Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies.
Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies.
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DOI：
10.1016/j.ajhg.2022.08.004
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发表时间：
2022-09-01
影响因子：
9.8
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中科院分区：
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--
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低氧诱导因子脯氨酰羟化酶抑制剂（HIF-PHIs）目前正在临床开发中，用于治疗慢性肾脏病（CKD）贫血，但监测其心血管安全性非常重要。遗传变异可以用作预测因子，以帮助告知与药物治疗相关的不良反应的潜在风险。因此，我们的目的是利用人类遗传学来帮助评估与治疗改变EPO水平相关的不良心血管事件的风险，以帮助研究HIF-PHI安全性的临床试验。通过对EPO进行全基因组关联荟萃分析（n = 6，127），我们鉴定了位于EPO启动子区的顺式EPO变体（rs 1617640）。我们通过使用遗传和功能方法，包括单碱基基因编辑，验证了这种变异在控制EPO水平方面最有可能是因果关系。使用这种变异作为EPO治疗调节的部分预测因子和孟德尔随机化试验中的大基因组关联数据，我们没有发现证据表明（p < 0.05）遗传学预测内源性EPO的长期升高，相当于增加2.2个单位，增加冠状动脉疾病的风险（CAD，OR [95% CI] = 1.01 [0.93，1.07]）、心肌梗死（MI，OR [95% CI] = 0.99 [0.87，1.15]）或卒中（OR [95% CI] = 0.97 [0.87，1.07]）。我们可以排除增加2.2单位EPO增加1.15的心血管疾病几率。遗传和功能研究的结合提供了一种强有力的方法来研究EPO增加疗法治疗CKD贫血的潜在治疗特征。我们通过GWAS鉴定了一种与EPO水平相关的常见遗传变异。我们通过使用基因编辑技术成功地验证了遗传变异的因果关系。最后，我们使用该变异作为EPO升高治疗的部分预测因子，并没有发现长期EPO升高会导致不良心血管事件的证据。
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD. We identified a common genetic variant associated with EPO levels by performing a GWAS. We successfully validated the genetic variant as causal by using gene-editing techniques. Finally, we used the variant as a partial predictor for EPO-raising therapies and found no evidence of adverse cardiovascular events with long-term EPO rises.
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