Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada.
Am J Cardiol. 2010 Jun 15;105(12):1740-5. doi: 10.1016/j.amjcard.2010.01.352.
The cardiovascular safety of cyclooxygenase-2-selective (coxibs) and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) is of concern, although most users remain free of adverse outcomes. A gene-drug interaction could modulate this cardiovascular risk through prostaglandin synthesis or inflammatory pathways. From an existing acute coronary syndrome cohort (Recurrence and Inflammation in the Acute Coronary Syndromes Study) (n = 1,210), a case-only study was performed by identifying 115 patients exposed to NSAIDs (rofecoxib [n = 43], celecoxib [n = 49], or nonselective NSAIDs [n = 23]) and 345 unexposed patients matched for age, gender, and hospital center. These patients were genotyped for 115 candidate single-nucleotide polymorphisms (SNPs). Statistically significant associations between NSAID exposure and 9 SNPs in 6 genes were observed. Analyzing patients exposed only to coxibs and their matched unexposed cases, significant associations remained for 5 SNPs at 4 loci (prostaglandin-endoperoxide synthase-1 [PTGS1], chromosome 9p21.3, C-reactive protein [CRP], and klotho [KL]). Two independent SNPs from the PTGS1 gene gave similar results under a recessive model, with odds ratios for the association with NSAID exposure of 6.94 (95% confidence interval 1.35 to 35.65, p = 0.016) and 7.11 (95% confidence interval 1.38 to 36.74, p = 0.033). A significant association was also observed for a SNP in the CRP gene (rs1205) (additive odds ratio 1.64, 95% confidence interval 1.18 to 2.27, p = 0.003). In conclusion, these findings suggest that genetic variability may contribute to the susceptibility for acute coronary syndromes observed in some NSAID users. In particular, genetic polymorphisms in the PTGS1 and CRP genes appear to be candidates for a possible gene-drug interaction influencing the acute coronary risk associated with NSAID use, but these findings will require confirmation in larger cohorts.
环氧化酶 - 2 选择性（coxibs）和非选择性非甾体抗炎药（NSAIDs）的心血管安全性令人关注，尽管大多数使用者仍未出现不良后果。基因 - 药物相互作用可能通过前列腺素合成或炎症途径调节这种心血管风险。在现有的急性冠状动脉综合征队列（Recurrence and Inflammation in the Acute Coronary Syndromes Study）（n = 1210）中，通过识别 115 名接受 NSAIDs（罗非昔布[n = 43]，塞来昔布[n = 49]或非选择性 NSAIDs [n = 23]）和 345 名年龄、性别和医院中心匹配的未暴露患者，进行了病例对照研究。这些患者进行了 115 个候选单核苷酸多态性（SNP）的基因分型。观察到 NSAID 暴露与 6 个基因中的 9 个 SNP 之间存在统计学显著关联。在仅接受 coxibs 的患者及其匹配的未暴露病例中进行分析，在 4 个基因座（前列腺素内过氧化物合酶-1 [PTGS1]，9p21.3 染色体，C 反应蛋白 [CRP]和 klotho [KL]）的 5 个 SNP 中仍存在显著关联。PTGS1 基因中的 2 个独立 SNP 在隐性模型下给出了类似的结果，与 NSAID 暴露相关的优势比为 6.94（95%置信区间 1.35 至 35.65，p = 0.016）和 7.11（95%置信区间 1.38 至 36.74，p = 0.033）。CRP 基因（rs1205）中的 SNP 也存在显著关联（加性优势比 1.64，95%置信区间 1.18 至 2.27，p = 0.003）。总之，这些发现表明遗传变异性可能导致一些 NSAID 使用者中观察到的急性冠状动脉综合征易感性。特别是，PTGS1 和 CRP 基因中的遗传多态性似乎是可能的基因 - 药物相互作用的候选物，影响与 NSAID 使用相关的急性冠状动脉风险，但这些发现需要在更大的队列中得到证实。
