Study Finds HMGCR Variants Associated With Increased Risk of Cataracts

Common and rare variants of the HMGCR gene were associated with an increased risk of cataracts, according to a study published in the Journal of the American Heart Association.

The study evaluated the HMGCR gene as a proxy for inhibition of 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase and the resulting risk of cataracts. Statins, which are used to lower low-density lipoprotein (LDL) cholesterol, inhibit HMG-CoA, the authors explained.

"With a growing elderly population, the incidence of cataracts is likely to rise," they wrote. "Therefore, identification of risk factors for developing lens opacities must be prioritized from a public health standpoint."

The study used the UK Biobank, which contains data on approximately 500,000 participants aged 40 to 69 years and recruited from 2006 to 2010. The researchers used a previously published 5 single-nucleotide polymorphism HMGCR genetic score to HMG-CoA reductase inhibition.

Participants were defined as people carrying a rare HMGCR predicted loss-of-function (pLoF) variant and the control group were people not carrying an HMGCR predicted loss-of-function variant. These were determined using the exome sequenced data for HMGCR from participants of European ancestry.

The study used genotyped data on 402,750 participants of European ancestry. In this group the researchers found a strong association between HMGCR genetic score and LDL cholesterole levels (–1.32 mg/dL per SD increase; 95% CI, –1.42 to –1.21)

The genetically proxied HMG-CoA reductase inhibition was associated with both cataract (OR, 1.14; 95% CI, 1.00-1.29) and cataract surgery (OR, 1.19; 95% CI, 1.04-1.36) for each 38.7 mg/dL (1 mmol/L) reduction in LDL-C levels.

There were 32 participants with 1 of 17 HMGCR pLoF variants (0.02% carrier frequency). HMGCR pLoF carriers had lower LDL-C (–13.1 mg/dL; 95% CI, –25.1 to –1.2) and cholesterol (–17.4 mg/dL; 95% CI, –32.9 to –1.5) compared with noncarriers.

There were 8 of the 32 HMGCR pLoF carriers (25%) who had cataracts compared with 12,928 of 169,140 (7.6%) noncarriers (OR, 4.54; 95% CI, 1.96-10.53). A higher percentage of carriers had cataract surgery compared with noncarriers (25% vs 6.7%), with an odds ratio of 5.27 (95% CI, 2.27-12.25).

An analysis of the aggregate effects of rare deleterious variants on cataract found a concordant direction of effects with attenuated effect estimates (cataract: OR, 1.34; 95% CI, 0.97-1.84. Cataract surgery: OR, 1.51; 95% CI, 1.09-2.08). Results were largely consistent in the sensitivity analyses after adjusting for risk factors that are linked with cataracts.

There were no significant associations found between PCSK9 and NPC1L1 on cataracts or cataract surgery. There were also no significant associations between genetically proxied inhibition of PCSK9, NPC1L1, or genetically proxied lower LDL cholesterol levels and cataracts and cataract surgery.

There were some limitations to this study. The study weighed the genetic score by their effect on LDL cholesterol, which is an indirect measure, rather than studying the effect of the variants on enzymatic activity. The population of the study was entirely of European ancestry, which may bias the results and limit the generalizability. Effect estimates reflected life-long exposure to HMG-CoA inhibition and may not reflect adults with shorter treatment duration times. There was no derived from a human lens, which limits the ability to explore site-specific functional effects. Approximately 4% of the coding variants were cited as having “low quality.”

"The beneficial effects of statins are unequivocal and the reported link with lens opacities should not prevent statin initiation in high-risk adults, but should be disclosed to the patient, especially when indicated for primary prevention," the authors concluded. "Moreover, younger patients with familial hypercholesterolemia, who are subject to almost life-long statin therapy often initiated in childhood or early adolescence, may warrant closer clinical follow-up."

Reference

Ghouse J, Ahlberg G, Guldhammer A, Bundgaard H, Olesen M. Association of common and rare genetic variation in the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene and cataract risk. J Am Heart Assoc. 2022;11:e025361. doi:10.1161/JAHA.122.025361