Genetic study shows cholesterol-lowering statins may increase cataract risk

According to new research, people who have genetic variations associated with lowering LDL cholesterol similar to statins appear to have an increased risk of developing cataracts and undergoing cataract surgery.

Statins, a drug used to lower LDL (“bad cholesterol”), are taken by more than 40 million Americans. In fact, it is the most common class of prescription drugs in the United States. Some of the most common statins include Atorvastatin, Lovastatin, Pravastatin, Fluvastatin, Rosuvastatin, Simvastatin, and Pitavastatin under brand names such as Lipitor, Crestor, Lescol XL, Altoprev, Livalo, Pravachol, Ezallor, Zocor and Zypitamag.

Although effective in lowering cholesterol and lowering your risk of heart attack or stroke, there are potential side effects. Some are bad, like memory loss, confusion, kidney damage, and liver damage, but fortunately they are rare. Another side effect is a higher risk of cataracts.

Cataracts are cloudy regions in the eye that lead to impaired vision. These usually develop slowly over time, affecting one or both eyes, leading to increasingly blurred vision. For the most part, they can be treated with surgery that restores vision.

Research Highlights:

  • The researchers used large-scale genotyping and exome sequencing from the UK Biobank to better understand the expected effects of long-term statin use on cataract risk.
  • The analysis found that genetic variants common in more than 402,000 people, who were not taking statins, that mimic the LDL cholesterol-lowering effects of statins are associated with a higher risk of cataracts and cataract surgery.
  • They also found that rare genetic mutations in 169,172 people, mimicking statin treatment, increased the risk of developing cataracts nearly fivefold.

People who have genetic variations associated with lowering LDL cholesterol similar to statins appear to have an increased risk of developing cataracts and undergoing cataract surgery, according to new research, according to new research published today (15 June 2022) in the Journal of the American Heart Association (JAAH). JAHA is an open access, peer-reviewed journal of the American Heart Association.

Previous research has found evidence that statins may increase the risk of cataracts. In this study, researchers explored whether certain genes that mimic statin activity may also independently increase the risk of developing cataracts.

Statins reduce LDL cholesterol levels by inhibiting an enzyme called HMG-CoA-reductase (HMGCR). Previous research efforts have confirmed that variants in the HMGCR gene region of the human genome affect how people metabolize cholesterol.

“We were able to link genetic variants that mimic HMGCR inhibition to the development of cataracts,” said study lead author Jonas Ghouse, MD, Ph.D., member of the Cardiac Genetics Group of the Molecular Cardiology Laboratory of the Department of Biomedical Sciences at the University of Copenhagen in Denmark. “We found no association between newer, non-statin lipid-lowering drugs and cataract risk, so this effect is likely statin-specific. However, it is important to emphasize that the benefits of statins for lowering low-low density in people with high blood cholesterol completely outweighs the low risk of cataracts, and cataract surgery is effective and safe.

Using the UK Biobank, an extensive database of UK residents that tracks the serious health and medical conditions of nearly half a million adults, researchers analyzed genetic data from more than 402,000 people. The researchers focused on five previously identified common genetic variants that lower LDL cholesterol levels. They then calculated genetic scores based on each variant’s previously identified impact on LDL cholesterol. Genetic coding data was examined to identify carriers of a rare mutation in the HMGCR gene called the predicted loss-of-function mutation.

“When we carry a loss-of-function mutation, the gene is less likely to work,” Ghouse said. “If this gene is not working, the body cannot produce this protein. Simply put, the loss-of-function mutation in the HMGCR gene is equivalent to taking a statin drug.

The study found:

  • The HMGCR genetic risk score identified people at higher risk for cataracts and cataract surgery. Each 38.7 mg/dL reduction in LDL cholesterol by genetic score was associated with a 14% higher risk of cataracts and a 25% higher risk of cataract surgery.
  • Among 169,172 with HMGCR sequencing data, 32 (0.02%) carried one of 17 rare mutations predicting HMGCR loss of function. Compared to non-carriers, carriers of these rare mutations were more than four and a half times more likely to develop cataracts and more than five times more likely to undergo cataract surgery.

Ghouse said he was surprised by the magnitude of the association. “The main difference between the two assays is that the loss-of-function mutations are actually more detrimental than the common variants, meaning they mimic the changes often induced by drugs,” he said. “We think the true effect is closer to the loss-of-function mutation association than the common variant association. When you take statins you have almost complete inhibition of this protein, and when you have a loss of function mutation you also have a greatly reduced ability to produce this protein.

According to the authors, a major limitation of the study is that while carrying these genetic variants constitutes a lifetime risk of developing cataracts, this risk should not be assessed in the same way for people who start to take statins later in life given the positive impact of statins. may have by lowering blood cholesterol levels. Further evaluation of this association in other clinical trials is needed to confirm these results.

“Our associations reflect lifelong treatment, whereas statin treatment typically occurs later in life,” Ghouse said. “However, there is a specific group of patients who are diagnosed with high cholesterol in childhood and start statin therapy at a young age, so that they can be identified and followed more closely for cataracts.”

Reference: “Association of Common and Rare Genetic Variation in the 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Gene and Cataract Risk” June 15, 2022, Journal of the American Heart Association.
DOI: 10.1161/JAHA.122.025361

Co-authors are Gustav Ahlberg, M.Sc., Ph.D.; Anne Guldhammer Skov, MD; Henning Bundgaard, MD, DMSc.; and Morten S. Olesen, M.Sc., Ph.D. Author disclosures are listed in the manuscript.

The study was funded by BRIDGE – Translational Excellence Program, John and Birthe Meyer Foundation, Denmark Innovation Fund (PM Heart), NordForsk and Hallas-Møller Emerging Investigator Fellowship.

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