Delles Christian, Padmanabhan Sandosh, Lee Wai Kwong, Miller William H, McBride Martin W, McClure John D, Brain Nick J, Wallace Chris, Marçano Ana C B, Schmieder Roland E, Brown Morris J, Caulfield Mark J, Munroe Patricia B, Farrall Martin, Webster John, Connell John M, Dominiczak Anna F
British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
J Hypertens. 2008 Jul;26(7):1343-52. doi: 10.1097/HJH.0b013e3282fe1d67.
Glutathione S-transferases are involved in defences against oxidative stress. We have recently demonstrated reduced expression of glutathione S-transferase mu type 1 (Gstm1) in a rat model of hypertension. Here, we examine the association between GSTM variants and hypertension in human.
We screened 83 patients with hypertension and 46 controls for single nucleotide polymorphisms in GSTM genes by TaqMan single nucleotide polymorphism genotyping assays and DNA sequencing. We then genotyped 753 trios from the Medical Research Council British Genetics of Hypertension Study transmission disequilibrium test cohort for 10 single nucleotide polymorphisms and the GSTM1 deletion and examined renal GSTM expression in a cohort of 27 hypertensive and 18 normotensive subjects. Finally, we attempted to replicate our findings in 1675 cases and 1654 controls from the Medical Research Council British Genetics of Hypertension Study case-control cohort.
We identified two major linkage disequilibrium blocks including GSTM4/GSTM2 and GSTM5/GSTM3 separated by the GSTM1 gene. In the British Genetics of Hypertension transmission disequilibrium test resource, a single nucleotide polymorphism in the 3' region of GSTM5 (rs11807) was found to be associated with hypertension (P = 0.01) with the T-allele being over-transmitted to hypertensive offspring. GSTM5 mRNA expression was found to be reduced in kidney tissue of subjects homozygous for the T-allele of rs11807 as compared to C-allele homozygous and CT heterozygous subjects (P = 0.02). Nevertheless, rs11807 was not associated with hypertension in the British Genetics of Hypertension case-control cohort (P = 0.61).
Our studies do not provide an evidence of an association of GSTM gene variants with hypertension in humans. They, however, illustrate the essential role of replication of initial results in a second cohort.
谷胱甘肽S-转移酶参与抗氧化应激防御。我们最近在高血压大鼠模型中证明了谷胱甘肽S-转移酶μ1型（Gstm1）的表达降低。在此，我们研究人类中GSTM基因变异与高血压之间的关联。
我们通过TaqMan单核苷酸多态性基因分型检测和DNA测序，对83例高血压患者和46例对照进行GSTM基因单核苷酸多态性筛查。然后，我们对医学研究委员会英国高血压遗传学研究传递不平衡检验队列中的753个三联体进行10个单核苷酸多态性以及GSTM1缺失的基因分型，并检测27例高血压患者和18例血压正常受试者队列中的肾脏GSTM表达。最后，我们试图在医学研究委员会英国高血压遗传学研究病例对照队列的1675例病例和1654例对照中重复我们的研究结果。
我们确定了两个主要的连锁不平衡区域，包括由GSTM1基因分隔的GSTM4/GSTM2和GSTM5/GSTM3。在英国高血压遗传学研究传递不平衡检验资源中，发现GSTM5的3'区域的一个单核苷酸多态性（rs11807）与高血压相关（P = 0.01），T等位基因过度传递给高血压后代。与C等位基因纯合子和CT杂合子受试者相比，发现rs11807的T等位基因纯合子受试者的肾脏组织中GSTM5 mRNA表达降低（P = 0.02）。然而，在英国高血压遗传学研究病例对照队列中，rs11807与高血压无关（P = 0.61）。
我们的研究没有提供GSTM基因变异与人类高血压相关的证据。然而，它们说明了在第二个队列中重复初始结果的重要作用。
