Association Study Of Haplotypes Of The CYP Gene With Essential Hypertension And Myocardial Infarction

Objective: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 regulation of blood pressure in humans. Recently, it was reported that disruption of the murine cyp4a14 and cyp4a10 genes, which are homologues of human CYP4A11, causes hypertension. The gene-disrupted male mice had higher blood pressure than the gene-disrupted females. One aim of the present study was to assess the association between the human CYP4A11 gene and essential hypertension(EH), using a haplotype-based case-control study that included a separate analysis of the gender groups. CYP4F2, which is also a member of the cytochrome P450 family, acts mainly as an enzyme that not only the metabolism leukotriene B4 but also arachidonic acid. It converts arachidonic acid to 20-hydroxyeicosatetraenoic acid(20-HETE), a metabolite involved in the maintenance of cardiovascular health. Recently, a functional variant in the human CYP4F2 gene(rs2108622, V433M)was identified which can altered the production of 20-HETE from AA. Another aim of the present study was to assess the association between the human CYP4F2 gene and MI and EH, using a haplotype-based case-control study with a separate analysis of the gender groups.Methods:There were 304 EH patients and 207 age-matched controls genotyped for 3 SNPs of the human CYP4A11 gene(rs2269231, rs1126742, rs9333025). The data were assessed for 3 separate groups: the total subjects, men and women.There were 234 MI patients and 248 control subjects genotyped for 5 SNPs of the human CYP4F2 gene(rs3093105, rs3093135, rs1558139, rs2108622, rs3093200). The data were assessed for 3 separate groups: the total subjects, men and women.There were 249 EH patients and 238 age-matched controls genotyped for 5 SNPs of the human CYP4F2 gene (rs3093105, rs3093135, rs1558139, rs2108622, rs3093200). Tata were assessed for 3 separate groups: total subjects, men and women. Results:The study results of CYP4A11 gene show that for the total, the genotypic distribution of rs1126742 differed significantly between the EH and control groups(P=0.005). For the total, and the men and women groups, the recessive model(CC versus TC+TT)of rs1126742 differed significantly between the EH and control groups(P=0.007, P=0.043, and P=0.045, respectively). Logistic regression analysis showed that the TC+TT genotype was significantly higher in EH patients than in controls for the total subjects and the men(P=0.022 and P=0.043, respectively). The frequency of the A-T-G haplotype(established by rs2269231, rs1126742, rs9333025)was significantly higher in EH men than in control men(P=0.043).The study results of CYP4F2 gene show that for men subjects, G allele of was significantly higher in the MI patients than the control subjects. For men, the overall distribution of the haplotypes were significantly different between the MI patients and the control subjects(P=0.001). Also for the men, the frequency of T-C-G haplotype was significantly higher for MI patients than for control subjects(P=0.001), and the frequency of T-C-A haplotype was significantly lower for MI patients than for control subjects(P=0.002).The study results of CYP4F2 gene show that for the total and male subjects, the distribution of the dominant model of rs1558139 (CC versus CT + TT) differed significantly between the EH patients and control subjects (P=0.037, P=0.005, respectively), the CC genotype was higher in the EH patients than in the control subjects. Logistic regression showed that for the men, the CC genotype of rs1558139 was higher in the EH patients than in the control subjects (P=0.026), while for the total, 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).Conclusions:The present results indicate that EH is associated with the TC+TT genotype of rs1126742 in the human CYP4A11 gene for Japanese men. The A-T-G haplotype of CYP4A11 gene appears to be a useful genetic marker of EH in Japanese men. The G allele of rs2108622 in CYP4F2 gene is associated with MI in Japanese men. The T-C-G haplotype of CYP4F2 gene appears to be a useful genetic marker of MI in Japanese men.The present results indicate the CC genotype and C allele of rs1558139 in CYP4F2 gene might be a genetic marker for EH and the T-T-G haplotype might be a protective genetic marker for EH in Japanese men.