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Genomic editing of metformin efficacy-associated genetic variants in SLC47A1 does not alter SLC47A1 expression

Kalamajski, Sebastian LU ; Huang, Mi LU ; Dalla-Riva, Jonathan LU ; Keller, Maria LU ; Dawed, Adem Y ; Hansson, Ola LU orcid ; Pearson, Ewan R LU ; Mulder, Hindrik LU orcid and Franks, Paul W LU (2022) In Human Molecular Genetics 31(4). p.491-498
Abstract

Several pharmacogenetics studies have identified an association between a greater metformin-dependent reduction in HbA1c levels and the minor A allele at rs2289669 in intron 10 of SLC47A1, encoding multidrug and toxin extrusion 1 (MATE1), a presumed metformin transporter. It is currently unknown if the rs2289669 locus is a cis-eQTL, which would validate its role as predictor of metformin efficacy. We looked at association between common genetic variants in the SLC47A1 gene region and HbA1c reduction after metformin treatment using locus-wise meta-analysis from the MetGen consortium. CRISPR-Cas9 was applied to perform allele editing of, or genomic deletion around, rs2289669 and of the closely linked rs8065082 in HepG2 cells. The... (More)

Several pharmacogenetics studies have identified an association between a greater metformin-dependent reduction in HbA1c levels and the minor A allele at rs2289669 in intron 10 of SLC47A1, encoding multidrug and toxin extrusion 1 (MATE1), a presumed metformin transporter. It is currently unknown if the rs2289669 locus is a cis-eQTL, which would validate its role as predictor of metformin efficacy. We looked at association between common genetic variants in the SLC47A1 gene region and HbA1c reduction after metformin treatment using locus-wise meta-analysis from the MetGen consortium. CRISPR-Cas9 was applied to perform allele editing of, or genomic deletion around, rs2289669 and of the closely linked rs8065082 in HepG2 cells. The genome-edited cells were evaluated for SLC47A1 expression and splicing. None of the common variants including rs2289669 showed significant association with metformin response. Genomic editing of either rs2289669 or rs8065082 did not alter SLC47A1 expression or splicing. Experimental and in silico analyses show that the rs2289669-containing haploblock does not appear to carry genetic variants that could explain its previously reported association with metformin efficacy.

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author
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author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
31
issue
4
pages
491 - 498
publisher
Oxford University Press
external identifiers
  • scopus:85125008935
  • pmid:34505146
ISSN
0964-6906
DOI
10.1093/hmg/ddab266
language
English
LU publication?
yes
id
14131283-9aa1-48cf-a391-0cc7d267695a
date added to LUP
2021-09-16 16:10:22
date last changed
2024-10-17 23:29:33
@article{14131283-9aa1-48cf-a391-0cc7d267695a,
  abstract     = {{<p>Several pharmacogenetics studies have identified an association between a greater metformin-dependent reduction in HbA1c levels and the minor A allele at rs2289669 in intron 10 of SLC47A1, encoding multidrug and toxin extrusion 1 (MATE1), a presumed metformin transporter. It is currently unknown if the rs2289669 locus is a cis-eQTL, which would validate its role as predictor of metformin efficacy. We looked at association between common genetic variants in the SLC47A1 gene region and HbA1c reduction after metformin treatment using locus-wise meta-analysis from the MetGen consortium. CRISPR-Cas9 was applied to perform allele editing of, or genomic deletion around, rs2289669 and of the closely linked rs8065082 in HepG2 cells. The genome-edited cells were evaluated for SLC47A1 expression and splicing. None of the common variants including rs2289669 showed significant association with metformin response. Genomic editing of either rs2289669 or rs8065082 did not alter SLC47A1 expression or splicing. Experimental and in silico analyses show that the rs2289669-containing haploblock does not appear to carry genetic variants that could explain its previously reported association with metformin efficacy.</p>}},
  author       = {{Kalamajski, Sebastian and Huang, Mi and Dalla-Riva, Jonathan and Keller, Maria and Dawed, Adem Y and Hansson, Ola and Pearson, Ewan R and Mulder, Hindrik and Franks, Paul W}},
  issn         = {{0964-6906}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{491--498}},
  publisher    = {{Oxford University Press}},
  series       = {{Human Molecular Genetics}},
  title        = {{Genomic editing of metformin efficacy-associated genetic variants in SLC47A1 does not alter SLC47A1 expression}},
  url          = {{http://dx.doi.org/10.1093/hmg/ddab266}},
  doi          = {{10.1093/hmg/ddab266}},
  volume       = {{31}},
  year         = {{2022}},
}