Association of Common and Rare Genetic Variation in the 3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Gene and Cataract Risk
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 stati...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-06-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.122.025361 |
| _version_ | 1797301695644958720 |
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| author | Jonas Ghouse Gustav Ahlberg Anne Guldhammer Skov Henning Bundgaard Morten S. Olesen |
| author_facet | Jonas Ghouse Gustav Ahlberg Anne Guldhammer Skov Henning Bundgaard Morten S. Olesen |
| author_sort | Jonas Ghouse |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T23:26:19Z |
| format | Article |
| id | doaj.art-fbc5f8f384234a6cbf3e6708f485fa13 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-03-07T23:26:19Z |
| publishDate | 2022-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-fbc5f8f384234a6cbf3e6708f485fa132024-02-21T04:31:45ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802022-06-01111210.1161/JAHA.122.025361Association of Common and Rare Genetic Variation in the 3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Gene and Cataract RiskJonas Ghouse0Gustav Ahlberg1Anne Guldhammer Skov2Henning Bundgaard3Morten S. Olesen4Laboratory for Molecular Cardiology Department of Cardiology Copenhagen University Hospital, Rigshospitalet Copenhagen DenmarkLaboratory for Molecular Cardiology Department of Cardiology Copenhagen University Hospital, Rigshospitalet Copenhagen DenmarkDepartment of Ophthalmology Copenhagen University HospitalRigshospitalet‐GlostrupUniversity of Copenhagen DenmarkDepartment of Cardiology Copenhagen University Hospital, RigshospitaletUniversity of Copenhagen DenmarkLaboratory for Molecular Cardiology Department of Cardiology Copenhagen University Hospital, Rigshospitalet Copenhagen DenmarkBackground 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.https://www.ahajournals.org/doi/10.1161/JAHA.122.025361ADRcataractHMG‐CoA reductaseHMGCRloss‐of‐functionstatins |
| spellingShingle | Jonas Ghouse Gustav Ahlberg Anne Guldhammer Skov Henning Bundgaard Morten S. Olesen Association of Common and Rare Genetic Variation in the 3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Gene and Cataract Risk Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease ADR cataract HMG‐CoA reductase HMGCR loss‐of‐function statins |
| title | Association of Common and Rare Genetic Variation in the 3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Gene and Cataract Risk |
| title_full | Association of Common and Rare Genetic Variation in the 3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Gene and Cataract Risk |
| title_fullStr | Association of Common and Rare Genetic Variation in the 3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Gene and Cataract Risk |
| title_full_unstemmed | Association of Common and Rare Genetic Variation in the 3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Gene and Cataract Risk |
| title_short | Association of Common and Rare Genetic Variation in the 3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Gene and Cataract Risk |
| title_sort | association of common and rare genetic variation in the 3 hydroxy 3 methylglutaryl coenzyme a reductase gene and cataract risk |
| topic | ADR cataract HMG‐CoA reductase HMGCR loss‐of‐function statins |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.122.025361 |
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