A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction
A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction
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DOI：
10.1038/ng1692
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发表时间：
2006-01-01
期刊：
影响因子：
30.8
通讯作者：
Stefansson, K
中科院分区：
文献类型：
--
作者：
Helgadottir, A;Manolescu, A;Stefansson, K
编码花生四烯酸5-脂氧合酶激活蛋白的基因ALOX5AP(也称为Flat)的变异已知与心肌梗死的风险有关。在这里，我们显示了编码白三烯A4水解酶的LTA4H基因的单倍型(HapK)，这是一种与ALOX5AP处于相同生化途径的蛋白质，在冰岛队列中具有适度的心肌梗死风险。对白三烯B4(LTB4)产生的测量表明，这种风险是通过白三烯途径上调而介导的。来自美国的三个队列也表明，HapK在欧洲裔美国人中具有适度的相对风险(1.16)，但在非裔美国人中具有三倍以上的风险。大约27%的欧洲美国人控制组携带至少一个HapK拷贝，相比之下，非洲裔美国人控制组只有6%。我们的分析表明，HapK在非洲非常罕见，它在非裔美国人中的出现是由于欧洲人的混合。与非裔美国人中更常见的其他遗传或环境风险因素的相互作用可能解释了HapK在这一群体中赋予的更大相对风险。
Variants of the gene ALOX5AP ( also known as FLAP) encoding arachidonate 5-lipoxygenase activating protein are known to be associated with risk of myocardial infarction(1). Here we show that a haplotype (HapK) spanning the LTA4H gene encoding leukotriene A4 hydrolase, a protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggest that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also show that HapK confers a modest relative risk (1.16) in European Americans, but it confers a threefold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Our analyses indicate that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group.