TY - JOUR

T1 - Association of Common and Rare Genetic Variation in the 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Gene and Cataract Risk

AU - Ghouse, Jonas

AU - Ahlberg, Gustav

AU - Skov, Anne Guldhammer

AU - Bundgaard, Henning

AU - Olesen, Morten S.

N1 - Publisher Copyright: © 2022 The Authors.

PY - 2022

Y1 - 2022

N2 - BACKGROUND: Results from animal models and observational studies have raised concerns regarding the potential cataractogenic effects of statin treatment. We 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. METHODS AND RESULTS: We 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, we constructed an HMGCR genetic score consisting of 5 common variants weighted by their association with low-density lipoprotein cholesterol. Second, we analyzed exome sequencing data to identify carriers of predicted loss-of-function mutations in HMGCR. Common and rare variants in aggregate were then tested for association with cataract and cataract surgery. In an analysis of >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, 1.14 [95% CI, 1.00–1.39], P=0.045) and cataract surgery (odds ratio, 1.25 [95% CI, 1.06– 1.48], P=0.009). Among 169 172 individuals with HMGCR sequencing data, we 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 (odds ratio, 4.54 [95% CI, 1.96–10.53], P=0.001) and cataract surgery (odds ratio, 5.27 [95% CI, 2.27–12.25], P=5.37×10−4). In exploratory analyses, we found no significant association between genetically proxied inhibition of PCSK9, NPC1L1, or circulating low-density lipoprotein cholesterol levels (P>0.05 for all) and cataract risk. CONCLUSIONS: We found that genetically proxied inhibition of the HMGCR gene mimicking long-term statin treatment associated with higher risk of cataract. Clinical trials with longer follow-up are needed to confirm these findings.

AB - BACKGROUND: Results from animal models and observational studies have raised concerns regarding the potential cataractogenic effects of statin treatment. We 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. METHODS AND RESULTS: We 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, we constructed an HMGCR genetic score consisting of 5 common variants weighted by their association with low-density lipoprotein cholesterol. Second, we analyzed exome sequencing data to identify carriers of predicted loss-of-function mutations in HMGCR. Common and rare variants in aggregate were then tested for association with cataract and cataract surgery. In an analysis of >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, 1.14 [95% CI, 1.00–1.39], P=0.045) and cataract surgery (odds ratio, 1.25 [95% CI, 1.06– 1.48], P=0.009). Among 169 172 individuals with HMGCR sequencing data, we 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 (odds ratio, 4.54 [95% CI, 1.96–10.53], P=0.001) and cataract surgery (odds ratio, 5.27 [95% CI, 2.27–12.25], P=5.37×10−4). In exploratory analyses, we found no significant association between genetically proxied inhibition of PCSK9, NPC1L1, or circulating low-density lipoprotein cholesterol levels (P>0.05 for all) and cataract risk. CONCLUSIONS: We found that genetically proxied inhibition of the HMGCR gene mimicking long-term statin treatment associated with higher risk of cataract. Clinical trials with longer follow-up are needed to confirm these findings.

KW - ADR

KW - cataract

KW - HMG-CoA reductase

KW - HMGCR

KW - loss-of-function

KW - statins

UR - http://www.scopus.com/inward/record.url?scp=85132454487&partnerID=8YFLogxK

U2 - 10.1161/JAHA.122.025361

DO - 10.1161/JAHA.122.025361

M3 - Journal article

C2 - 35703387

AN - SCOPUS:85132454487

VL - 11

SP - 1

EP - 39

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 12

M1 - e025361

ER -