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Association of common and rare genetic variation in HMGCR gene and cataract risk


Results from animal models and observational studies have raised concerns regarding the potential cataractogenic effects of statin treatment.
A study has investigated whether common and rare genetic variants in HMGCR are associated with cataract risk, to gauge the likely long‐term effects of statin treatment on lenticular opacities.

Researchers have used genotyping data and exome sequencing data of unrelated European individuals in the UK Biobank to test the association between genetically proxied inhibition of HMGCR and cataract risk.

First, investigators have constructed an HMGCR genetic score consisting of 5 common variants weighted by their association with low‐density lipoprotein cholesterol.
Second, exome sequencing data to identify carriers of predicted loss‐of‐function mutations in HMGCR were analyzed.

Common and rare variants in aggregate were then tested for association with cataract and cataract surgery.

In an analysis of more than 402 000 individuals, a 38.7 mg/dL ( 1 mmol/L ) reduction in low‐density lipoprotein C by the HMGCR genetic score was associated with higher risk for cataract ( odds ratio, OR=1.14 [ 95% CI, 1.00–1.39 ], P=0.045 ) and cataract surgery ( OR=1.25 [ 95% CI, 1.06–1.48 ], P=0.009 ).

Among 169 172 individuals with HMGCR sequencing data, researchers have identified 32 participants ( 0.02% ), who carried a rare HMGCR predicted loss‐of‐function variant.
Compared with noncarriers, heterozygous carriers of HMGCR predicted loss‐of‐function had a higher risk of developing cataract ( OR=4.54 [ 95% CI, 1.96–10.53 ], P=0.001 ) and cataract surgery ( OR=5.27 [ 95% CI, 2.27–12.25 ], P=5.37×10−4 ).

In exploratory analyses, researchers found no significant association between genetically proxied inhibition of PCSK9, NPC1L1, or circulating low‐density lipoprotein cholesterol levels ( P more than 0.05 for all ) and cataract risk.

In conclusion, genetically proxied inhibition of the HMGCR gene mimicking long‐term statin treatment was associated with higher risk of cataract.
Clinical trials with longer follow‐up are needed to confirm these findings. ( Xagena )

Ghouse J et al, J Am Heart Assoc 2022; Online ahead of print

XagenaMedicine_2022



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