Background: As aromatase-deficient mice, which are deficient in estrogens, reportedly have reduced blood pressure, the aromatase gene (CYP19A1) is thought to be a susceptibility gene for essential hypertension (EH).The aim of the present study was to investigate the relationship between CYP19A1 and EH by examining single nucleotide polymorphisms (SNPs).Methods: Five SNPs in the human CYP19A1 gene (rs1870049, rs936306, rs700518, rs10046 and rs4646) were selected, and an association study was performed in 218 Japanese EH patients and 225 age-matched normotensive (NT) individuals.Results: There were significant differences between these groups in the distribution of genotypes rs700518 and rs10046 in male subjects, and genotypes rs700518, rs10046 and rs4646 in female subjects.On multiple logistic regression analysis, a significant association between rs700518 (p=0.023) and rs10046 (p=0.036) in male subjects and rs700518 in female subjects (p=0.018) was noted.Interestingly, the risk genotypes of rs700518 and rs10046 showed a sex-dependent inverse relationship.Both SBP and DBP levels were higher in total (cases and controls) male subjects with the G/G genotype with rs700518 or the T/T genotype with rs10046 than in male subjects without the G/G genotype or T/T genotype.SBP levels were lower in female subjects with the G/G genotype with rs700518 than in female subjects without G/G.The A-T haplotype constructed with rs1870049 and rs10046 was a susceptibility marker for EH.Conclusions: We confirmed that rs700518 and rs10046, as well as a haplotype constructed with rs1870049 and rs10046, in the human CYP19A1 gene can be used as genetic markers for gender-specific EH.
Aim: To determine the lipid lowering effectiveness, cost effectiveness, and safety of rosuvastatin compared with pitavastatin in dyslipidemic patients with concurrent renal disorders.Methods: This single-center, prospective, open-label, randomized, 12-month study evaluated rosuvastatin (2.5 mg) and pitavastatin (1 or 2 mg) in 134 dyslipidemic patients with concurrent chronic kidney disease (CKD; rosuvastatin group, n=68; pitavastatin group, n=66). Lipid parameters [i.e., low density lipoprotein cholesterol (LDL-C), etc.], renal function parameters [i.e., estimated glomerular filtration rate (eGFR), etc.], glycated hemoglobin (HbA1c), and high-sensitivity C-reactive protein (hs-CRP) were measured at enrollment (baseline), month 6, and month 12.Results: The mean daily dose of rosuvastatin and pitavastatin was 2.5 mg and 1.4 mg, respectively. All lipid parameters were significantly more improved in the rosuvastatin group. eGFR improved from baseline in the rosuvastatin group (p<0.0001) and showed no tendency to worsen in the pitavastatin group (p=0.2232). In multiple regression analysis (n=134), it was significantly associated with a percent change in total cholesterol (β=0.2296; p=0.0112), smoking (β=0.1927; p=0.0224), and HbA1c (β=-0.1606; p=0.0585). Hs-CRP was significantly improved in both groups. An analysis eliminating the influence of antidiabetic medication showed a significant difference between groups in the change of HbA1c at month 6 from baseline (p=0.0016). No subjects in either group had new onset of diabetes mellitus. The cost of statin medication required to reduce LDL-C by 10 mg/dL was significantly lower for 2.5 mg of rosuvastatin (p=0.0116).Conclusions: Rosuvastatin 2.5 mg had superior lipid lowering and cost effectiveness in dyslipidemic patients with concurrent CKD.(UMIN ID: UMIN000005812)
This study determined the changes in international normalized ratio (INR) that occur during hemodialysis (HD) treatment of patients receiving warfarin. Twenty patients were enrolled in the study (15 males, 5 females; mean age, 71 ± 7 years). We investigated changes in INR and R-isomer and S-isomer of warfarin concentrations before (pre-) and after (post-) HD. Post-HD INR levels were significantly decreased compared with pre-HD levels (P < 0.01), whereas plasma concentrations of both R-isomer and S-isomer of warfarin were significantly increased post-HD compared with pre-HD (P < 0.01). There was a negative correlation between INR changes and changes in warfarin concentration or changes in serum albumin levels during HD. Multivariate analysis revealed that change of serum albumin was the only factor that was significantly related to the change of INR (P = 0.0051, R2 = 0.501). We suggest that the free fraction of plasma warfarin decreased with increases in serum albumin levels because the protein-binding rate of warfarin is very high and free fractions were bound to albumin during HD sessions. The INR depletion was therefore dependent on circulating plasma volumes and serum albumin concentrations. Caution should be taken for those HD patients who have absolute indications of anticoagulation therapy with warfarin.
Ischemic stroke (IS) is thought to be a multifactorial disorder associated with genetic backgrounds and environmental factors. In the circulating plasma, tissue plasminogen activator (tPA) catalyzes the reaction from plasminogen to plasmin. If there is a functional disability of tPA, induction of thrombosis and infarction disorders can occur. The aim of this study was to perform a haplotype-based case-control study using single nucleotide polymorphisms (SNPs) in the human tPA gene, and to assess the association between the tPA gene and IS. We genotyped 182 IS individuals and 403 controls for five SNPs in the human tPA gene, rs7007329, rs732612, rs8178750, rs2020922, and rs4471024. Using these five SNPs, a haplotype-based case control study was performed. There were seven SNP combinations that exhibited significant differences in the overall distribution between the IS and control groups. Linkage disequilibrium analysis showed that the combination of rs7007329 and rs8178750 was useful in identification of the susceptibility haplotype. The frequency of the G-T haplotype at rs7007329-rs8178750 was significantly higher in the IS group (1.2%) as compared to the control group (0.0%) (p = 0.003). Diplotype analysis also showed a significant association of the diplotype with the G-T haplotype at rs7007329-rs8178750 (OR:11.4, 95%CI:1.32-97.9, p = 0.013). These results suggest that the G-T haplotype at rs7007329-rs8178750 of the tPA gene is a genetic marker for IS, and that tPA or a neighboring gene is a susceptibility gene for IS.
Complement-activating capacity through the classical pathway in type 2 diabetes mellitus (T2DM) was examined in the context of free sialic acid as a potential modulator of complement activation. Complement-activating capacity was investigated in an incubation study of heat-aggregated IgG (HAG) and sera from 42 T2DM patients. The study demonstrated diminished in-vitro complement-activating capacity through the classical pathway in T2DM. Various doses of N-acetyl neuraminic acid (NANA) were incubated with normal serum and HAG. Complement activation product levels decreased in a NANA dose-dependent manner. Isoelectrofocusing analysis in a mixture of NANA and purified C3 indicated that C3 changed pI dose-dependently, resulting in the downregulation of complement activation. The serum levels of free sialic acid were determined by fluorometric assay in the 42 T2DM sera samples, and were significantly increased in patients with diminished complement activation. These data indicate that increased serum sialic acid may become a candidate for decreasing complement-activating capacity in T2DM.
