Genetic Variants in HMGCR Gene Linked to Cataract Risk in Study of UK Biobank

Individuals with common and rare genetic variants in the HMGCR gene are at increased risk of developing cataracts, a finding that could have implications for when statins are used to lower cholesterol levels, according to a new study.

Cataracts affect more than 20 million people in the US and are a leading cause of blindness. Treatment with statins that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase to reduce low-density lipoprotein cholesterol are suspected to increase the risk of blindness.

To examine that link further, researchers from Copenhagen University Hospital examined the effects of genetic variation of the HMGCR gene, which encodes HMG-CoA reductase, on the development of cataracts. As they reported in the Journal of the American Heart Association on Wednesday, the researchers found that individuals in the UK Biobank with common HMGCR gene variants that affect LDL-C levels also had an increased risk of developing cataracts or undergoing surgery for cataracts. That effect was further pronounced among individuals with rare, loss-of-function variants affecting HMGCR.

"We were able to establish a link between genetic variants that mimic inhibition of HMGCR and the development of cataracts," first author Jonas Ghouse, a fellow in the cardiac genetics group at Copenhagen, said in a statement. "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."

Ghouse added that "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."

For their analysis, the researchers developed an HMGCR genetic score based on five common variants, which they weighted based on their ability to lower LDL-C levels. After using data from the UK Biobank to confirm that there was a strong association between HMGCR genetic scores and LDL-C levels, the researchers then examined whether the HMGCR genetic scores were also associated with having cataracts or undergoing cataract surgery. For each genetically prescribed 38.7mg/dl decrease in LDL-C, individuals in the UK Biobank had a 14 percent higher risk of cataracts and 25 percent higher risk of cataract surgery.

The researchers also examined the effect of predicted loss-of-function variants in HMGCR on cataract risk. These variants — the most frequent of them being the nonsynonymous splice region variant p.Leu521Phe — were associated with a 4.5-times higher risk of cataracts and a more than fivefold risk of cataract surgery, as compared to individuals without these variants.

"The main difference between the two analyses is that loss-of-function mutations are really more detrimental than common variants, meaning they mimic change that is often induced by medications," Ghouse said. "We believe that the true effect lies closer to the loss-of-function mutation association than the common variant association. 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."

The researchers noted, though, that this study focuses on individuals who have lifelong exposure to HMG-CoA reduction or inhibition, while most people who are prescribed statins begin taking them later in life, which limits their exposure.

In other, exploratory analyses, the researchers noted that this effect appears limited to the HMG-CoA pathway, as they found no association between genetically gauged inhibition of NPC1L1 or PCSK9 and cataract risk or with genetically lower LDL-C levels and cataract risk. This suggested to them that the link between HMG-CoA and cataracts may be due to the role of HMG-CoA reductase in lens sterol synthesis.