Genetically proxied therapeutic prolyl-hydroxylase inhibition and cardiovascular risk.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
13 01 2023
13 01 2023
Historique:
received:
05
06
2022
revised:
05
08
2022
accepted:
22
08
2022
pubmed:
2
9
2022
medline:
24
1
2023
entrez:
1
9
2022
Statut:
ppublish
Résumé
Prolyl hydroxylase (PHD) inhibitors are in clinical development for anaemia in chronic kidney disease. Epidemiological studies have reported conflicting results regarding safety of long-term therapeutic haemoglobin (Hgb) rises through PHD inhibition on risk of cardiovascular disease. Genetic variation in genes encoding PHDs can be used as partial proxies to investigate the potential effects of long-term Hgb rises. We used Mendelian randomization to investigate the effect of long-term Hgb level rises through genetically proxied PHD inhibition on coronary artery disease (CAD: 60 801 cases; 123 504 controls), myocardial infarction (MI: 42 561 cases; 123 504 controls) or stroke (40 585 cases; 406 111 controls). To further characterize long-term effects of Hgb level rises, we performed a phenome-wide association study (PheWAS) in up to 451 099 UK Biobank individuals. Genetically proxied therapeutic PHD inhibition, equivalent to a 1.00 g/dl increase in Hgb levels, was not associated (at P < 0.05) with increased odds of CAD; odd ratio (OR) [95% confidence intervals (CI)] = 1.06 (0.84, 1.35), MI [OR (95% CI) = 1.02 (0.79, 1.33)] or stroke [OR (95% CI) = 0.91 (0.66, 1.24)]. PheWAS revealed associations with blood related phenotypes consistent with EGLN's role, relevant kidney- and liver-related biomarkers like estimated glomerular filtration rate and microalbuminuria, and non-alcoholic fatty liver disease (Bonferroni-adjusted P < 5.42E-05) but these were not clinically meaningful. These findings suggest that long-term alterations in Hgb through PHD inhibition are unlikely to substantially increase cardiovascular disease risk; using large disease genome-wide association study data, we could exclude ORs of 1.35 for cardiovascular risk with a 1.00 g/dl increase in Hgb.
Identifiants
pubmed: 36048866
pii: 6682819
doi: 10.1093/hmg/ddac215
pmc: PMC9851745
doi:
Substances chimiques
Prolyl Hydroxylases
EC 1.14.11.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
496-505Subventions
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/T002239/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M008924/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P016065/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/WO14548/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C18281/A29019
Pays : United Kingdom
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press.
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