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

• Published in: Journal of the American Heart Association 2022-06, Vol.11 (12), p.e025361-e025361
• Main Authors: Ghouse, Jonas, Ahlberg, Gustav, Skov, Anne Guldhammer, Bundgaard, Henning, Olesen, Morten S
• Format: Article
• Language: English
• Subjects: ADR; cataract; Cataract - diagnosis; Cataract - epidemiology; Cataract - genetics; Cholesterol, LDL; Coenzyme A - genetics; Genetic Variation; HMGCR; HMG‐CoA reductase; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; loss‐of‐function; Original Research; Proprotein Convertase 9 - genetics; statins
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.122.025361

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 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 and cataract risk. First, we constructed an 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 . 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 genetic score was associated with higher risk for cataract (odds ratio, 1.14 [95% CI, 1.00-1.39], =0.045) and cataract surgery (odds ratio, 1.25 [95% CI, 1.06-1.48], =0.009). Among 169 172 individuals with sequencing data, we identified 32 participants (0.02%), who carried a rare predicted loss-of-function variant. Compared with noncarriers, heterozygous carriers of predicted loss-of-function had a higher risk of developing cataract (odds ratio, 4.54 [95% CI, 1.96-10.53], =0.001) and cataract surgery (odds ratio, 5.27 [95% CI, 2.27-12.25] =5.37×10 ). In exploratory analyses, we found no significant association between genetically proxied inhibition of , or circulating low-density lipoprotein cholesterol levels ( >0.05 for all) and cataract risk. Conclusions We found that genetically proxied inhibition of the gene mimicking long-term statin treatment associated with higher risk of cataract. Clinical trials with longer follow-up are needed to confirm these findings.