A genomic exploration identifies mechanisms that may explain adverse cardiovascular effects of COX-2 inhibitors.
A genomic exploration identifies mechanisms that may explain adverse cardiovascular effects of COX-2 inhibitors.
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DOI：
10.1038/s41598-017-10928-4
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发表时间：
2017-08-31
影响因子：
4.6
通讯作者：
Schunkert H
中科院分区：
文献类型：
--
作者：
Brænne I;Willenborg C;Tragante V;Kessler T;Zeng L;Reiz B;Kleinecke M;von Ameln S;Willer CJ;Laakso M;Wild PS;Zeller T;Wallentin L;Franks PW;Salomaa V;Dehghan A;Meitinger T;Samani NJ;Asselbergs FW;Erdmann J;Schunkert H
环加氧酶 2 抑制剂 (coxib) 的特点是具有多种分子脱靶效应并增加冠状动脉疾病 (CAD) 风险。在这里，我们系统地探索了代表昔布分子靶标的基因的常见变异体与 CAD 的关联。鉴于考昔布具有广泛的多效性作用，我们的目的是缩小影响 CAD 风险的潜在机制，因为我们假设受影响的基因也可能显示冠状动脉疾病风险的基因组信号。药物基因相互作用数据库搜索发现 47 种基因产物受昔布影响。我们在 84,813 例 CAD 病例和 202,543 例对照中追踪了这些基因周围 200 kb 区域的关联信号。基于 1 × 10−5 的阈值（3131 个单倍型块的 Bonferroni 校正），四个基因位点产生了显着的关联。主要 SNP 为 rs7270354 (MMP9)、rs4888383 (BCAR1)、rs6905288 (VEGFA1) 和 rs556321 (CACNA1E)。通过额外的基因分型，MMP9 的 rs7270354 和 BCAR1 的 rs4888383 也达到了已建立的全基因组显着性 GWAS 阈值。研究结果表明，受昔布类药物影响的基因与介导 CAD 风险的基因存在重叠，并指出了可能导致与昔布类药物相关的 CAD 风险的进一步机制。这种新方法还表明，遗传学研究可能有助于探索脱靶药物效应的临床相关性。
Cyclooxygenase-2 inhibitors (coxibs) are characterized by multiple molecular off-target effects and increased coronary artery disease (CAD) risk. Here, we systematically explored common variants of genes representing molecular targets of coxibs for association with CAD. Given a broad spectrum of pleiotropic effects of coxibs, our intention was to narrow potential mechanisms affecting CAD risk as we hypothesized that the affected genes may also display genomic signals of coronary disease risk. A Drug Gene Interaction Database search identified 47 gene products to be affected by coxibs. We traced association signals in 200-kb regions surrounding these genes in 84,813 CAD cases and 202,543 controls. Based on a threshold of 1 × 10−5 (Bonferroni correction for 3131 haplotype blocks), four gene loci yielded significant associations. The lead SNPs were rs7270354 (MMP9), rs4888383 (BCAR1), rs6905288 (VEGFA1), and rs556321 (CACNA1E). By additional genotyping, rs7270354 at MMP9 and rs4888383 at BCAR1 also reached the established GWAS threshold for genome-wide significance. The findings demonstrate overlap of genes affected by coxibs and those mediating CAD risk and points to further mechanisms, which are potentially responsible for coxib-associated CAD risk. The novel approach furthermore suggests that genetic studies may be useful to explore the clinical relevance of off-target drug effects.
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影响因子：
10.3
作者：
Brinkman, A;van der Flier, S;Dorssers, LCJ
通讯作者：
Dorssers, LCJ
影响因子：
7.7
作者：
Evans, A;Salomaa, V;Kuulasmaa, K
通讯作者：
Kuulasmaa, K
影响因子：
5.8
作者：
Leslie, Richard;O'Donnell, Christopher J.;Johnson, Andrew D.
通讯作者：
Johnson, Andrew D.
影响因子：
2.6
作者：
Gong L;Thorn CF;Bertagnolli MM;Grosser T;Altman RB;Klein TE
通讯作者：
Klein TE
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium