Circ Genom Precis Med. 2026 Jul 9:e005666. doi: 10.1161/CIRCGEN.125.005666. Online ahead of print.
ABSTRACT
BACKGROUND: Genetic differences may contribute to interindividual variability in LDL-C (low-density lipoprotein cholesterol) lowering with statin therapy. Polygenic risk scores may help identify individuals unlikely to achieve guideline-concordant LDL-C targets on statins, enabling earlier therapy intensification.
METHODS: We developed a multiancestry polygenic risk score for statin nongoal response (PRS-NGR) and evaluated its association with failure to achieve an on-statin LDL-C level of ≤70 mg/dL and with percent LDL-C reduction. This longitudinal cohort study used genotyping and electronic health record-linked data from the All of Us Research Program (2018-2025), the UK Biobank (2014-2023), and the Biobank Japan (2003-2008). Participants were statin users with at least 1 prestatin and 1 on-statin LDL-C measurement. Associations were assessed overall and by genetic ancestry, with replication in the UK Biobank and Biobank Japan.
RESULTS: The study included 46 564 participants from All of Us, 37 009 from the UK Biobank, and 3613 from Biobank Japan. In All of Us, higher PRS-NGR was associated with increased odds of nongoal response (odds ratio per SD, 1.43 [95% CI, 1.37-1.49]). Compared with the middle quintile, individuals in the top 1% had a higher risk, whereas those in the bottom 1% had a lower risk of nongoal response. Associations of PRS-NGR were consistent across African, European, and Latin American ancestry groups. Each SD increase in PRS-NGR corresponded to a 1.2-percentage-point smaller LDL-C reduction. Findings were replicated in the UK Biobank (odds ratio per SD, 2.39 [95% CI, 2.23-2.57]) and in Biobank Japan (odds ratio per SD, 1.31 [95% CI, 1.17-1.46]). Integration of PRS-NGR with guideline-based criteria identified individuals who derived a higher LDL-C% change and increased identification of statin-eligible individuals.
CONCLUSIONS: We developed and validated a multiancestry polygenic risk score that estimates the risk of nongoal LDL-C response to statin therapy. Incorporation of polygenic risk into lipid-lowering treatment paradigms may improve risk stratification and support more tailored therapy intensification strategies.
PMID:42422963 | DOI:10.1161/CIRCGEN.125.005666
