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.

Haplotype-based case-control study on human apurinic/apyrimidinic endonuclease 1/redox effector factor-1 gene and essential hypertension.

BACKGROUND: Oxidative DNA damage is involved in the pathophysiology of essential hypertension (EH), which is a multifactorial disorder. Apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/REF-1) is an essential endonuclease in the base excision repair pathway of oxidatively damaged DNA, in addition to having reducing properties that promote the binding of redox-sensitive transcription factors. Blood pressure in APE1/REF-1-knockout mice is reported to be significantly higher than in wild-type mice. The aim of this study was to investigate the relationship between EH and the human APE1/REF-1 gene through a haplotype-based case-control study using single-nucleotide polymorphisms (SNPs). METHODS: We selected five SNPs in the human APE1/REF-1 gene (rs1760944, rs3136814, rs17111967, rs3136817, and rs1130409), and performed case-control studies in 265 EH patients and 266 age-matched normotensive (NT) subjects. RESULTS: rs17111967 was found to show nonheterogeneity among Japanese subjects. There were no significant differences in the overall distribution of genotypes or alleles for each SNP between EH and NT groups. In the overall distribution of the haplotype-based case-control study constructed based on rs1760944, rs3136817, and rs1130409, the frequency of the G-T-T haplotype was significantly higher in the EH group than in the NT group (2.1% vs. 0.0%, P = 0.001). Multiple logistic regression analysis also revealed significant differences for the G-T-T haplotype, even after adjustment for confounding factors (OR = 8.600, 95% CI: 1.073-68.951, P = 0.043). CONCLUSIONS: Based on the present results, the G-T-T haplotype appears to be a genetic marker of EH, and the APE1/REF-1 gene appears to be a susceptibility gene for EH.

Relationship between haplotypes of KCNN4 gene and susceptibility to human vascular diseases in Japanese.

BACKGROUND: Human vascular diseases such as myocardial infarction (MI) and cerebral infarction (CI) are thought to be affected by several environmental factors and genetic variants. It has been suggested that the expression of the KCNN4 calcium-activated potassium channel is associated with the developing vascular smooth-muscle cells of human neointimal hyperplasia. The aim of this study was to investigate the relationship between single-nucleotide polymorphisms (SNPs) in the human KCNN4 gene or haplotypes and the incidence of MI or CI in Japanese. MATERIAL/METHODS: Three hundred thirteen MI and 176 CI patients with 290 controls were enrolled in two independent case-control studies that examined the use of a haplotype-based case-control study involving five SNPs of the human KCNN4 gene (rs670950, rs2306801, rs2306799, rs347519, and rs3786954). RESULTS: There were significant differences between the MI and control groups in the overall distribution of genotypes and dominant or recessive models of rs670950, rs2306799, and rs3786954. Multiple logistic regression analyses revealed that even after adjusting for confounding factors (odds ratio: 1.96), the frequency of the G/G genotype of rs2306799 in the MI group was significantly higher than in the control group (p=0.005). Furthermore, the G-T-A haplotype of rs2306799-rs347519-rs3786954 was significantly more frequent in the MI (88.8%) than in the control group (83.6%). CONCLUSIONS: The specific SNPs and haplotypes in the KCNN4 gene showed significant differences between MI and control patients. These results indicate that these polymorphisms and haplotypes could be genetic markers for MI.

Haplotype-based case-control study between human apurinic/apyrimidinic endonuclease 1/redox effector factor-1 gene and cerebral infarction.

OBJECTIVES: The aim of this study was to investigate the relationship between cerebral infarction (CI) and the human apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/REF-1) gene using single-nucleotide polymorphisms (SNPs) and a haplotype-based case-control study. DESIGN AND METHODS: We selected 5 SNPs in the human APE1/REF1 gene (rs1760944, rs3136814, rs17111967, rs3136817 and rs1130409), and performed case-control studies in 177 CI patients and 309 control subjects. RESULTS: rs17111967 was found to have no heterogeneity in Japanese. The overall distribution of the haplotype-based case-control study constructed by rs1760944, rs3136814 and rs1130409 showed a significant difference. The frequency of the G-C-T haplotype was significantly higher in the CI group than in the control group (2.5% vs. 0.0%, p>0.001). CONCLUSIONS: Based on the results of the haplotype-based case-control-study, the G-C-T haplotype may be a genetic marker of CI, and the APE1/REF-1 gene may be a CI susceptibility gene.

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.

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.