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Genetic Assessment of Potential Long-Term On-Target Side Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin
Christopher P Nelson1,2, Florence Y Lai1,2, Mintu Nath1,2
1Department 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.).
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<6.25×10-4) 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.
Insights
Genetic variants in PCSK9 (proprotein convertase subtilisin/kexin type 9) are linked to an increased risk of type 2 diabetes mellitus (T2DM). Long-term PCSK9 inhibition may share similar risks to statins, warranting further investigation into potential side effects.
Area of Science:
- Genetics and Pharmacology
- Cardiovascular Disease Research
- Metabolic Disease Epidemiology
Background:
- Long-term safety of PCSK9 inhibitors is not well-established, despite short-term trial data.
- Genetic variants offer insights into potential long-term drug side effects, as seen with statin targets.
- Previous studies linked PCSK9 and HMGCR gene variants to type 2 diabetes mellitus (T2DM) risk.
Purpose of the Study:
- To investigate the long-term safety of PCSK9 inhibition using genetic proxies.
- To examine associations between PCSK9 and HMGCR gene variants and a wide range of diseases and traits.
- To assess potential links between PCSK9 inhibition and increased risk of T2DM and other conditions.
Main Methods:
- Utilized UK Biobank data from up to 479,922 individuals.
- Examined an LDL-lowering PCSK9 variant (rs1159147) and two LDL-lowering HMGCR variants (rs17238484, rs12916).
- Assessed associations with 80 diseases and traits, including T2DM, and performed mediation analyses.
Main Results:
- The PCSK9 T allele strongly associated with T2DM, increased BMI, waist circumference, waist-hip ratio, diastolic blood pressure, type 1 diabetes, and insulin use.
- HMGCR variants also associated with T2DM, but prior anthropometric associations were confounded.
- Mediation analysis indicated PCSK9's T2DM risk association was largely independent of BMI and central obesity; nominal associations found with peptic ulcer disease, depression, asthma, CKD, and VTE.
Conclusions:
- Findings support genetic evidence suggesting long-term PCSK9 inhibition may increase T2DM risk, similar to statins.
- Further research is needed to monitor other potential side effects of PCSK9 inhibitors.
- Current genetic data does not raise significant concerns about the overall long-term safety of PCSK9 inhibitors.
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