Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
12 01 2023
12 01 2023
Historique:
received:
20
06
2022
accepted:
03
01
2023
entrez:
12
1
2023
pubmed:
13
1
2023
medline:
17
1
2023
Statut:
epublish
Résumé
Sex differences have been widely observed in human health. However, little is known about the underlying mechanism behind these observed sex differences. We hypothesize that sex-differentiated genetic effects are contributors of these phenotypic differences. Focusing on a collection of drug metabolism enzymes and transporters (DMET) genes, we discover sex-differentiated genetic regulatory mechanisms between these genes and human complex traits. Here, we show that sex-differentiated genetic effects were present at genome-level and at DMET gene regions for many human complex traits. These sex-differentiated regulatory mechanisms are reflected in the levels of gene expression and endogenous serum biomarkers. Through Mendelian Randomization analysis, we identify putative sex-differentiated causal effects in each sex separately. Furthermore, we identify and validate sex differential gene expression of a subset of DMET genes in human liver samples. We observe higher protein abundance and enzyme activity of CYP1A2 in male-derived liver microsomes, which leads to higher level of an active metabolite formation of clozapine, a commonly prescribed antipsychotic drug. Taken together, our results demonstrate the presence of sex-differentiated genetic effects on DMET gene regulation, which manifest in various phenotypic traits including disease risks and drug responses.
Identifiants
pubmed: 36635277
doi: 10.1038/s41467-023-35808-6
pii: 10.1038/s41467-023-35808-6
pmc: PMC9837057
doi:
Substances chimiques
Membrane Transport Proteins
0
CYP1A2 protein, human
EC 1.14.14.1
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
175Subventions
Organisme : NCI NIH HHS
ID : R01 CA229618
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG011405
Pays : United States
Informations de copyright
© 2023. The Author(s).
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