The c.–292C>T promoter polymorphism increases reticulocyte-type 15-lipoxygenase-1 activity and could be atheroprotective
The c.–292C>T promoter polymorphism increases reticulocyte-type 15-lipoxygenase-1 activity and could be atheroprotective
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DOI：
10.1515/cclm.2007.103
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发表时间：
2007
期刊：
影响因子：
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通讯作者：
J. Wittwer;Mathias Bayer;A. Mosandl;J. Muntwyler;M. Hersberger
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文献类型：
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作者：
J. Wittwer;Mathias Bayer;A. Mosandl;J. Muntwyler;M. Hersberger
摘要背景：网织红细胞型15-脂氧合酶-1（ALOX 15）具有抗炎和炎症作用，并与哮喘、关节炎和动脉粥样硬化的发展有关。以前，我们筛选了人类ALOX 15基因的变异，因为ALOX 15的遗传变异可能会影响这些疾病。我们发现ALOX 15启动子c.-292位的C>T取代为转录因子SPI 1创造了一个新的结合位点，并增加了c.-292 CT杂合志愿者单核细胞中ALOX 15 mRNA的水平。研究方法：为了测试较高的mRNA水平是否导致较高的ALOX 15活性，我们进行了活性测定并通过HPLC分析测量了花生四烯酸代谢物15（S）-羟基-二十碳四烯酸[15（S）-HETE]。为了检验这种多态性是否与冠状动脉疾病（CAD）相关，我们在一项涉及498名白人的病例对照研究中调查了它的相关性。结果：c.-292 C>T多态性与杂合子携带者较高的酶活性相关。有趣的是，这种多态性也显示出对动脉粥样硬化有保护作用的趋势。结论：这些结果表明，增加的ALOX 15活性可以减轻炎症，这可能是由15（S）-HETE的增加并最终由其代谢产物脂氧素引起的。临床化学实验室医学2007;45：487-92。
Abstract Background: Reticulocyte-type 15-lipoxygenase-1 (ALOX15) has anti-inflammatory and inflammatory effects and is implicated in the development of asthma, arthritis and atherosclerosis. Previously, we screened the human ALOX15 gene for variations because genetic variability in ALOX15 might influence these diseases. We found a C>T substitution at position c.–292 in the ALOX15 promoter that created a novel binding site for the transcription factor SPI1 and increased ALOX15 mRNA levels in monocytes from c.–292CT heterozygous volunteers. Methods: To test whether the higher mRNA levels led to higher ALOX15 activity, we performed an activity assay and measured the arachidonic acid metabolite 15(S)-hydroxy-eicosatetraenoic acid [15(S)-HETE] by HPLC analysis. To test whether this polymorphism was associated with coronary artery disease (CAD), we investigated its association in a case-control study involving 498 Caucasians. Results: The c.–292C>T polymorphism was associated with higher enzyme activity in heterozygous carriers. Intriguingly, this polymorphism also showed a tendency to be protective against atherosclerosis. Conclusions: These results suggest that increased ALOX15 activity may attenuate inflammation, which could be caused by an increase in 15(S)-HETE and eventually by its metabolites, the lipoxins. Clin Chem Lab Med 2007;45:487–92.