藏族人群G蛋白偶联受体激酶4基因多态性及其与盐敏感性共同对高血压的影响研究

背景　高血压是遗传与环境因素共同作用的结果，研究发现G蛋白偶联受体激酶4（GRK4）基因与盐敏感性均会影响高血压的发生，且GRK4基因与盐敏感性之间可能存在交互作用，但具体的关系尚不明确，目前我国少数民族中有关这方面的资料比较缺乏。目的　研究藏族人群的GRK4基因多态性及其与盐敏感性共同对高血压的影响。方法　2013年8月-2014年11月采用多阶段随机抽样的方法，选取甘南藏族自治州夏河县和合作市藏族成年高血压患者799例作为病例组，674例血压正常的藏族成年人作为对照组。采用项目组统一设计的调查表，调查其性别、年龄、职业、文化程度、生活行为方式（吸烟、饮酒、体育锻炼）等。测量调查对象的血压、身高、体质量，并计算其体质指数（BMI）。利用改良盐负荷方法检测血压盐敏感性，采集外周静脉血检测GRK4基因多态性位点。比较两组人群一般资料及各基因型的分布情况，采用多因素Logistic回归分析GRK4基因与盐敏感性及其交互作用对高血压的影响。结果　两组间性别、年龄、职业、文化程度、吸烟、饮酒、体育锻炼、收缩压、BMI、盐敏感性比较，差异均有统计学意义（P<0.05）。两组间GRK4基因的rs2488815、rs12506119、rs1419043、rs1801058基因型和等位基因频率比较，差异均有统计学意义（P<0.05）。rs12506119、rs1419043、rs2471338和rs3733219四个基因位点在两组中的分布符合H-W定律（P>0.05）。多因素Logistic回归分析结果显示，盐敏感性〔OR=1.69，95%CI（1.14，2.50）〕是高血压的危险因素，rs1419043的CG基因型〔OR=0.13，95%CI（0.02，0.99）〕是高血压的保护因素（P<0.05）。基因与盐敏感性的交互作用分析结果显示，在无盐敏感性的基础上，rs12506119的GA基因型〔OR=0.33，95%CI（0.15，0.73）〕及rs1419043的CG基因型〔OR=0.32，95%CI（0.15，0.68）〕是高血压的保护因素（P<0.05）；在盐敏感性的基础上，rs12506119的GG基因型〔OR=1.45，95%CI（1.09，1.92）〕、rs1419043的GG基因型〔OR=1.43，95%CI（1.07，1.90）〕、rs2471338的AA基因型〔OR=1.49，95%CI（1.11，2.00）〕、rs3733219的TT基因型〔OR=1.40，95%CI（1.02，1.91）〕及CT基因型〔OR=1.60，95%CI（1.07，2.40）〕是高血压的危险因素（P<0.05）。结论　藏族人群GRK4基因可能与高血压有关，且GRK4基因的不同位点对高血压的作用受盐敏感性的影响而不同。

Effect of G Protein-coupled Receptor Kinase 4 Gene Polymorphism and Its Combined with Salt Sensitivity on Hypertension in Tibetans

Background　Hypertension is associated with both genetic and environmental factors.Studies have found that either G protein-coupled receptor kinase 4（GRK4）gene or salt sensitivity can affect the occurrence of hypertension，and there may be an interaction between GRK4 gene and salt sensitivity，but the specific relationship is still unclear，and relevant studies in ethnic minorities are rare in China.Objective　To explore the influence of GRK4 gene polymorphism and its combined with salt sensitivity on hypertension among Tibetan population in Gannan Tibetan Autonomous Prefecture.Methods　A total of 799 Tibetans with essential hypertension and 674 Tibetans with normal blood pressure were selected from Xiahe County and Hezuo City，Gannan Tibetan Autonomous Prefecture with multistage random sampling method from August 2013 to November 2014.A questionnaire developed by our project team was used to survey data regarding gender，age，occupation，educational level，lifestyle（smoking，drinking，physical exercise）.Blood pressure，weight，and height were examined，and body mass index（BMI）was calculated.Salt sensitivity was determined by using improved salt-loading test.The single nucleotide polymorphisms（SNP）of GRK4 in the peripheral venous sample was tested.The differences of basic characteristics and distribution of genotypes at each locus among two groups were analyzed.Logistic regression was used to analyze the effect of GRK4 and salt sensitivity and their interaction on hypertension.Results　The gender ratio，average age，distribution of occupation and education level，prevalence of smoking，drinking，and physical exercise，average systolic blood pressure，BMI and salt sensitivity all were significantly different in two groups（all P<0.05）.The distributions of genotypes and allele frequencies in rs2488815，rs12506119，rs1419043 and rs1801058 were significantly different in two groups（all P<0.05）.The four SNPs of rs12506119，rs1419043，rs2471338 and rs3733219 in GRK4 gene were consistent with Hardy-Weinberg equilibrium in two groups（all P>0.05）.Results from logistic regression analysis showed that，salt sensitivity was associated with increased risk of hypertension〔OR=1.69，95%CI（1.14，2.50）P<0.05〕，while CG genotype of rs1419043 was associated with decreased risk of hypertension〔OR=0.13，95%CI（0.02，0.99）P<0.05〕.Analysis of the interaction between genes and salt sensitivity showed that，in participants without salt sensitivity，GA genotype of rs12506119〔OR=0.33，95%CI（0.15，0.73）〕and CG genotype of rs1419043〔OR=0.32，95%CI（0.15，0.68）〕were associated with decreased risk of hypertension（P<0.05）.In those with salt sensitivity，GG genotype of rs12506119〔OR=1.45，95%CI（1.09，1.92）〕，GG genotype of rs1419043〔OR=1.43，95%CI（1.07，1.90）〕，AA genotype of rs2471338〔OR=1.49，95%CI（1.11，2.00）〕，TT genotype〔OR=1.40，95%CI（1.02，1.91）〕and CT genotype〔OR=1.60，95%CI（1.07，2.40）〕of rs3733219 were risk factors of hypertension（P<0.05）.Conclusion　GRK4 gene may be related to hypertension in Tibetans，and the effects of different loci in GRK4 gene on hypertension varied significantly by salt sensitivity.