Genetic HMG-CoA reductase inhibition may raise cataract risk
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Genetic inhibition of HMG-CoA reductase, a state that mimics long-term statin use, was associated with greater risk for developing cataract compared with individuals without genetic inhibition, researchers reported.
According to data published in the Journal of the American Heart Association, individuals with an especially rare variant of genetic HMG-CoA reductase inhibition experienced a fivefold risk for developing cataract and undergoing cataract surgery, compared with noncarriers of the variant.
“We were able to establish a link between genetic variants that mimic inhibition of HMGCR and the development of cataracts,” Jonas Ghouse, MD, PhD, fellow in the cardiac genetics group, Laboratory for Molecular Cardiology in the department of biomedical sciences at the University of Copenhagen, Denmark, said in a press release. “We were not able to find any association between newer non-statin, lipid-lowering medications and cataract risk, so this effect is likely specific to statins. However, it’s important to stress that the benefits of statins for lowering levels of low-density lipoproteins in people who have high blood cholesterol levels completely outweighs the small risk of cataracts, and cataract surgery is effective and safe.”
Equivalent of statin use
Ghouse and colleagues utilized genotyping and exome sequencing data of more than 402,000 unrelated individuals in the UK Biobank who were not taking a statin; constructed an HMG-CoA reductase genetic score consisting of common variants associated with LDL; and analyzed exome sequencing data to identify individuals with HMG-CoA reductase loss-of-function mutations.
Researchers assessed the association between genetic inhibition of HMG-CoA reductase and risk for developing cataract and undergoing cataract surgery.
“When we carry a loss-of-function mutation, the gene is less likely to work,” Ghouse said in the release. “If that gene doesn’t work, the body can’t produce that protein. Simply put, the loss-of-function mutation in the HMGCR gene equals taking a statin medication.”
HMG-CoA reductase inhibition and cataract risk
Researchers observed that every 38.7 mg/dL (1 mmol/L) reduction in LDL due to genetic HMG-CoA reductase inhibition was associated with increased risk for cataract (OR = 1.14; 95% CI, 1-1.39; P = .045) and undergoing cataract surgery (OR = 1.25; 95% CI, 1.06-1.48; P = .009).
Of the overall cohort, 169,172 individuals had HMG-CoA reductase sequencing data, of which 0.02% carried a rare HMG-CoA reductase predicted loss-of-function variant.
Compared with noncarriers of the rare variant, carriers experienced greater risk for developing cataract (OR = 4.54; 95% CI, 1.96-10.53; P = .001) and undergoing cataract surgery (OR = 5.27; 95% CI, 2.27-12.25; P = .000537).
“Our associations reflect lifelong treatment, whereas statin treatment typically occurs later in life,” Ghouse said in the release. “However, there is a specific group of patients who are diagnosed with high cholesterol in childhood and start statin treatment at a young age, so they could be identified and followed up more closely for cataracts.”
Moreover, the researchers reported no significant association between genetic inhibition of PCSK9, Niemann-Pick C1-Like 1 or circulating LDL levels and risk for cataract (P for all > .05).
“We believe that the true effect lies closer to the loss-of-function mutation association than the common variant association,” Ghouse said in the release. “When taking statins, you have an almost-complete inhibition of that protein, and when you have a loss-of-function mutation you also have a significantly reduced ability to produce that protein.”
Reference:
- Cholesterol-lowering gene changes may increase the risk of cataracts. newsroom.heart.org/news/cholesterol-lowering-gene-changes-may-increase-the-risk-of-cataracts. Published June 15, 2022. Accessed June 15, 2022.
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