A statin-dependent QTL for GATM expression is associated with statin-induced myopathy.
A statin-dependent QTL for GATM expression is associated with statin-induced myopathy.
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他汀类药物被广泛用于降低血浆低密度脂蛋白（LDL）浓度和心血管疾病风险，但在治疗反应方面存在相当大的个体差异，并且越来越多地关注潜在的不良反应，包括肌病和2型糖尿病。尽管有证据表明遗传对低密度脂蛋白浓度有重大影响，但药物基因组学试验未能确定遗传变异对他汀类药物疗效或毒性有重大影响，并且关于调节他汀类药物反应的机制的信息也很少。在这里，我们通过筛选体外他汀暴露对来自480名辛伐他汀治疗临床试验参与者的淋巴母细胞样细胞系基因表达水平的遗传相关性的影响，确定了他汀治疗的下游靶点。该分析确定了6个与辛伐他汀暴露相互作用的表达数量性状位点（eqtl），包括rs9806699，这是编码甘氨酸氨基转移酶的基因GATM的顺式eqtl，甘氨酸氨基转移酶是肌酸合成中的限速酶。我们发现，在两个不同的人群中，该基因座与他汀类药物诱导的肌毒性发生率相关（meta分析优势比= 0.60,95%可信区间= 0.45-0.81，P=6.0×10-4）。此外，我们发现肝细胞来源细胞系中GATM敲低可减弱对胆固醇消耗的转录反应，这表明GATM可能在他汀介导的胆固醇降低和他汀诱导的肌病易感性之间发挥功能联系。
Statins are widely prescribed for lowering plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk, but there is considerable interindividual variation in treatment response and increasing concern regarding the potential for adverse effects, including myopathy and type 2 diabetes. Despite evidence for substantial genetic influence on LDL concentrations, pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy or toxicity, and have yielded little information regarding mechanisms that modulate statin response. Here we identify a downstream target of statin treatment by screening for the effects of in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment. This analysis identified six expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure including rs9806699, a cis-eQTL for the gene GATM that encodes glycine amidinotransferase, a rate-limiting enzyme in creatine synthesis. We found this locus to be associated with incidence of statin-induced myotoxicity in two separate populations (meta-analysis odds ratio = 0.60, 95% confidence interval = 0.45-0.81, P=6.0×10-4). Furthermore, we found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated cholesterol lowering and susceptibility to statin-induced myopathy.
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