SLCO1B1 V174A - GET-Evidence

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

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Curation:
Currentness:

SLCO1B1 V174A

(SLCO1B1 Val174Ala)


Short summary

Increased plasma AUC with repaglinide.

Variant evidence
Computational -
Functional -
Case/Control -
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

  • C @ chr12:21331549: 11.3% (1214/10758) in EVS
  • C @ chr12:21222815: 7.8% (10/128) in GET-Evidence
  • Frequency shown in summary reports: 11.3% (1214/10758)

Publications
 

Tirona RG, Leake BF, Merino G, Kim RB. Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem. 2001 Sep 21;276(38):35669-75. Epub 2001 Jul 26. PubMed PMID: 11477075.

 

Kalliokoski A, Neuvonen M, Neuvonen PJ, Niemi M. Different effects of SLCO1B1 polymorphism on the pharmacokinetics and pharmacodynamics of repaglinide and nateglinide. J Clin Pharmacol. 2008 Mar;48(3):311-21. Epub 2008 Jan 10. PubMed PMID: 18187595.

 

Zaïr ZM, Eloranta JJ, Stieger B, Kullak-Ublick GA. Pharmacogenetics of OATP (SLC21/SLCO), OAT and OCT (SLC22) and PEPT (SLC15) transporters in the intestine, liver and kidney. Pharmacogenomics. 2008 May;9(5):597-624. Review. PubMed PMID: 18466105.

 

SEARCH Collaborative Group, Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R. SLCO1B1 variants and statin-induced myopathy--a genomewide study. N Engl J Med. 2008 Aug 21;359(8):789-99. Epub 2008 Jul 23. PubMed PMID: 18650507.

 

Pasanen MK, Miettinen TA, Gylling H, Neuvonen PJ, Niemi M. Polymorphism of the hepatic influx transporter organic anion transporting polypeptide 1B1 is associated with increased cholesterol synthesis rate. Pharmacogenet Genomics. 2008 Oct;18(10):921-6. PubMed PMID: 18794729.

 

He YJ, Zhang W, Chen Y, Guo D, Tu JH, Xu LY, Tan ZR, Chen BL, Li Z, Zhou G, Yu BN, Kirchheiner J, Zhou HH. Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism. Clin Chim Acta. 2009 Jul;405(1-2):49-52. Epub 2009 Apr 14. PubMed PMID: 19374892.

 

Voora D, Shah SH, Spasojevic I, Ali S, Reed CR, Salisbury BA, Ginsburg GS. The SLCO1B1*5 genetic variant is associated with statin-induced side effects. J Am Coll Cardiol. 2009 Oct 20;54(17):1609-16. PubMed PMID: 19833260.

 

Picard N, Yee SW, Woillard JB, Lebranchu Y, Le Meur Y, Giacomini KM, Marquet P. The role of organic anion-transporting polypeptides and their common genetic variants in mycophenolic acid pharmacokinetics. Clin Pharmacol Ther. 2010 Jan;87(1):100-8. Epub 2009 Nov 4. PubMed PMID: 19890249; PubMed Central PMCID: PMC2884029.

 

Treviño LR, Shimasaki N, Yang W, Panetta JC, Cheng C, Pei D, Chan D, Sparreboom A, Giacomini KM, Pui CH, Evans WE, Relling MV. Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J Clin Oncol. 2009 Dec 10;27(35):5972-8. Epub 2009 Nov 9. PubMed PMID: 19901119; PubMed Central PMCID: PMC2793040.

 

Genomes
 

hu025CEA - CGI sample GS01669-DNA_D02 from PGP sample 27316983
het C @ chr12:21331549

 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
het C @ chr12:21331549

 

hu0E64A1 - CGI sample GS01173-DNA_B02 from PGP sample 94378523
het C @ chr12:21331549

 

hu241DEA - CGI sample GS01175-DNA_D05 from PGP sample 1205491
het C @ chr12:21331549

 

 

 

hu8229AE - CGI sample GS01173-DNA_A07 from PGP sample 96240009
hom C @ chr12:21331549

 

huAE6220 - CGI sample GS00253-DNA_H01_200_37
hom C @ chr12:21331549

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het C @ chr12:21331549

 

huC30901 - CGI sample GS00253-DNA_B01_200_37
het C @ chr12:21331549

 

GS06985 - var-GS06985-1100-36-ASM
het C @ chr12:21222816

 

GS07357 - var-GS07357-1100-36-ASM
het C @ chr12:21222816

 

GS18526 - var-GS18526-1100-36-ASM
het C @ chr12:21222816

 

GS20509 - var-GS20509-1100-36-ASM
het C @ chr12:21222816

 

Other external references
 

    dbSNP
  • rs4149056
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GWAS
  • Serum bilirubin levels (rs4149056-C)
    Johnson 4-May-09 in Hum Mol Genet
    OR or beta: 0.05 [0.03-0.07] umol/l increase in l
    Risk allele frequency: 0.15
    p-value: 7.00E-13
    Initial sample: 9,264 individuals
    Replication sample: NR
    www.ncbi.nlm.nih.gov/pubmed/19414484
  • Response to statin therapy (rs4149056-C)
    The SEARCH Collaborative Group 23-Jul-08 in N Engl J Med
    OR or beta: 4.5 [2.60-7.70]
    Risk allele frequency: 0.13
    p-value: 2.00E-09
    Initial sample: 85 cases, 90 controls
    Replication sample: 19,856 individuals
    www.ncbi.nlm.nih.gov/pubmed/18650507
    PharmGKB
  • [Organ Transplantation]
    [mycophenolate mofetil; mycophenolic acid; sirolimus; tacrolimus]
    Risk or phenotype-associated allele: SLCO1B1*15 defined by rs2306283 Asn130Asp (338A>G) and rs4149056 Val174Ala (521T>C). Phenotype: SLCO1B1*15 allele was associated with higher mycophenolic acid (MPA) AUC(0-12 hours) (p = 0.0246) and lower ratio of MPAG (MPA glucuronide)/MPA (p = 0.0267), but no association with MPAG AUC(0-9 h). Study size: 70. Study population/ethnicity: Caucasian cohort from the SOPHIE study cotreated with mycophenylate mofetil (MMF) and either sirolimus or tacrolimus. Significance metric(s): p < 0.03. Type of association: GN; PK
    www.ncbi.nlm.nih.gov/pubmed/19890249
  • [pravastatin]
    Associated with increased pravastatin plasma AUC.
    www.pharmgkb.org/search/annotatedGene/slco1b
  • Studies into the effect of the 521T>C (V174A) SNP in SLCO1B1 yielded discrepancies in the transport data of estradiol-17?-D-glucuronide and estrone-3-sulfate.
    www.ncbi.nlm.nih.gov/pubmed/18466105
  • [Muscular Diseases; Myopathy, Central Core]
    [simvastatin]
    This variant in the SLCO1B1 gene is strongly associated with an increased risk of statin-induced myopathy. This study also showed an association between rs4149056 and the cholesterol-lowering effects of simvastatin.
    www.ncbi.nlm.nih.gov/pubmed/18650507
  • [atorvastatin; fluvastatin; pravastatin; rosuvastatin; simvastatin]
    The cholesterol synthesis rate was higher in CC individuals than in TT individuals. There was no association between this SNP and the short-term effects of statins on cholesterol synthesis rates.
    www.ncbi.nlm.nih.gov/pubmed/18794729
  • [Myopathy, Central Core]
    GWAS results: SLCO1B1 Variants and Statin-Induced Myopathy--A Genomewide Study. (Initial Sample Size: 85 cases, 90 controls; Replication Sample Size: 19,856 individuals); (Region: 12p12.1; Reported Gene(s): SLCO1B1; Risk Allele: rs4149056-C); (p-value= 0.000000002).This variant is associated with Myopathy.
    www.ncbi.nlm.nih.gov/pubmed/18650507; Web Resource:http://www.genome.gov/gwastudie
  • Variant with C allele showed reduced cell surface expression
    www.ncbi.nlm.nih.gov/pubmed/11477075
  • [pravastatin]
    Variant with C allele had reduced transport, relative to variant with T allele (based upon lower plasma AUC) of pravastatin
    www.ncbi.nlm.nih.gov/pubmed/12811365; PubMed ID:17177112
  • [nateglinide]
    Variant with C allele showed NO plasma AUC of nateglinide relative to T allele, in contrast to repaglinide
    www.ncbi.nlm.nih.gov/pubmed/18187595
  • [repaglinide]
    Variant with C allele showed increased plasma AUC of repaglinide relative to T
    www.ncbi.nlm.nih.gov/pubmed/18187595
  • [atorvastatin]
    In a study of 16 subjects rifampicin increased atorvastatin plasma concentration in accordance with SLCO1B1 521T>C genotype. Rifampicin pharmacokinetics were not altered by SLCO1B1 genotype.
    www.ncbi.nlm.nih.gov/pubmed/19374892
  • [Hypercholesterolemia; Muscular Diseases; Myalgia unspecified]
    [atorvastatin; pravastatin; simvastatin]
    Risk or phenotype-associated allele: SLCO1B1*5 allele, defined by rs4149056 (521T>C, Val174Ala). Phenotype: SLCO1B1*5 allele (rs4149056, V174A) was associated with the adverse events from statins (chi-square = 4.2, p = 0.03, FDR = 0.24), with greatest risk with simvastatin. There were significantly more females (66%) with adverse events than females without adverse events (50%) (p < 0.01). Among subjects with adverse effects (n = 99), females bore greater risk of adverse events (OR = 2.0, p = 0.004). In multivariate analysis adjusted for race, female sex (OR = 2.2, p = 0.001) and SLCO1B1*5 genotype (OR = 1.7, p = 0.03) were independently associated with adverse events to statins (p < 0.05 for both). Simvastatin plasma concentration was positively correlated with SLCO1B1*5 both at 20 mg (p = 0.006) and 80 mg (p = 0.03). Study size: 452. Study population/ethnicity: Hypercholesterolemia outpatients given 1 of 3 statins (atorvastatin, simvastatin, or pravastatin) between 2001 and 2002 Significance metric(s): OR (1.7 - 2.2), p < 0.05 Type of association: CO; GN; PK; ADR
    www.ncbi.nlm.nih.gov/pubmed/19833260
  • [Precursor Cell Lymphoblastic Leukemia-Lymphoma]
    [methotrexate]
    Risk or phenotype-associated allele: C allele (174Ala). Phenotype: Genome-wide analysis of 398,699 germline SNPs showed association of the rs4149056 C allele (174Ala) with methotrexate (MTX) plasma clearance. Study size: 434 (discovery cohort), 206 (independent validation cohort). Study population/ethnicity: Multiethnic children (5.92 median age , 1.02-18.85 range) with ALL given 3,014 courses of methotrexate at 2-5 g/m(2) enrolled in Tennessee. Significance metric(s): p = 1.9 x 10(-7) (n = 434); p = 1.2 x 10(-7) (n = 206). Type of association: CO; GN; PK
    www.ncbi.nlm.nih.gov/pubmed/19901119

Other in silico analyses
 

  • NBLOSUM100 score = 2
  • GET-Evidence autoscore = 2

Edit history
 

Gene search

"GENE" or "GENE A123C":

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