Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (C.P.N., F.Y.L., M.N., S.Y., T.R.W., N.J.S.).
National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom (C.P.N., F.Y.L., M.N., S.Y., T.R.W., N.J.S.).
Circ Genom Precis Med. 2019 Jan;12(1):e002196. doi: 10.1161/CIRCGEN.118.002196.
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.
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.
The PCSK9 T allele was significantly (Bonferroni P<6.25×10) 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 T allele 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 T allele were also seen with peptic ulcer disease, depression, asthma, chronic kidney disease, and venous thromboembolism.
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.
虽然短期试验表明，PCSK9（脯氨酰肽链内切酶/枯草溶菌素 9）抑制剂是安全的，可以降低心血管疾病的风险，但它们的长期安全性尚不清楚。与基因活性降低相关的遗传变异可以作为药物潜在长期副作用的替代指标，最近他汀类药物靶点 HMGCR（羟甲基戊二酰辅酶 A 还原酶）和 PCSK9 基因中的 LDL（低密度脂蛋白）降低变异与 2 型糖尿病（T2DM）风险增加相关的情况就是例证。然而，尚未采用遗传方法分析 PCSK9 抑制的全部潜在副作用谱。
我们在 UK Biobank 中对 PCSK9 基因中的 LDL 降低变异（rs1159147 的 T 等位基因）以及 2 个 LDL 降低的 HMGCR 变异（rs17238484 的 G 等位基因和 rs12916 的 T 等位基因）与多达 479522 名个体的 80 种疾病和特征进行了关联分析。
PCSK9 T 等位基因与 T2DM、体重指数增加、腰围、腰臀比、舒张压、1 型糖尿病和胰岛素使用风险显著相关（Bonferroni P<6.25×10）。HMGCR 变异也与 T2DM 风险相关，尽管它们之前与人体测量特征的关联被发现是混杂的。中介分析表明，PCSK9 T 等位基因与 T2DM 风险的关联，而不是与舒张压的关联，在很大程度上独立于与体重指数和中心性肥胖的关联。PCSK9 T 等位基因与消化性溃疡病、抑郁症、哮喘、慢性肾脏病和静脉血栓栓塞的关联也具有显著意义。
我们的发现支持先前的遗传分析结果，即长期使用 PCSK9 抑制剂，如他汀类药物，可能与 T2DM 风险增加相关。在未来对 PCSK9 抑制剂的研究中，需要寻找其他一些潜在的副作用，但我们没有发现任何信号表明其长期安全性存在严重问题。
