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首页> 外文期刊>Circulation. Genomic and precision medicine. >Genetic Assessment of Potential LongTerm On-Target Side Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors
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Genetic Assessment of Potential LongTerm On-Target Side Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors

机译：遗传评估潜在的长期目标PCSK9的副作用(Proprotein转化酶枯草杆菌蛋白酶/ 9)抑制剂可馨类型

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BACKGROUND: Although short-term trials have suggested that PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are safe and reduce risk of cardiovascular diseases, their long-term safety is unclear. Genetic variants associated with lower activity of a gene can act as proxies to identify potential long-term side effects of drugs as recently exemplified by association of LDL (low-density lipoprotein)-lowering variants in the HMGCR (target for statins) and PCSK9 genes with increased risk of type 2 diabetes mellitus (T2DM). However, analyses of the full spectrum of potential side effects of PCSK9 inhibition using a genetic approach have not been undertaken. METHODS: We examined the association of an LDL-lowering variant in the PCSK9 gene (T allele of rs1159147), as well as 2 LDL-lowering HGCMR variants (G allele of rs17238484 and T allele of rs12916) with 80 diseases and traits in up to 479 522 individuals in UK Biobank. RESULTS: The PCSK9 T allele was significantly (Bonferroni P<6.25x10-4) associated with risk of T2DM, increased body mass index, waist circumference, waist-hip ratio, diastolic blood pressure, type 1 diabetes mellitus, and insulin use. The HMGCR variants were also associated with risk of T2DM, although their previously reported associations with anthropometric traits were found to be confounded. Mediation analysis suggested that the association of the PCSK9 Tallele with risk of T2DM but not diastolic blood pressure was largely independent of its association with body mass index and central obesity. Nominally significant associations of the PCSK9 Tallele were also seen with peptic ulcer disease, depression, asthma, chronic kidney disease, and venous thromboembolism. CONCLUSIONS: Our findings support previous genetic analyses suggesting that long-term use of PCSK9 inhibitors, like statins, may be associated with increased risk of T2DM. Some other potential side effects need to be looked for in future studies of PCSK9 inhibitors, although we did not find signals that raise substantial concerns about their long-term safety.
机译：背景:虽然短期试验建议PCSK9 proprotein转化酶枯草杆菌蛋白酶/ 9)抑制剂是安全的和可馨类型减少心血管疾病的风险,他们长期安全性尚不清楚。降低活动的基因可以行动作为代理来识别潜在的长期的一面最近以药物的效果协会的LDL(低密度脂蛋白)降低HMGCR变体他汀类药物(目标)和PCSK9基因增加2型糖尿病的风险(2型糖尿病)。潜在的副作用PCSK9抑制基因的方法尚未进行。方法:我们研究了协会的ldl降低PCSK9基因变体(T等位基因rs1159147),以及2 ldl降低HGCMRrs17238484和T等位基因的变异(G等位基因rs12916)与80年到479年疾病和特征英国生物库的522人。T等位基因明显(BonferroniP < 6.25 x10-4)与2型糖尿病的风险,增加身体质量指数、腰围腰臀比、舒张压、类型1糖尿病,胰岛素的使用。变体也与二型糖尿病的风险,虽然他们之前报道的关联与人体测量特征被发现抱愧蒙羞。协会的PCSK9 Tallele的风险2型糖尿病但不是舒张压主要是独立的协会与身体质量指数和中央肥胖。协会的PCSK9 Tallele也见过与消化性溃疡疾病、抑郁、哮喘、慢性肾脏疾病和静脉血栓栓塞。支持先前的遗传分析表明长期使用PCSK9抑制剂,如他汀类药物,可能与二型糖尿病的风险增加有关。其他潜在的副作用需要在将来的研究中寻找PCSK9的抑制剂,尽管我们没有发现信号,提高大量长期的担忧安全。

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