| Title: | Uncovering Coenzyme Q10-Related Genetic Determinants of Statin-Associated Muscle Symptoms: Evidence from the UK Biobank and the All of Us Research Program |
| Journal: | Clinical Pharmacology & Therapeutics |
| Published: | 11 May 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42109163/ |
| DOI: | https://doi.org/10.1002/cpt.70325 |
Publication 20102
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Abstract
Statin-associated muscle symptoms (SAMS) are frequent adverse effects of statin therapy and have been hypothesized to result from impaired coenzyme Q10 (CoQ10) biosynthesis. Although genetic determinants of CoQ10 levels have been reported, genome-wide association studies (GWASs) conducted specifically in statin users are lacking. Moreover, direct CoQ10 measurements are unavailable in large-scale proteomic resources, necessitating suitable proxy biomarkers. COQ7, a key enzyme in the late steps of CoQ10 biosynthesis, was used as a proxy for CoQ10 biosynthetic capacity. We performed a GWAS of COQ7 protein levels in statin-treated participants from the UK Biobank. The lead variant was evaluated for association with SAMS in an independent cohort of statin users from the All of Us, followed by replication in an independent SAMS cohort from the UK Biobank. Gene-statin interaction analyses were conducted to assess statin-specific genetic effects. In addition, polygenic risk score (PRS) analyses were performed using previously reported CoQ10-associated variants from non-statin-specific cohorts. The GWAS identified the lead variant, rs66554427, with the A allele associated with lower COQ7 protein levels (β = -0.13, SE = 0.018, P = 1.1 × 10-13). In the All of Us, the rs66554427 A allele was associated with an increased risk of SAMS (OR = 1.27, 95% CI: 1.16-1.39, P = 5.16 × 10-8). These findings were consistently replicated in the UK Biobank SAMS cohort (OR = 1.23, 95% CI: 1.06-1.43, P = 6.89 × 10-3). Significant additive and multiplicative interactions between statin and rs66554427 were observed (P < 0.001). PRS analyses further demonstrated that genetically predicted lower CoQ10 levels were associated with a higher risk of SAMS. Using COQ7 protein levels as a proxy for CoQ10 biosynthesis, we identified statin-specific genetic susceptibility to SAMS and supported a causal role of impaired CoQ10 biosynthesis in SAMS.</p>
7 Authors
- Da Hoon Lee
- Yoon-A Park
- Yubin Song
- Ji-Min Han
- Kyung Hee Choi
- Myeong Gyu Kim
- Hye Sun Gwak
1 Application
| Application ID | Title |
|---|---|
| 126305 | Risk scoring system development of statin adverse events and resistance using clinical and genetic factors for individualized pharmaceutical care service |
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