (gene name: guanylate cyclase activator 2B, GUCA2B) is a peptide regulator of intestinal salt and water transport. It has been reported that the uroguanylin knockout mouse exhibits elevated blood pressure. Therefore, the GUCA2B gene is thought to be a susceptibility gene for essential hypertension (EH). Despite extensive studies, however, the relationship between the GUCA2B gene and EH has not yet been defined. The aim of this study was to assess the association between the human GUCA2B gene and EH. Using four single nucleotide polymorphisms (SNPs), we conducted a genetic association study in 281 EH patients and 279 age-matched normotensive (NT1) individuals. To derive more reliable data, we performed a duplicate case-control study in which we recruited another normotensive group (NT2). There was no significant difference in the overall distribution of alleles for any of the SNPs between the EH and NT1 groups, or between the EH and NT2 groups. Therefore, these four SNPs cannot be the genetic markers for EH. The occurrences of the C-A haplotype (rs883062-rs1047047) and the C-A-G haplotype (rs883062-rs1047047-rs2297566) were significantly higher in the EH group than in the NT1 group (p<0.0001) or the NT2 group (p<0.0001). These results suggest that the C-A haplotype and the C-A-G haplotype of the GUCA2B gene are the genetic markers for EH, and that GUCA2B or a neighboring gene might be a susceptibility gene for EH.

Association between prostaglandin E2 receptor gene and essential hypertension.

BACKGROUND: Essential hypertension (EH) is a complex multifactorial polygenic disorder that is thought to result from an interaction between an individual's genetic makeup and various environmental factors. In the kidney, prostaglandins (PGs) are important mediators of vascular tone and salt and water homeostasis, and are involved in the mediation and/or modulation of hormonal action. In previous studies, mice deficient in the prostaglandin E2 (PGE(2)) EP2 receptor had resting systolic blood pressure (BP) that was significantly lower than that of wild-type controls. The BP of those mice increased when they were put on a high-salt diet, suggesting that the EP2 receptor is involved in sodium handling by the kidney. In the present study, we investigated the association between EH and nucleotide polymorphisms in the gene encoding the prostaglandin E2 receptor subtype EP2 (PTGER2). METHODS: We selected three single-nucleotide polymorphisms (SNP) in the human PTGER2 gene (rs1254601, rs2075797, and rs17197), and we performed a genetic association study of 266 EH patients and 253 age-matched normotensive (NT) controls. RESULTS: There was no significant difference in overall distribution of genotypes or alleles of any of the SNP between the EH and NT groups. However, among men, the A/A type of the SNP rs17197 (rs17197, A/G in 3'UTR) was significantly more frequent in EH subjects than in NT subjects (P=0.041). CONCLUSION: The present findings suggest that rs17197 is useful as a genetic marker of EH in men.

A novel variable number of tandem repeat of the natriuretic peptide precursor B gene's 5'-flanking region is associated with essential hypertension among Japanese females.

BACKGROUND: Brain natriuretic peptide (BNP) acts primarily as a cardiac hormone; it is produced by the ventricle and has both vasodilatory and natriuretic actions. Therefore, the BNP gene is thought to be a candidate gene for essential hypertension (EH). The present study identified variants in the 5'-flanking region of natriuretic peptide precursor B (NPPB) gene and assessed the relationship between gene variants and EH. METHODS: The polymerase chain reaction-single strand conformation polymorphism method and nucleotide sequencing were used to identify variants. RESULTS: A novel variable number of tandem repeat (VNTR) polymorphism in the 5'-flanking region (-1241 nucleotides from the major transcriptional initiation site) was discovered. This VNTR polymorphism is a tandem repeat of the 4-nucleotide sequence TTTC. There were 8 alleles, ranging from 9-repeat to 19-repeat. An association study was done involving 317 EH patients and 262 age-matched normotensive (NT) subjects. The 11-repeat allele was the most frequent (88.2%); the 16-repeat allele was the second most frequent (10.5%) in the NT group. The observed and expected genotypes were in agreement with the predicted Hardy-Weinberg equilibrium values (P=0.972). Among females, the overall distribution of genotypes was significantly different between the EH and NT groups (p=0.039). The frequency of the 16-repeat allele was significantly lower in the female EH group (6.5%) than in the female NT group (12.2%, p=0.046). CONCLUSIONS: The 16-repeat allele of the VNTR in the 5'-flanking region of NPPB appears to be a useful genetic marker of EH in females.

Association of a novel single nucleotide polymorphism of the prostacyclin synthase gene with myocardial infarction.

BACKGROUND: Myocardial infarction (MI) is a complex multifactorial and polygenic disorder that is thought to result from an interaction between an individual's genetic makeup and various environmental factors. The purpose of this study was to investigate the association between a novel single nucleotide polymorphism in the prostacyclin synthase gene and MI. METHODS AND RESULTS: By the use of polymerase chain reaction-single-strand conformation polymorphism analysis, we identified a single nucleotide polymorphism, C1117A, in exon 8. This nucleotide change did not cause an amino acid change in codon 373. We performed an association study of the polymorphism in 138 patients and 130 healthy control subjects. Multiple logistic linear regression analysis showed the genotype distributions were significantly different between the control group and the MI group (odds ratio, 2.12; 95% CI, 1.47-3.05, P =.04). The C/C genotype was found more frequently in the MI group than in the control group. CONCLUSIONS: We conclude that the C1117A polymorphism in exon 8 is associated with risk for MI and may be a genetic marker of MI in Japanese persons.

Two medium-chain acyl-coenzyme A synthetase genes, SAH and MACS1, are associated with plasma high-density lipoprotein cholesterol levels, but they are not associated with essential hypertension.

BACKGROUND AND OBJECTIVES: SAH has been proposed as a candidate gene for essential hypertension (EH) because elevated expression of SAH was observed in the kidneys of spontaneously hypertensive rats. Recently, a homology search of SAH in the human genome revealed the presence of the SAH gene family, which includes SAH, MACS1, MACS2, and MACS3. SAH and MACS1 are located within a 150-kb region on human chromosome 16p13.11. SAH and MACS1 are thought to function as acyl-coenzyme A synthetases, which are involved in fatty acid metabolism. In the present study, we analyzed six single nucleotide polymorphisms (SNPs) in the SAH and MACS1 genes in a Japanese population, and examined whether these SNPs contribute to EH and multiple risk factors. METHODS AND RESULTS: We performed association studies of six SNPs in 287 EH patients and 259 normotensive subjects. Multiple logistic linear regression analysis revealed that the allele frequencies of these six SNPs in SAH and MACS1 genes were not significantly different between EH patients and normotensives. SNP in exon 8 of the A/G polymorphism of the MACS1 gene and the G/T SNP in intron 3 of the SAH gene were associated with plasma levels of plasma high-density lipoprotein cholesterol. CONCLUSIONS: SNPs in the MACS1 and SAH genes contribute to plasma levels of high-density lipoprotein cholesterol.

An association study in essential hypertension using functional polymorphisms in lymphotoxin-alpha gene.

BACKGROUND: Lymphotoxin-alpha (LTA), a member of the tumor necrosis factor family, is a cytokine produced by lymphocytes. The substance LTA mediates a wide variety of inflammatory, immunostimulatory, and antiviral responses. In 2002, LTA was identified as a major risk factor for myocardial infarction (MI) in Japanese individuals, in a large-scale case-control study using 92,788 gene-based single-nucleotide polymorphism (SNP) markers in the whole human genome. Essential hypertension (EH) is thought to be a multifactorial disorder involved in endothelial dysfunction and atherosclerosis. Although hypertension is one of the greatest risk factors for MI, there have been no reports estimating the association between EH and LTA. The aim of the present study was to evaluate the association between EH and the LTA gene. METHODS: In the present study, we assessed the association between EH and SNP and haplotypes of the LTA gene in a case-control study of 202 EH patients and 217 age-matched normotensive control subjects. RESULTS: The overall distribution of genotypes for each SNP did not significantly differ between the two groups. Furthermore, the haplotype analysis revealed no association between the EH and normotensive groups. CONCLUSIONS: Polymorphisms of the LTA gene were not associated with EH. This finding suggests differences in genetic backgrounds between EH and MI.