Quintana L F, Guzmán B, Collado S, Clària J, Poch E
Servicio de Nefrología, Hospital Clínic, Universidad de, Barcelona, Barcelona, Spain.
Kidney Int. 2006 Feb;69(3):526-30. doi: 10.1038/sj.ki.5000147.
The arachidonic acid-derived metabolite 12-(S)hydroxyeicosatetraenoic acid (12(S)-HETE), catalyzed by 12-lipoxygenase (12-LOX, ALOX12), exhibits a variety of biological activities with implications in cardiovascular disease. Previous studies have shown higher urinary excretion of this metabolite in essential hypertension. The aim of this study was to analyze the association of polymorphisms in ALOX12 with hypertension and urinary levels of 12(S)-HETE. We studied 200 patients with essential hypertension (aged 56+/-1 years, mean+/-s.e.m., 97 males) and 166 matched controls (aged 54+/-1 years, 91 males). Out of six polymorphisms in the coding region of ALOX12, only R261Q determined a nonconservative amino-acid change and was evaluated by polymerase chain reaction and restriction digestion. Urinary 12(S)-HETE was measured in Sep-Pack-extracted samples using specific enzyme-linked immunosorbent assay. The distribution of genotypes of the R261Q polymorphism was significantly different between patients and controls: patients 92 (0.46) GG, 84 (0.42) GA, 24 (0.12) AA vs controls 56 (0.34) GG, 78 (0.47) GA, 32 (0.19) AA (P=0.030). On the contrary, no association was observed for two intronic polymorphisms. The urinary excretion of 12(S)-HETE (ng/mg creatinine) was significantly higher in GG homozygous patients (13.0+/-1.5) than in GA (8.2+/-1.8) or in AA (8+/-1.5) patients (P=0.018). These results indicate that a nonsynonymous polymorphism in ALOX12 is associated to essential hypertension and to urinary levels of 12(S)-HETE, thus suggesting a role for this gene in this disease.
由花生四烯酸衍生的代谢产物12-(S)-羟基二十碳四烯酸(12(S)-HETE)，在12-脂氧合酶(12-LOX, ALOX12)的催化下，具有多种生物学活性，与心血管疾病相关。既往研究表明，原发性高血压患者尿中该代谢产物的排泄量较高。本研究旨在分析ALOX12基因多态性与高血压及尿中12(S)-HETE水平的相关性。我们研究了200例原发性高血压患者(年龄56±1岁，平均±标准误，男性97例)和166例匹配的对照者(年龄54±1岁，男性91例)。在ALOX12编码区的6个多态性中，只有R261Q导致了非保守氨基酸改变，并通过聚合酶链反应和限制性酶切进行评估。使用特异性酶联免疫吸附测定法在Sep-Pack提取的样本中测量尿12(S)-HETE。患者和对照者中R261Q多态性的基因型分布有显著差异：患者92例(0.46) GG、84例(0.42) GA、24例(0.12) AA，对照者56例(0.34) GG、78例(0.47) GA、32例(0.19) AA (P=0.030)。相反，未观察到两个内含子多态性的相关性。GG纯合子患者尿中12(S)-HETE(ng/mg肌酐)的排泄量(13.0±1.5)显著高于GA患者(8.2±1.8)或AA患者(8±1.5)(P=0.018)。这些结果表明，ALOX12中的一个非同义多态性与原发性高血压及尿中12(S)-HETE水平相关，提示该基因在该疾病中起作用。
