Heterogeneity in statin responses explained by variation in the human gut microbiome.
Translation to patients
cardiometabolic health
microbiome
personalized medicine
pharmacogenomics
pharmacomicrobiomics
statins
Journal
Med (New York, N.Y.)
ISSN: 2666-6340
Titre abrégé: Med
Pays: United States
ID NLM: 101769215
Informations de publication
Date de publication:
10 06 2022
10 06 2022
Historique:
received:
17
12
2021
revised:
17
04
2022
accepted:
19
04
2022
entrez:
11
6
2022
pubmed:
12
6
2022
medline:
15
6
2022
Statut:
ppublish
Résumé
Statins remain one of the most prescribed medications worldwide. While effective in decreasing atherosclerotic cardiovascular disease risk, statin use is associated with adverse effects for a subset of patients, including disrupted metabolic control and increased risk of type 2 diabetes. We investigated the potential role of the gut microbiome in modifying patient responses to statin therapy across two independent cohorts (discovery n = 1,848, validation n = 991). Microbiome composition was assessed in these cohorts using stool 16S rRNA amplicon and shotgun metagenomic sequencing, respectively. Microbiome associations with markers of statin on-target and adverse effects were tested via a covariate-adjusted interaction analysis framework, utilizing blood metabolomics, clinical laboratory tests, genomics, and demographics data. The hydrolyzed substrate for 3-hydroxy-3-methylglutarate-coenzyme-A (HMG-CoA) reductase, HMG, emerged as a promising marker for statin on-target effects in cross-sectional cohorts. Plasma HMG levels reflected both statin therapy intensity and known genetic markers for variable statin responses. Through exploring gut microbiome associations between blood-derived measures of statin effectiveness and adverse metabolic effects of statins, we find that heterogeneity in statin responses was consistently associated with variation in the gut microbiome across two independent cohorts. A Bacteroides-enriched and diversity-depleted gut microbiome was associated with more intense statin responses, both in terms of on-target and adverse effects. With further study and refinement, gut microbiome monitoring may help inform precision statin treatment. This research was supported by the M.J. Murdock Charitable Trust, WRF, NAM Catalyst Award, and NIH grant U19AG023122 awarded by the NIA.
Sections du résumé
BACKGROUND
Statins remain one of the most prescribed medications worldwide. While effective in decreasing atherosclerotic cardiovascular disease risk, statin use is associated with adverse effects for a subset of patients, including disrupted metabolic control and increased risk of type 2 diabetes.
METHODS
We investigated the potential role of the gut microbiome in modifying patient responses to statin therapy across two independent cohorts (discovery n = 1,848, validation n = 991). Microbiome composition was assessed in these cohorts using stool 16S rRNA amplicon and shotgun metagenomic sequencing, respectively. Microbiome associations with markers of statin on-target and adverse effects were tested via a covariate-adjusted interaction analysis framework, utilizing blood metabolomics, clinical laboratory tests, genomics, and demographics data.
FINDINGS
The hydrolyzed substrate for 3-hydroxy-3-methylglutarate-coenzyme-A (HMG-CoA) reductase, HMG, emerged as a promising marker for statin on-target effects in cross-sectional cohorts. Plasma HMG levels reflected both statin therapy intensity and known genetic markers for variable statin responses. Through exploring gut microbiome associations between blood-derived measures of statin effectiveness and adverse metabolic effects of statins, we find that heterogeneity in statin responses was consistently associated with variation in the gut microbiome across two independent cohorts. A Bacteroides-enriched and diversity-depleted gut microbiome was associated with more intense statin responses, both in terms of on-target and adverse effects.
CONCLUSIONS
With further study and refinement, gut microbiome monitoring may help inform precision statin treatment.
FUNDING
This research was supported by the M.J. Murdock Charitable Trust, WRF, NAM Catalyst Award, and NIH grant U19AG023122 awarded by the NIA.
Identifiants
pubmed: 35690059
pii: S2666-6340(22)00173-8
doi: 10.1016/j.medj.2022.04.007
pmc: PMC9261472
mid: NIHMS1802947
pii:
doi:
Substances chimiques
Hydroxymethylglutaryl-CoA Reductase Inhibitors
0
RNA, Ribosomal, 16S
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
388-405.e6Subventions
Organisme : NIA NIH HHS
ID : U19 AG023122
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests Arivale, which closed in May 2019, partially funded this study. At the time this study was conceived and designed, J.L., S.A.K., A.M., N.P., and L.H. held positions and/or held stock options in the company. The authors declare no ongoing financial interests in Arivale. The authors declare no other competing interests.
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