SNPs associated with colorectal cancer at 15q13.3 affect risk enhancers that modulate GREM1 gene expression.
GWAS
SNP
SNV
colorectal cancer
enhancers
genomics
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
05
02
2020
revised:
12
08
2020
accepted:
03
11
2020
pubmed:
22
1
2021
medline:
1
4
2022
entrez:
21
1
2021
Statut:
ppublish
Résumé
Several genome wide association studies of colorectal cancer (CRC) have identified single nucleotide polymorphisms (SNPs) on chromosome 15q13.3 associated with CRC risk. To identify functional variant(s) underlying this association, we investigated SNPs in linkage disequilibrium with the risk-associated SNP rs4779584 that overlapped regulatory regions/enhancer elements characterized in colon-related tissues and cells. We identified several SNP-containing regulatory regions that exhibited enhancer activity in vitro, including one SNP (rs1406389) that correlated with allele-specific effects on enhancer activity. Deletion of either this enhancer or another enhancer that had previously been reported in this region correlated with decreased expression of GREM1 following CRISPR/Cas9 genome editing. That GREM1 is one target of these enhancers was further supported by an expression quantitative trait loci correlation between rs1406389 and GREM1 expression in the transverse but not sigmoid colon in the Genotype-Tissue Expression dataset. Taken together, we conclude that the 15q13.3 region contains at least two functional variants that map to distinct enhancers and impact CRC risk through modulation of GREM1 expression.
Identifiants
pubmed: 33476087
doi: 10.1002/humu.24166
pmc: PMC7898835
mid: NIHMS1665798
doi:
Substances chimiques
GREM1 protein, human
0
Intercellular Signaling Peptides and Proteins
0
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
237-245Subventions
Organisme : NCI NIH HHS
ID : R01 CA204279
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA143237
Pays : United States
Organisme : NHGRI NIH HHS
ID : U41 HG007823
Pays : United States
Informations de copyright
© 2021 The Authors. Human Mutation Published by Wiley Periodicals LLC.
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