SLC22A1 R61C - GET-Evidence

Note: This variant has not been sufficiently evaluated by a GET-Evidence editor.

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Curation:
Currentness:

SLC22A1 R61C

(SLC22A1 Arg61Cys)


Short summary

Variant potentially involved in metabolism of metformin, used to treat diabetes

Variant evidence
Computational -
Functional -
Case/Control -1

Zhou et all found no relationship in a large (1500+) person study of metformin effectiveness.

See Zhou K et al. 2009 (19336679).

Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Insufficiently evaluated pharmacogenetic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • T @ chr6:160543148: 5.7% (615/10758) in EVS
  • T @ chr6:160463137: 2.4% (3/124) in GET-Evidence
  • Frequency shown in summary reports: 5.7% (615/10758)

Publications
 

Shu Y, Brown C, Castro RA, Shi RJ, Lin ET, Owen RP, Sheardown SA, Yue L, Burchard EG, Brett CM, Giacomini KM. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther. 2008 Feb;83(2):273-80. Epub 2007 Jul 4. PubMed PMID: 17609683; PubMed Central PMCID: PMC2976713.

 

Zhou K, Donnelly LA, Kimber CH, Donnan PT, Doney AS, Leese G, Hattersley AT, McCarthy MI, Morris AD, Palmer CN, Pearson ER. Reduced-function SLC22A1 polymorphisms encoding organic cation transporter 1 and glycemic response to metformin: a GoDARTS study. Diabetes. 2009 Jun;58(6):1434-9. doi: 10.2337/db08-0896. Epub 2009 Mar 31. PubMed PMID: 19336679; PubMed Central PMCID: PMC2682689.

OBJECTIVE:
Metformin is actively transported into the liver by the organic cation transporter (OCT)1 (encoded by SLC22A1). In 12 normoglycemic individuals, reduced-function variants in SLC22A1 were shown to decrease the ability of metformin to reduce glucose excursion in response to oral glucose. We assessed the effect of two common loss-of-function polymorphisms in SLC22A1 on metformin response in a large cohort of patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS:
The Diabetes Audit and Research in Tayside Scotland (DARTS) database includes prescribing and biochemistry information and clinical phenotypes of all patients with diabetes within Tayside, Scotland, from 1992 onwards. R61C and 420del variants of SLC22A1 were genotyped in 3,450 patients with type 2 diabetes who were incident users of metformin. We assessed metformin response by modeling the maximum A1C reduction in 18 months after starting metformin and investigated whether a treatment target of A1C <7% was achieved. Sustained metformin effect on A1C between 6 and 42 months was also assessed, as was the time to metformin monotherapy failure. Covariates were SLC22A1 genotype, BMI, average drug dose, adherence, and creatinine clearance.
RESULTS:
A total of 1,531 patients were identified with a definable metformin response. R61C and 420del variants did not affect the initial A1C reduction (P = 0.47 and P = 0.92, respectively), the chance of achieving a treatment target (P = 0.83 and P = 0.36), the average A1C on monotherapy up to 42 months (P = 0.44 and P = 0.75), or the hazard of monotherapy failure (P = 0.85 and P = 0.56).
CONCLUSIONS:
The SLC22A1 loss-of-function variants, R61C and 420del, do not attenuate the A1C reduction achieved by metformin in patients with type 2 diabetes.

Genomes
 

 

huA0E089 - CGI sample GS01175-DNA_B04 from PGP sample 88590671
het T @ chr6:160543148

 

huC30901 - CGI sample GS00253-DNA_B01_200_37
het T @ chr6:160543148

 

huE80E3D - CGI sample GS00253-DNA_D01_200_37
het T @ chr6:160543148

 

Other external references
 

    dbSNP
  • rs12208357
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PharmGKB
  • [metformin; MPP+]
    Reduced metformin and MPP+ uptake in transfected cells
    www.ncbi.nlm.nih.gov/pubmed/19940846
  • [metformin]
    SNP contributes to variation in the pharmacokinetics of metformin.
    www.ncbi.nlm.nih.gov/pubmed/17609683
    PolyPhen-2
  • Score: 1.0 (probably damaging)
    Web search results (80 hits -- see all)
  • SLC22A1 [PharmGKB]
    rs12208357 at chr6:160463138 in SLC22A1. SNP contributes to variation in the ... uptake in transfected cells. Variant Name: SLC22A1: R61C. Related Drugs: ...
    www.pharmgkb.org/do/serve?objId=PA329
  • metformin [PharmGKB]
    rs12208357 at chr6:160463138 in SLC22A1. SNP contributes to variation ... 160492856 in SLC22A1. This intronic variant (rs622342) of the SLC22A1 gene was associated ...
    www.pharmgkb.org/do/serve?objId=PA450395
  • Reduced-Function SLC22A1 Polymorphisms Encoding Organic ...
    R61C and 420del variants of SLC22A1 were genotyped in 3,450 patients ... CONCLUSIONS The SLC22A1 loss-of-function variants, R61C and 420del, do not ...
    diabetes.diabetesjournals.org/content/58/6/1434.short?...
  • Reduced-function SLC22A1 polymorphisms encoding organic ...
    R61C and 420del variants of SLC22A1 were genotyped in 3,450 patients ... CONCLUSIONS: The SLC22A1 loss-of-function variants, R61C and 420del, do not ...
    www.ncbi.nlm.nih.gov/pubmed/19336679
  • OCT1 (SLC22A1) R61C polymorphism and response to imatinib ...
    OCT1 (SLC22A1) R61C polymorphism and response to imatinib treatment in chronic myeloid ... Octamer Transcription Factor-1/genetics* Piperazines/adverse effects ...
    www.ncbi.nlm.nih.gov/pubmed/19021069
  • Reduced function SLC22A1 polymorphisms encoding Organic ...
    The SLC22A1 loss of function variants, R61C and 420del, do not attenuate the ... We genotyped R61C (rs12208357) and 420del variants of SLC22A1 by ...
    diabetes.diabetesjournals.org/content/early/2009/03/31/...
  • SLC22A1 Gene - GeneCards | S22A1 Protein | S22A1 Antibody
    EntrezGene summary for SLC22A1: Polyspecific organic cation transporters in the liver, ... SLC22A1 Gene in genomic location: bands according to Ensembl, locations ...
    www.genecards.org/cgi-bin/carddisp.pl?gene=SLC22A1
  • UCSF PMT - Snp Publications
    Reduced function SLC22A1 polymorphisms encoding Organic Cation ... Zellhofer B, Lutz D. OCT1 (SLC22A1) R61C polymorphism and response to imatinib treatment ...
    pharmacogenetics.ucsf.edu/cgi-bin/PubMed.py?uid=3936
  • IngentaConnect Table Of Contents: Leukemia and Lymphoma
    Ingenta is not responsible for the content or availability of external websites ... OCT1 (SLC22A1) R61C polymorphism and response to imatinib treatment in chronic ...
    ingentaconnect.com/content/apl/glal/2008/00000049/00000011
  • Table S1
    rs12208357. Ex1-231C>T. p.R61C. ROF. 70% MPP+ uptake. Kerb et al., 2002; Shu et al., 2003 ... SLC22A1-04_Chr6:160463219_GCCTTCcTTGGCCAG[T>C]GCAGGCGCTATGAAG_C> ...
    files.chuv.ch/internet-docs/imu/imu_lubomirov2007_tables1...

Other in silico analyses
 

  • NBLOSUM100 score = 8
  • GET-Evidence autoscore = 3

Edit history
 

Gene search

"GENE" or "GENE A123C":

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