【作者】 付真彦；

【导师】 马依彤；

【作者基本信息】 新疆医科大学 ， 心血管内科， 2008， 博士

【摘要】 目的:CYP4A11是细胞色素P450家族成员之一,它的主要功能是催化花生四烯酸生成20-羟二十烷四烯酸(20-HETE),20-HETE具有调节血压的作用。近来有报道,cyp4a14和cyp4a10(人类CYP4A11基因的同形体)基因敲除小鼠引起高血压,而且雄性基因敲除小鼠比雌性基因敲除小鼠血压增加更高。本研究的目的之一是应用病例对照单体型分析的方法研究在不同性别中,CYP4A11基因单体型与高血压的关系。CYF4F2,也是细胞色素P450家族成员之一,它不仅参与了白三烯B4的代谢,而且参与了花生四烯酸的代谢。CYF4F2催化花生四烯酸生成20-羟二十烷四烯酸(20-HETE),20-HETE在维护心血管健康方面具有重要的作用。近来证实,CYP4F2基因的一个单核苷酸多态性(SNP,rs2108622)会导致花生四烯酸生成20-HETE的变化。本研究的另一目的就是应用病例对照单体型分析的方法研究在不同性别中,CYP4F2基因单体型与心肌梗死的关系以及与高血压的关系。方法:304例原发性高血压患者和207例对照分别分为全体,男性,女性。选择CYP4A11基因的3个SNPs(rs2269231,rs9333025,rs1126742)应用TaqMan SNP基因分型方法进行基因分型,并应用病例对照单体型分析方法进行相关性研究。234例心肌梗死患者和248例对照分别分为全体,男性,女性。选择CYPF2基因的5个SNPs(rs3093105,rs3093135,rs1558139,rs2108622,rs3093200),应用TaqMan SNP基因分型的方法进行基因分型,并应用病例对照单体型分析的方法进行相关性研究。249例原发性高血压患者和238例年龄匹配的对照分别分为整体组,男性组,女性组。选择CYPF2基因的5个SNPs(rs3093105,rs3093135,rs1558139,rs2108622,rs3093200)应用TaqMan SNP基因分型的方法进行基因分型,并应用病例对照单体型分析的方法进行相关性研究。结果:CYP4A11基因的研究结果显示,对于全体,rs1126742的基因型分布在高血压组和对照组之间有显著差异(P=0.005);对于全体、男性、女性,rs112674的隐性模式分布(CC versus TC+TT)在高血压组和对照组之间均有显著差异(P=0.007,P=0.043,P=0.045)。Logistic回归分析显示,在剔除一些主要危险因素的干扰后,对于全体、男性,高血压组rs1126742的TC+TT基因型频率显著高于对照组rs1126742的TC+TT基因型频率(P=0.022 and P=0.043).对于男性,高血压组的A-T-G单体型频率显著高于对照组的A-T-G单体型频率(P=0.043)。CYP4F2基因的研究结果显示,对于男性,心肌梗死患者rs2108622的G等位基因频率远远高于对照(P=0.001);心肌梗死患者和对照相比较,单体型的总体分布在男性组显著不同(P=0.001);男性组心肌梗死患者的T-C-G单体型频率显著高于对照(P=0.009),男性组心肌梗死患者的T-C-A单体型频率显著低于对照(P=0.002)。CYP4F2基因的研究结果显示,高血压患者和对照相比较,rs1558139基因型的显性模式分布(CC versus CT+TT)在整体组和男性组中显著不同,(P=0.037,P=0.005),高血压患者的CC基因型频率显著高于对照的CC基因型频率。Logistic回归分析显示,在剔除一些主要危险因素的干扰后,男性组rs1558139的CC基因型分布在高血压患者和对照之间仍然保持差异(P=0.026),而整体组高血压患者和对照之间CC基因型分布的差异消失(P=0.247)。高血压患者和对照相比较,单体型的总体分布在男性组显著不同(P=0.042),男性组高血压患者的T-T-G单体型频率显著低于对照的T-T-G单体型频率(P=0.009)。结论:CYP4A11基因的rs1126742位点,其TC+TT基因型与日本男性高血压有关。A-T-G单体型可作为日本男性高血压的易感基因标志。CYP4F2基因rs2108622的G等位基因与日本男性心肌梗死相关,T-C-G单体型可做为日本男性心肌梗死的易感基因标记,T-C-A单体型可做为日本男性心肌梗死的抵抗基因标记。CYP4F2基因rs1558139的CC基因型和C等位基因可做为日本男性高血压的基因标记,CYP4F2基因的T-T-G单体型可做为日本男性高血压的抵抗性基因标记。更多还原

【Abstract】 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.更多还原