Association of Common and Rare Genetic Variation in the 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Gene and Cataract Risk

Research output: Contribution to journalJournal articleResearchpeer-review


  • Fulltext

    Final published version, 0.98 MB, PDF document

BACKGROUND: Results from animal models and observational studies have raised concerns regarding the potential cataractogenic effects of statin treatment. We investigated whether common and rare genetic variants in HMGCR are associated with cataract risk, to gauge the likely long-term effects of statin treatment on lenticular opacities. METHODS AND RESULTS: We used genotyping data and exome sequencing data of unrelated European individuals in the UK Biobank to test the association between genetically proxied inhibition of HMGCR and cataract risk. First, we constructed an HMGCR genetic score consisting of 5 common variants weighted by their association with low-density lipoprotein cholesterol. Second, we analyzed exome sequencing data to identify carriers of predicted loss-of-function mutations in HMGCR. Common and rare variants in aggregate were then tested for association with cataract and cataract surgery. In an analysis of >402 000 individuals, a 38.7 mg/dL (1 mmol/L) reduction in low-density lipoprotein C by the HMGCR genetic score was associated with higher risk for cataract (odds ratio, 1.14 [95% CI, 1.00–1.39], P=0.045) and cataract surgery (odds ratio, 1.25 [95% CI, 1.06– 1.48], P=0.009). Among 169 172 individuals with HMGCR sequencing data, we identified 32 participants (0.02%), who carried a rare HMGCR predicted loss-of-function variant. Compared with noncarriers, heterozygous carriers of HMGCR predicted loss-of-function had a higher risk of developing cataract (odds ratio, 4.54 [95% CI, 1.96–10.53], P=0.001) and cataract surgery (odds ratio, 5.27 [95% CI, 2.27–12.25], P=5.37×10−4). In exploratory analyses, we found no significant association between genetically proxied inhibition of PCSK9, NPC1L1, or circulating low-density lipoprotein cholesterol levels (P>0.05 for all) and cataract risk. CONCLUSIONS: We found that genetically proxied inhibition of the HMGCR gene mimicking long-term statin treatment associated with higher risk of cataract. Clinical trials with longer follow-up are needed to confirm these findings.

Original languageEnglish
Article numbere025361
JournalJournal of the American Heart Association
Issue number12
Pages (from-to)1-39
Publication statusPublished - 2022

Bibliographical note

Publisher Copyright:
© 2022 The Authors.

    Research areas

  • ADR, cataract, HMG-CoA reductase, HMGCR, loss-of-function, statins

Number of downloads are based on statistics from Google Scholar and

No data available

ID: 314065982