Mikano Sato

Dopamine D1 Receptor Gene Polymorphism Is Associated With Essential Hypertension

Dopamine has been shown to influence renal sodium excretion through a direct interaction with the dopamine receptor (DR). The dopamine D1 receptor (DRD1) has been localized to the proximal tubules and is known to increase sodium excretion by inhibiting Na-H exchanger and Na,K-ATPase activity. Defective renal dopamine production and/or DR function have been reported in essential hypertension (EH) as well as in genetic models of animal hypertension. With a restriction fragment length polymorphism of the DRD1 gene, we performed an association study in patients with EH. One hundred thirty-one subjects with EH and 136 age-matched normotensive (NT) controls were studied. Polymerase chain reaction was used to amplify the A-48G polymorphic site in the DRD1 gene, and restriction analysis of the polymerase chain reaction product was used to score the A and G alleles. The allele frequencies in the EH group and NT group were then compared. The G allele was observed more frequently in the EH group than in the NT group, and the allele frequencies in the 2 groups differed significantly (chi(2)=6.5, P=0.01). Multiple logistic linear regression analysis revealed that the genotype frequencies of A/A, A/G, and G/G differed significantly (odds ratio=2.1; 95% CI=1.19 to 3.66) between the EH and NT groups. EH patients who possess the G allele had a higher diastolic blood pressure than those lacking the G allele (P<0.01). Thus, the alleles detected by this restriction fragment length polymorphism in the DRD1 gene are associated with EH, and they appear to influence the diastolic blood pressure of Japanese EH patients.

Splicing mutation of the prostacyclin synthase gene in a family associated with hypertension

Prostacyclin inhibits platelet aggregation, smooth muscle cell proliferation, and vasoconstriction. The prostacyclin synthase (PGIS) gene is a candidate gene for cardiovascular disease. The purpose of this study was to locate possible mutations in the PGIS gene related to hypertension and cerebral infarction. Using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method, we discovered a T to C transition at the +2 position of the splicing donor site of intron 9 in patients with essential hypertension (EH). In vitro expression analysis of an allelic minigene consisting of exons 8-10 revealed that the nucleotide transition causes skipping of exon 9. This in turn alters the translational reading frame of exon 10 and introduces a premature stop codon (TGA). A three-dimensional model shows that the splice site mutation produces a truncated protein with a deletion in the heme-binding region. This splice site mutation was found in only one subject in 200 EH patients and 200 healthy controls. Analysis of the patients family members revealed the mutation in two of the three siblings. The urinary excretion of prostacyclin metabolites in subjects with the mutation was significantly decreased. All subjects displaying the splice site mutation in the PGIS gene were hypertensive. In this study, we report a novel splicing mutation in the PGIS gene, which is associated with hypertension in a family. It is thought that this mechanism may involve in the pathophysiology of their hypertension.

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 of the CYP4F2 Gene is Associated With Cerebral Infarction in Japanese Men

BACKGROUND CYP4F2, a member of the cytochrome P450 family, acts mainly as an enzyme and is involved not only in the metabolism of leukotriene B4, but also in that of arachidonic acid. It converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite involved in the regulation of the vascular tone in the brain. The aim of this study was to assess the association between the human CYP4F2 gene and cerebral infarction (CI), using a haplotype-based case-control study with separate analyses of data from the gender groups. METHODS A total of 175 CI patients and 246 control subjects were genotyped for five single-nucleotide polymorphisms (SNPs) of the human CYP4F2 gene (rs3093105, rs3093135, rs1558139, rs2108622, rs3093200). For data analysis, three separate groups were assessed: all subjects, men, and women. RESULTS In the male subjects, the G allele frequency for rs2108622 was significantly higher in CI patients as compared to control subjects (P = 0.025). The overall distribution of the haplotypes in the men was significantly different between the CI patients and the control subjects (P = 0.027). Additionally, the frequency of the T-C-G haplotype for men was significantly higher in the CI patients than in the control subjects (P = 0.008). Multiple logistic regression analysis also revealed the significance of the T-C-G haplotype in men, even after adjustment for confounding factors. CONCLUSIONS The results of this study indicate that, in Japanese men, CI is associated with the G allele of rs2108622 and, in addition, that the T-C-G haplotype appears to be a useful genetic marker for CI.

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.

Association Study of the Elastin Microfibril Interfacer 1 (EMILIN1) Gene in Essential Hypertension

BACKGROUND Elastin microfibril interfacer 1 (EMILIN-1) is a negative regulator of the transforming growth factor-beta (TGF-beta) signaling, which is involved in blood pressure (BP) homeostasis. Emilin1 knockout mice display elevated BP. The aim of the present study was to assess the association between the human EMILIN1 gene and essential hypertension (EH) using a haplotype-based case-control study. METHODS A total of 287 EH patients and 253 age-matched controls were genotyped for the five single-nucleotide polymorphisms (SNPs) used as genetic markers for the human EMILIN1 gene (rs2289408, rs2289360, rs2011616, rs2304682, and rs4665947). Data were analyzed for three separate groups: the total subjects, men, and women. RESULTS For the total, the genotypic distribution of rs2289360, rs2011616, and rs2304682 differed significantly between control and EH (P = 0.010, P = 0.009, and P = 0.008, respectively). For the total and men, there were significant differences noted between the controls and the EH patients for both the dominant model (GG vs. AA+AG) (P = 0.006, P = 0.021, respectively), and the recessive model (AA vs. AG+GG) (P = 0.028, P = 0.038, respectively) of rs2011616. For the total and the men, logistic regression analysis indicated that the AG+GG genotype of rs2011616 was significantly higher in EH patients (P = 0.033, P = 0.043, respectively). The frequency of the G-G-T haplotype (established by rs2536512, rs2016116, rs17881426) was significantly higher in EH men (P = 0.007), and the G-A-T haplotype (established by rs2536512, rs2016116, rs17881426) was significantly higher in control men (P < 0.001). CONCLUSIONS We confirmed that rs2289360, rs2011616, and rs2304682 in the human EMILIN1 gene, as well as the haplotype constructed using rs2536512, rs2011616, and rs17881426 are useful genetic markers of EH in Japanese men.

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).

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.

Association of HSD3B1 and HSD3B2 gene polymorphisms with essential hypertension, aldosterone level, and left ventricular structure.

BACKGROUND HSD3B1 and HSD3B2 are crucial enzymes for the synthesis of hormonal steroids, including aldosterone. Therefore, HSD3B gene variations could possibly influence blood pressure (BP) by affecting the aldosterone level. METHODS We performed a haplotype- and diplotype-based case-control study to investigate the association between the HSD3B gene variations and essential hypertension (EH), aldosterone level, and left ventricular hypertrophy (LVH). A total of 275 EH patients and 286 controls were genotyped for four SNPs of the HSD3B1 gene (rs3765945, rs3088283, rs6203, and rs1047303) and for two SNPs of the HSD3B2 gene (rs2854964 and rs1819698). Aldosterone and LVH were investigated in 240 and 110 subjects respectively. RESULTS Significant differences were noted for the total and the male subject groups for the recessive model (CC versus TC+TT) of rs6203 between the controls and EH patients (P=0.030 and P=0.008 respectively). The frequency of the T-C haplotype established by rs3088283-rs1047303 was significantly higher for EH patients compared with the controls (P=0.014). Even though the polymorphism of HSB3B1 was not associated with LVH, the diplotype established by rs3088283-rs1047303 in the total subject group, along with the systolic BP, diastolic BP, and aldosterone level were significantly higher for those subjects who had the T-C haplotype versus those who did not (P=0.025, P=0.014, and P=0.006 respectively). CONCLUSION rs6203 and rs1047303 in the HSD3B1 gene are useful genetic markers for EH, while polymorphisms of HSD3B1 are associated with the BP and aldosterone level.

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.