Genetic Determinants of Reduced Arsenic Metabolism Efficiency in the 10q24.32 Region Are Associated With Reduced AS3MT Expression in Multiple Human Tissue Types.
AS3MT
Genotype-tissue Expression (GTEx) project
arsenic metabolism efficiency
colocalization
expression quantitative trait locus (eQTL)
multitissue
single nucleotide polymorphism (SNP)
Journal
Toxicological sciences : an official journal of the Society of Toxicology
ISSN: 1096-0929
Titre abrégé: Toxicol Sci
Pays: United States
ID NLM: 9805461
Informations de publication
Date de publication:
01 08 2020
01 08 2020
Historique:
pubmed:
21
5
2020
medline:
12
8
2021
entrez:
21
5
2020
Statut:
ppublish
Résumé
Approximately 140 million people worldwide are exposed to inorganic arsenic through contaminated drinking water. Chronic exposure increases risk for cancers as well as cardiovascular, respiratory, and neurologic diseases. Arsenic metabolism involves the AS3MT (arsenic methyltransferase) gene, and arsenic metabolism efficiency (AME, measured as relative concentrations of arsenic metabolites in urine) varies among individuals. Inherited genetic variation in the 10q24.32 region, containing AS3MT, influences AME, but the mechanisms remain unclear. To better understand these mechanisms, we use tissue-specific expression data from GTEx (Genotype-tissue Expression project) to identify cis-eQTLs (expression quantitative trait loci) for AS3MT and other nearby genes. We combined these data with results from a genome-wide association study of AME using "colocalization analysis," to determine if 10q24.32 SNPs (single nucleotide polymorphisms) that affect AME also affect expression of AS3MT or nearby genes. These analyses identified cis-eQTLs for AS3MT in 38 tissue types. Colocalization results suggest that the casual variant represented by AME lead SNP rs4919690 impacts expression of AS3MT in 13 tissue types (> 80% probability). Our results suggest this causal SNP also regulates/coregulates expression of nearby genes: BORCS7 (43 tissues), NT5C2 (2 tissues), CYP17A1-AS1 (1 tissue), and RP11-724N1.1 (1 tissue). The rs4919690 allele associated with decreased AME is associated with decreased expression of AS3MT (and other coregulated genes). Our study provides a potential biological mechanism for the association between 10q24.32 variation and AME and suggests that the causal variant, represented by rs4919690, may impact AME (as measured in urine) through its effects on arsenic metabolism occurring in multiple tissue types.
Identifiants
pubmed: 32433756
pii: 5841224
doi: 10.1093/toxsci/kfaa075
pmc: PMC7531331
doi:
Substances chimiques
Methyltransferases
EC 2.1.1.-
AS3MT protein, human
EC 2.1.1.137
Arsenic
N712M78A8G
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
382-395Subventions
Organisme : NIA NIH HHS
ID : T32 AG051146
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES023834
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007281
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA107431
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG007601
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES027792
Pays : United States
Organisme : NIEHS NIH HHS
ID : R35 ES028379
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG000243
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.
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