PMID- 30645167 OWN - NLM STAT- MEDLINE DCOM- 20200312 LR - 20211204 IS - 2574-8300 (Electronic) IS - 2574-8300 (Linking) VI - 12 IP - 1 DP - 2019 Jan TI - Genetic Assessment of Potential Long-Term On-Target Side Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors. PG - e002196 LID - 10.1161/CIRCGEN.118.002196 [doi] AB - 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 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. 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. FAU - Nelson, Christopher P AU - Nelson CP AD - 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.). AD - 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.). FAU - Lai, Florence Y AU - Lai FY AD - 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.). AD - 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.). FAU - Nath, Mintu AU - Nath M AD - 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.). AD - 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.). FAU - Ye, Shu AU - Ye S AD - 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.). AD - 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.). FAU - Webb, Thomas R AU - Webb TR AD - 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.). AD - 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.). FAU - Schunkert, Heribert AU - Schunkert H AD - Deutsches Herzzentrum Munchen, Technische Universitat Munchen, Munchen, Germany (H.S.). AD - Deutsches Zentrum fur Herz- und Kreislaufforschung (DZHK), Munich Heart Alliance, Munchen, Germany (H.S.). FAU - Samani, Nilesh J AU - Samani NJ AD - 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.). AD - 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.). LA - eng GR - MC_PC_17228/MRC_/Medical Research Council/United Kingdom GR - MC_QA137853/MRC_/Medical Research Council/United Kingdom GR - SP/16/4/32697/BHF_/British Heart Foundation/United Kingdom GR - DH_/Department of Health/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Circ Genom Precis Med JT - Circulation. Genomic and precision medicine JID - 101714113 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Anticholesteremic Agents) RN - 0 (Cholesterol, LDL) RN - 0 (PCSK9 Inhibitors) RN - EC 3.4.21.- (PCSK9 protein, human) RN - EC 3.4.21.- (Proprotein Convertase 9) RN - LKC0U3A8NJ (evolocumab) SB - IM MH - Antibodies, Monoclonal/adverse effects MH - Antibodies, Monoclonal, Humanized/*adverse effects MH - Anticholesteremic Agents/*adverse effects MH - Cardiovascular Diseases/*etiology/pathology MH - Case-Control Studies MH - Cholesterol, LDL/blood MH - Diabetes Mellitus, Type 2/*etiology/pathology MH - Female MH - *Genetic Variation MH - Humans MH - Male MH - Middle Aged MH - *PCSK9 Inhibitors MH - Proprotein Convertase 9/*genetics OTO - NOTNLM OT - PCSK9 inhibitors OT - gene OT - hydroxymethylglutaryl-CoA reductase inhibitors OT - lipids OT - risk assessment EDAT- 2019/01/16 06:00 MHDA- 2020/03/13 06:00 CRDT- 2019/01/16 06:00 PHST- 2019/01/16 06:00 [entrez] PHST- 2019/01/16 06:00 [pubmed] PHST- 2020/03/13 06:00 [medline] AID - 10.1161/CIRCGEN.118.002196 [doi] PST - ppublish SO - Circ Genom Precis Med. 2019 Jan;12(1):e002196. doi: 10.1161/CIRCGEN.118.002196.