A near null variant of 12/15-LOX encoded by a novel SNP in ALOX15 and the risk of coronary artery disease
A near null variant of 12/15-LOX encoded by a novel SNP in ALOX15 and the risk of coronary artery disease
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DOI：
10.1016/j.atherosclerosis.2007.09.003
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发表时间：
2008-05-01
期刊：
影响因子：
5.3
通讯作者：
Quertermous, Thomas
中科院分区：
文献类型：
--
作者：
Assimes, Thernistocles L.;Knowles, Joshua W.;Quertermous, Thomas
目的：小鼠遗传模型表明12/15-LOX酶的功能促进动脉粥样硬化。我们测试了人类12/15-LOX基因外显子和/或启动子单核苷酸多态(SNPs)改变症状性冠状动脉疾病(CAD)风险的假设。方法和结果：我们对ALOX15进行了重新测序，然后对1809名CAD患者和1734名来自Kaiser Permanente的对照(包括青年冠状动脉风险发展研究参与者的子集)的一个常见启动子和一个不太常见的新编码SNP(T560M)进行了基因分型。我们没有发现启动子SNP与冠心病风险之间的关联。然而，与非携带者相比，携带560M等位基因的杂合子携带者患冠心病的风险增加(调整后的OR为1.62；P=0.02)。体外研究表明，与560T相比，560M的催化活性降低了20倍。然后，我们对社区动脉粥样硬化风险研究的12,974名参与者的T560M进行了基因分型，类似地发现杂合子携带者比非携带者有更高的冠心病风险(调整后的HR，1.31；P=0.06)。在这两项人群研究中，纯合子携带者是罕见的，与非携带者相比，冠心病的风险没有显著降低(调整后的OR，0.55；P=0.63，HR，0.93；P=0.9)。结论：编码ALOX15(T560M)的SNP导致人类12/15-LOX的近零变异。假设遗传方式是共显性的，这种变异不能预防冠心病。假设这是一种隐性遗传模式，这种突变的影响尚不清楚，但不太可能提供老鼠基因敲除研究所建议的程度的保护作用。(C)2007爱思唯尔爱尔兰有限公司。保留所有权利。
Objective: Murine genetic models suggest that function of the 12/15-LOX enzyme promotes atherosclerosis. We tested the hypothesis that exonic and/or promoter single nucleotide polymorphisms (SNPs) in the human 12/15-LOX gene (ALOX15) alter the risk of symptomatic coronary artery disease (CAD).Methods and results: We resequenced ALOX15 and then genotyped a common promoter and a less common novel coding SNP (T560M) in 1809 subjects with CAD and 1734 controls from Kaiser Permanente including a subset of participants of the Coronary Artery Risk Development in Young Adults study. We found no association between the promoter SNP and the risk of CAD. However, heterozygote carriers of the 560M allele had an increased risk of CAD (adjusted OR, 1.62; P = 0.02) compared to non-carriers. In vitro studies demonstrated a 20-fold reduction in the catalytic activity of 560M when compared to 560T. We then genotyped T560M in 12,974 participants of the Atherosclerosis Risk in Communities study and similarly found that heterozygote carriers had an increased risk of CAD compared to non-carriers (adjusted HR, 1.31; P = 0.06). In both population studies, homozygote carriers were rare and associated with a non-significant decreased risk of CAD compared to non-carriers (adjusted OR, 0.55; P = 0.63 and HR, 0.93; P = 0.9).Conclusions: A coding SNP in ALOX15 (T560M) results in a near null variant of human 12/15-LOX. Assuming a co-dominant mode of inheritance, this variant does not protect against CAD. Assuming a recessive mode of inheritance, the effect of this mutation remains unclear, but is unlikely to provide a protective effect to the degree suggested by mouse knockout Studies. (c) 2007 Elsevier Ireland Ltd. All rights reserved.