盐敏感性高血压易感基因多态性的种族差异性研究

目的 探讨HapMap数据库中四个种族人群盐敏感性高血压易感基因频率的分布差异.方法 利用HapMap数据库中犹他州的欧洲西部和北部的后裔(CEU)、中国北京汉族人(CHB)、日本东京人(JPT)以及尼日利亚的约巴鲁人(YRI)四个种族人群的基因频率数据,建立盐敏感性高血压易感基因多态性(血管紧张肽原基因多态性AGT/M235T、血管紧张素转换酶基因多态性ACE/ID、醛固酮合成酶基因多态性CYP11B2/C344T、α-内收蛋白基因多态性α-adducin/G460T、G蛋白β3亚基基因多态性GNB3/C825T和细胞色素P450 3A酶基因多态性CYP3A5/A6986G)基因数据库(n=395).应用拟合优度卡方检验验证每个基因型分布频率是否符合Hardy-Weinberg平衡定律.利用χ2检验,对不同种族盐敏感性易感基因的基因型频率和等位基因频率进行比较,并进行趋势性检验.同时,运用χ2分割方法 进行两组间的多重比较.结果 四个种族人群盐敏感性易感基因的频率分布存在统计学差异(P＜0.05＝.组间两两比较的结果 发现CHB与JPT人群间的基因型和易感等位基因频率分布没有显著性差异.除了GNB3/825T等位基因频率没有显著性差异(38.8%比34.4%,P=0.521)外,与CEU人群相比,CHB人群的AGT/235T(79.2%比41.2%,P＜0.001＝、ACE/I(56.5%比43.5%,P＜0.001＝、CYP11B2/-344T(74.1%比56.7%,P=0.001)、ADDI/460Trp(51.8%比20.4%,P＜0.001＝和CYP3A5/A6986(30.1%比3.6%,P＜0.001＝等位基因突变频率明显偏高.ADDI/460Trp等位基因在YRI群中分布极低,仅为4%,明显低于CHB人群(51.8%,P＜0.001＝,而AGT/235T、CYP11B2/-334T、GNB3/825T、CYP3A5/6986A基因多态性突变频率均显著地高于CHB人群.根据CEU、CHB、YRI三个人群的趋势性检验的结果 发现,AGT/235T(41.2%＜79.2%＜92.0%,P＜0.001＝、CYP11B2/-334T(56.7%＜74.1%＜84.8%,P＜0.001＝和CYP3A5/6986A(3.6%＜30.1%＜84.5%,P＜0.001＝三个盐敏感性易感基因所携带的突变等位基因型频率呈现显著增加趋势.结论 利用HapMap数据库提供的四个种族基因多态性检测数据进行分析的结果 提示我们,盐敏感性高血压易感基因多态性在不同种族人群中的分布具有显著性差异.北京汉族人群盐敏感性易感等位基因的频率近似于JPT人群,高于CEU人群而低于YRI人群,说明北京汉族人群有较高的盐敏感性,针对高危人群进行预防和个体化治疗将有助于降低盐敏感性高血压和心血管疾病的发生.

A ross-racial analysis on the susceptible gene polymorphisms of salt-sensitive hypertension

Objective To compare the genetic distributions of salt-sensitivity of four ethnic populations in Hapmap database. Methods The frequencies data (395 subjects ) of salt-sensitivity polymorphisms ( AGT/M235T, ACE/ID, CYP11B2/C-344T, ADDI/Gly460Trp, GNB3/C825 and CYP3A5/A6986G)of Utah residents with ancestry from northern and western Europe (CEU), Han Chinese in Beijing ( CHB), Japanese in Tokyo (JPT) and Yoruba mother-father-child trios in Ibadan, Nigeria (YRI) were obtained from International HapMap Project. The good-fit χ2 test was performed to test whether the frequencies of each genotype reached Hardy-Weinberg equilibrium. The differences of the genotype and allele distribution and trend analysis were detected via χ2 test. Furthermore, multiple comparisons between two populations were analyzed by Lancaster's partition of chi-squares. Results There were significant differences of each genotype distribution among four ethnic populations ( P ＜ 0. 05 ). The distribution of genotype frequencies and susceptible allele frequencies of salt sensitive candidate genes were similar between CHB and JPT. Excepted for GNB3/825T allele ( 38. 8% vs. 34. 4%, P = 0. 521 ), susceptible allele frequencies in AGT/235T (79. 2% vs. 41.2%, P ＜0. 001 ), ACE/I (56. 5% vs. 43.5%, P ＜0. 001 ),CYP11B2/-344T (74. 1% vs. 56.7%, P=0. 001), ADDI/460Trp (51.8% vs. 20.4%, P＜0.001) and CYP3A5/A6986 (30. 1% vs. 3.6%, P ＜0.001 ) were significantly higher in CHB than in CEU. There distribution of ADDI/460Trp allele was significant lower in YRI (4%) than in CHB (51.8%, P＜0. 001 ).However frequencies of AGT/235T, CYP11B2/-334T, GNB3/825T and CYP3A5/6986A in CHB were significantly lower than those in YRI ( P ＜ 0. 05 ). Trend analyses showed significantly increased trend in AGT/235T (41.2% ＜79.2% ＜92.0%, P＜0.001), CYP11B2/-334T (56.7% ＜74.1% ＜84.8%, P ＜ 0. 001 ) and CYP3A5/6986A (3.6% ＜ 30. 1% ＜ 84. 5%, P ＜ 0. 001 ) in CEU, CHB and YRI. Conclusions There are significant discrepancy of salt-sensitivity variant distributions among four ethnic populations in Hapmap database. The frequencies of the susceptible polymorphisms related to salt-sensitivity in Beijing Han population was similar with JPT, higher than in CEU but lower than in YRI, suggesting high salt-sensitive and risk for hypertension in Beijing Han population. Prevention and individual therapy for high-risk population will help to reduce the prevalence of salt-sensitive hypertension and cardiovascular diseases.