ABCB1 S893A - GET-Evidence

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ABCB1 S893A

(ABCB1 Ser893Ala)


You are viewing an old version of this page that was saved on November 29, 2012 at 5:01am by Genome Importing Robot.

Short summary

 

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 @ chr7:87160618: 68.3% (7345/10758) in EVS
  • C @ chr7:86998553: 64.8% (83/128) in GET-Evidence
  • Frequency shown in summary reports: 68.3% (7345/10758)

Publications
 

Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, Taylor A, Xie HG, McKinsey J, Zhou S, Lan LB, Schuetz JD, Schuetz EG, Wilkinson GR. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther. 2001 Aug;70(2):189-99. PubMed PMID: 11503014.

 

Kimchi-Sarfaty C, Gribar JJ, Gottesman MM. Functional characterization of coding polymorphisms in the human MDR1 gene using a vaccinia virus expression system. Mol Pharmacol. 2002 Jul;62(1):1-6. PubMed PMID: 12065748.

 

Morita N, Yasumori T, Nakayama K. Human MDR1 polymorphism: G2677T/A and C3435T have no effect on MDR1 transport activities. Biochem Pharmacol. 2003 Jun 1;65(11):1843-52. PubMed PMID: 12781336.

 

Oselin K, Gerloff T, Mrozikiewicz PM, Pähkla R, Roots I. MDR1 polymorphisms G2677T in exon 21 and C3435T in exon 26 fail to affect rhodamine 123 efflux in peripheral blood lymphocytes. Fundam Clin Pharmacol. 2003 Aug;17(4):463-9. PubMed PMID: 12914549.

 

Haas DW, Wu H, Li H, Bosch RJ, Lederman MM, Kuritzkes D, Landay A, Connick E, Benson C, Wilkinson GR, Kessler H, Kim RB. MDR1 gene polymorphisms and phase 1 viral decay during HIV-1 infection: an adult AIDS Clinical Trials Group study. J Acquir Immune Defic Syndr. 2003 Nov 1;34(3):295-8. PubMed PMID: 14600574.

 

Sparreboom A, Marsh S, Mathijssen RH, Verweij J, McLeod HL. Pharmacogenetics of tipifarnib (R115777) transport and metabolism in cancer patients. Invest New Drugs. 2004 Aug;22(3):285-9. PubMed PMID: 15122075.

 

Mai I, Perloff ES, Bauer S, Goldammer M, Johne A, Filler G, Budde K, Roots I. MDR1 haplotypes derived from exons 21 and 26 do not affect the steady-state pharmacokinetics of tacrolimus in renal transplant patients. Br J Clin Pharmacol. 2004 Nov;58(5):548-53. PubMed PMID: 15521904; PubMed Central PMCID: PMC1884628.

 

Kim DH, Park JY, Sohn SK, Lee NY, Baek JH, Jeon SB, Kim JG, Suh JS, Do YR, Lee KB. Multidrug resistance-1 gene polymorphisms associated with treatment outcomes in de novo acute myeloid leukemia. Int J Cancer. 2006 May 1;118(9):2195-201. PubMed PMID: 16331627.

 

Gréen H, Söderkvist P, Rosenberg P, Horvath G, Peterson C. mdr-1 single nucleotide polymorphisms in ovarian cancer tissue: G2677T/A correlates with response to paclitaxel chemotherapy. Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):854-9. PubMed PMID: 16467099.

 

Sissung TM, Mross K, Steinberg SM, Behringer D, Figg WD, Sparreboom A, Mielke S. Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia. Eur J Cancer. 2006 Nov;42(17):2893-6. Epub 2006 Sep 6. PubMed PMID: 16950614; PubMed Central PMCID: PMC1647318.

 

Daniel F, Loriot MA, Seksik P, Cosnes J, Gornet JM, Lémann M, Fein F, Vernier-Massouille G, De Vos M, Boureille A, Treton X, Flourié B, Roblin X, Louis E, Zerbib F, Beaune P, Marteau P. Multidrug resistance gene-1 polymorphisms and resistance to cyclosporine A in patients with steroid resistant ulcerative colitis. Inflamm Bowel Dis. 2007 Jan;13(1):19-23. PubMed PMID: 17206635.

 

Kato M, Fukuda T, Serretti A, Wakeno M, Okugawa G, Ikenaga Y, Hosoi Y, Takekita Y, Mandelli L, Azuma J, Kinoshita T. ABCB1 (MDR1) gene polymorphisms are associated with the clinical response to paroxetine in patients with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Feb 15;32(2):398-404. Epub 2007 Sep 15. PubMed PMID: 17913323.

 

Lal S, Wong ZW, Sandanaraj E, Xiang X, Ang PC, Lee EJ, Chowbay B. Influence of ABCB1 and ABCG2 polymorphisms on doxorubicin disposition in Asian breast cancer patients. Cancer Sci. 2008 Apr;99(4):816-23. PubMed PMID: 18377430.

 

Maggini V, Buda G, Martino A, Presciuttini S, Galimberti S, Orciuolo E, Barale R, Petrini M, Rossi AM. MDR1 diplotypes as prognostic markers in multiple myeloma. Pharmacogenet Genomics. 2008 May;18(5):383-9. PubMed PMID: 18408561.

 

Zhang YT, Yang LP, Shao H, Li KX, Sun CH, Shi LW. ABCB1 polymorphisms may have a minor effect on ciclosporin blood concentrations in myasthenia gravis patients. Br J Clin Pharmacol. 2008 Aug;66(2):240-6. PubMed PMID: 18717915; PubMed Central PMCID: PMC2492911.

 

Rebecchi IM, Rodrigues AC, Arazi SS, Genvigir FD, Willrich MA, Hirata MH, Soares SA, Bertolami MC, Faludi AA, Bernik MM, Dorea EL, Dagli ML, Avanzo JL, Hirata RD. ABCB1 and ABCC1 expression in peripheral mononuclear cells is influenced by gene polymorphisms and atorvastatin treatment. Biochem Pharmacol. 2009 Jan 1;77(1):66-75. Epub 2008 Sep 21. PubMed PMID: 18851956.

 

Gréen H, Söderkvist P, Rosenberg P, Mirghani RA, Rymark P, Lundqvist EA, Peterson C. Pharmacogenetic studies of Paclitaxel in the treatment of ovarian cancer. Basic Clin Pharmacol Toxicol. 2009 Feb;104(2):130-7. Epub 2008 Dec 16. PubMed PMID: 19143748.

 

Kim HS, Kim MK, Chung HH, Kim JW, Park NH, Song YS, Kang SB. Genetic polymorphisms affecting clinical outcomes in epithelial ovarian cancer patients treated with taxanes and platinum compounds: a Korean population-based study. Gynecol Oncol. 2009 May;113(2):264-9. Epub 2009 Feb 8. PubMed PMID: 19203783.

 

Kwan P, Wong V, Ng PW, Lui CH, Sin NC, Poon WS, Ng HK, Wong KS, Baum L. Gene-wide tagging study of association between ABCB1 polymorphisms and multidrug resistance in epilepsy in Han Chinese. Pharmacogenomics. 2009 May;10(5):723-32. PubMed PMID: 19450124.

 

Kroetz DL, Yee SW, Giacomini KM. The pharmacogenomics of membrane transporters project: research at the interface of genomics and transporter pharmacology. Clin Pharmacol Ther. 2010 Jan;87(1):109-16. Epub 2009 Nov 25. Review. PubMed PMID: 19940846; PubMed Central PMCID: PMC2923224.

 

Genomes
 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
hom C @ chr7:87160618

 

hu04FD18 - CGI sample GS00253-DNA_F01_200_37
hom C @ chr7:87160618

 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
het C @ chr7:87160618

 

 

 

 

 

 

 

 

 

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het C @ chr7:87160618

 

hu604D39 - CGI sample GS00253-DNA_B02_200_37
het C @ chr7:87160618

 

 

 

 

 

Added in this revision:

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
hom C @ chr7:87160618

 

 

 

 

 

 

 

 

huE80E3D - CGI sample GS00253-DNA_D01_200_37
het C @ chr7:87160618

 

 

GS06985 - var-GS06985-1100-36-ASM
hom C @ chr7:86998554

 

GS06994 - var-GS06994-1100-36-ASM
het C @ chr7:86998554

 

GS07357 - var-GS07357-1100-36-ASM
hom C @ chr7:86998554

 

GS10851 - var-GS10851-1100-36-ASM
het C @ chr7:86998554

 

GS12004 - var-GS12004-1100-36-ASM
hom C @ chr7:86998554

 

GS18501 - var-GS18501-1100-36-ASM
hom C @ chr7:86998554

 

GS18502 - var-GS18502-1100-36-ASM
hom C @ chr7:86998554

 

GS18504 - var-GS18504-1100-36-ASM
hom C @ chr7:86998554

 

GS18505 - var-GS18505-1100-36-ASM
hom C @ chr7:86998554

 

GS18508 - var-GS18508-1100-36-ASM
hom C @ chr7:86998554

 

GS18517 - var-GS18517-1100-36-ASM
hom C @ chr7:86998554

 

GS18947 - var-GS18947-1100-36-ASM
het C @ chr7:86998554

 

GS19017 - var-GS19017-1100-36-ASM
hom C @ chr7:86998554

 

GS19020 - var-GS19020-1100-36-ASM
hom C @ chr7:86998554

 

GS19025 - var-GS19025-1100-36-ASM
hom C @ chr7:86998554

 

GS19026 - var-GS19026-1100-36-ASM
hom C @ chr7:86998554

 

GS19129 - var-GS19129-1100-36-ASM
hom C @ chr7:86998554

 

GS19238 - var-GS19238-1100-36-ASM
hom C @ chr7:86998554

 

GS19239 - var-GS19239-1100-36-ASM
hom C @ chr7:86998554

 

GS19240 - var-GS19240-1100-36-ASM
hom C @ chr7:86998554

 

GS19648 - var-GS19648-1100-36-ASM
hom C @ chr7:86998554

 

GS19649 - var-GS19649-1100-36-ASM
hom C @ chr7:86998554

 

GS19669 - var-GS19669-1100-36-ASM
het C @ chr7:86998554

 

GS19670 - var-GS19670-1100-36-ASM
het C @ chr7:86998554

 

GS19700 - var-GS19700-1100-36-ASM
hom C @ chr7:86998554

 

GS19701 - var-GS19701-1100-36-ASM
hom C @ chr7:86998554

 

GS19703 - var-GS19703-1100-36-ASM
hom C @ chr7:86998554

 

GS19704 - var-GS19704-1100-36-ASM
hom C @ chr7:86998554

 

GS19834 - var-GS19834-1100-36-ASM
hom C @ chr7:86998554

 

GS20509 - var-GS20509-1100-36-ASM
het C @ chr7:86998554

 

GS21767 - var-GS21767-1100-36-ASM
hom C @ chr7:86998554

 

Other external references
 

    dbSNP
  • rs2032582
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PharmGKB
  • [rhodamine 123; rifampin; verapamil]
    ABCB1 rs2032582 and rs1045642 genotype and peripheral blood lymphocyte efflux of P-gp substrate, rhodamine 123 (Rh123), in vitro, in healthy males: there was no significant difference in Rh123 efflux in CD56+ NK cells after 5, 10, 15, and 30 min efflux, or in CD4+ T-helper cells after 15, 30, 60, and 90 min between individuals with different genotypes. Rh123 efflux was not enhanced by a 10-day administration of P-gp inducer, rifampin, in vivo in 15 individuals before and after rifampin treatment. No genotypic effect was observed for inhibition of Rh123 efflux by P-pg inhibitor, verapamil, in vitro with CD56+ and CD4+.
    www.ncbi.nlm.nih.gov/pubmed/12914549
  • [Coronary Artery Disease; Hypercholesterolemia]
    [atorvastatin]
    Risk or phenotype-associated allele: 2677 T (893Ser) and A (893Thr) alleles. Phenotype: Carriers of 3435 CT and TT genotypes (63%) and 2677 non-GG (non 893Ala/Ala) genotypes (64%) had higher frequency of family history of coronary artery disease (CAD) than the 3435CC (44%, p = 0.042) and 2677GG (46%, p = 0.043) carriers. The frequency of CAD in those carrying the 3435/2677 T/T haplotype (67%) was higher than that found in 3435/2677 non-T/T individuals (47%, p = 0.021). Reduction in ABCB1 expression in peripheral blood mononuclear cells was associated with 2677 T and A alleles (p = 0.039). ABCC1 mRNA expression was reduced 50% in response to atorvastatin (p < 0.05), and correlated with 2677 T (893Ser) allele carriers versus 2677 GG (893Ala/Ala) homozygotes (p = 0.04). Increased response to atorvastatin was found in 2677A allele carriers (OR = 5.69, 95% CI = 1.28-25.24, p = 0.022). ABCB1 substrates (antiarrhythmics, beta-blockers, diuretics, ACE inhibitors, and others) or inhibitors (antiarrhythmics, calcium antagonists, calcium channel blockers, antidepressants and others) did not affect the baseline ABCB1 expression, but ABCB1 inhibitors reversed the effects of atorvastatin on both ABCB1 and ABCC1 transporters. Study size: 136. Study population/ethnicity: Hypercholesterolemic individuals, treated with atorvastatin (10mg/day/4 weeks), evaluated for CAD risk factors at the Institute Dante Pazzanese of Cardiology and the Hospital of the Sao Paulo University in Sao Paulo City, Brazil. Significance metric(s): p < 0.05. Type of association: GN; PD; FA
    www.ncbi.nlm.nih.gov/pubmed/18851956
  • [Tipifarnib]
    Risk or phenotype-associated allele: none. Phenotype: There was no significant association between systemic exposure of tipifarnib (AUC levels) and rs2032582 genotype. Study size: 28 (16 male). Study population/ethnicity: Caucasian cancer patients, aged 34-75. Significance metric(s): Not significant, p = 0.92. Type of association: GN; PK
    www.ncbi.nlm.nih.gov/pubmed/15122075
  • [paclitaxel]
    Increased intracellular BODIPy-FL- paclitaxel levels (decreased function) in transfected cells
    www.ncbi.nlm.nih.gov/pubmed/19940846
  • [bisantrene; calcein; forskolin; prazosin; verapamil; vinblastine]
    Drug efflux and cell surface expression (by MRK-16 and C219 probes) of P-gp was not different between wild-type and variant forms (single mutants: N21D, F103L, S400N, A893S, A998T, and double mutants: 21D-S400N, N21D-A893S, and S400N-A893S) in an in vitro vaccinia virus-based transient expression system. Fluroescent substrates included calcein AM, bodipy-FL-forskolin, bodipy-FL-verapamil, bodipy-FL-vinblastine, bodipy-FL-prazosin, bisantrene, and bodipy-FL-paclitaxel. There was a slight increase in wild-type P-gp efflux of bodipy-FL-paclitaxel over mutants.
    www.ncbi.nlm.nih.gov/pubmed/12065748
  • This SNP is well-studied but there is no clear consensus on its significance for drug disposition, response or toxicity.
    www.pharmgkb.org/search/annotatedGene/abcb1/
  • [Multiple Myeloma]
    [dexamethasone; doxorubicin; vincristine]
    In multiple myeloma patients treated with dexamethasone, doxorubicin, and vincristine, followed by autologous stem cell transformation (ASCT), treatment efficacy was not related to this variant. However, the overall survival of patients with the G/G genotype of this variant was significantly lower than that of patients carrying T/T or G/T alleles. In ASCT nonresponders, diplotype analysis of this variant together with another variant (ABCB1 C3435T) showed that GC/GC patients survived for less time than GC/TT and TT/TT patients.
    www.ncbi.nlm.nih.gov/pubmed/18408561
  • [Depression]
    [paroxetine]
    This study suggests a possible association of ABCB1 variants with SSRIs response. In a Japanese major depression sample this non-synonymous SNP showed significant association with treatment response to paroxetine.
    www.ncbi.nlm.nih.gov/pubmed/17913323
  • [Ovarian Neoplasms]
    [paclitaxel]
    A study of 83 patients found that patients heterozygous for this variant in ABCB1 had a significantly higher clearance of paclitaxel than most other ABCB1 variants.
    www.ncbi.nlm.nih.gov/pubmed/19143748
  • [paclitaxel]
    This variant have been associated with response to palitaxel.
    www.ncbi.nlm.nih.gov/pubmed/16467099
  • [Neutropenia]
    [paclitaxel]
    Patients with both rs1045642 and rs2032582 variants have been associated with neutropenia from paclitaxel.
    www.ncbi.nlm.nih.gov/pubmed/16950614
  • [Ovarian Neoplasms]
    [carboplatin; cisplatin; docetaxel; paclitaxel]
    Patients with epithelial ovarian cancer, with this variant, have been associated with response to taxane- and platinum-based therapy and gastrointestinal toxicity.
    www.ncbi.nlm.nih.gov/pubmed/19203783
  • [Epilepsy]
    [carbamazepine; clobazam; clonazepam; gabapentin; lamotrigine; levetiracetam; phenobarbital; phenytoin; topiramate; valproic acid; vigabatrin]
    This variant maybe associated with drug resistance in chinese epilepsy patients. Sample size: 464 chinese epilepsy patients (270 drug responsive, 194 drug resistant).
    www.ncbi.nlm.nih.gov/pubmed/19450124
  • [Myasthenia Gravis]
    [cyclosporine]
    peak blood concentration of cyclosporin A (CsA) was significantly lower in in myasthenia gravis patients harboring the 2677 T allele (893Ser); and trough CsA levels were significantly greater in 2677 TT homozygotes versus CC homozygotes
    www.ncbi.nlm.nih.gov/pubmed/18717915
  • [Leukemia, Myeloid, Acute]
    [cytarabine; idarubicin]
    Clinical outcome and P-gp activity was studied in Asian patients with de novo acute myeloid leukemia taking cytarabine and idarubicin, relative to ABCB1 genotypes, C3435T (rs1045642) and G2677T/A (rs2032582, Ala893Ser/Thr). Three-year event-free survival (EFS) was higher in 2677 GG homozygotes (893Ala/Ala) (60.6%) versus non-GG genotypes (893Ser allele-harboring subjects) (21.9%; p = 0.02), and in 3435 CC homozygotes versus non-CC genotypes (p = 0.01), and for 2677GG (893Ala/Ala)/3435CC diplotypes (58.2%) versus other diplotypes (22.6%; p = 0.04); although no significant genotypic or haplotypic association was observed for overall survival (OS). The rate of complete remission was significantly higher in 3435 CC (p = 0.05) and 2677 GG (893Ala/Ala) (p = 0.04) homozygotes, and for the 3435CC/2677GG diplotype (p = 0.03) compared to non-GC haplotype homozygotes. Using an in vitro daunorubicin accumulation assay with leukemic mononuclear cells from AML patients, 3435 CC homozygotes showed significantly lower P-gp activity (7.5%) than for CT (10.7%) and TT (19.9%) genotypes (p = 0.029); and G2677T/A (Ala893Ser/Thr) genotype had no effect (p = 0.181).
    www.ncbi.nlm.nih.gov/pubmed/16331627
  • [digoxin; fexofenadine]
    893Ser-expressing (ABCB1:2677G>T (Ala893Ser)) cells showed 47% lower intracellular digoxin concentration (p < 0.002) than Ala893-expressing cells; and 893Ser/Ser homozygotes showed statistically different fenofexadine area under the concentration curve (AUC) values for 0-4 hours (p = 0.054) than 893Ala/Ala homozygotes.
    www.ncbi.nlm.nih.gov/pubmed/11503014
  • [Colitis, Ulcerative]
    [cyclosporine]
    There is a significant association between the G2677T/A polymorphism distribution and the risk for cyclosporin A (CsA) failure in patients from France and Belgium with steroid resistance ulcerative colitis (p = 0.0001), defined as requiring colectomy within 30 days of CsA initiation. The 2677 TT genotype was significantly associated with the risk compared with the two other genotypes (odds ratio, 3.77; 95% confidence interval, 1.42-9.97, p = 0.007).
    www.ncbi.nlm.nih.gov/pubmed/17206635
  • [Breast Neoplasms]
    [doxorubicin]
    Risk or phenotype-associated allele: T. Phenotype: A haplotype of ABCB1 c.1236C>T, c.2677G>A/T, and c.3435C>T (rs1128503, rs2032582 and rs1045642) was associated with increased drug exposure and reduced clearance. Study size: . Study population/ethnicity: Asian patients with Breast Neoplasms treated with doxorubicin. Significance metric(s): p = 0.03 (exposure); p= 0.01 (clearance). Type of association: PK.
    www.ncbi.nlm.nih.gov/pubmed/18377430
  • [cyclosporine; digoxin; verapamil; vinblastine]
    Functional study of rs1045642 (3435C>T) and rs1128503 (2677G>T/A): in LLC-PK1 cells expressing wild-type (2677G/3435C) or polymorphic (2677G/3435T, 2677A/3435C, 2677A/3435T, 2677T/3435C, 2677T/3435T) constructs of ABCB1 in vitro, no significant differences were observed in transcellular efflux of structurally diverse P-gp substrates, verapamil, digoxin, vinblastine or cyclosporin A.
    www.ncbi.nlm.nih.gov/pubmed/12781336
  • [cyclosporine; digoxin; verapamil; vinblastine]
    Functional study of rs1045642 (3435C>T) and rs2032582 (2677G>T/A): in LLC-PK1 cells expressing wild-type (2677G/3435C) or polymorphic (2677G/3435T, 2677A/3435C, 2677A/3435T, 2677T/3435C, 2677T/3435T) constructs of ABCB1 in vitro, no significant differences were observed in transcellular efflux of structurally diverse P-gp substrates, verapamil, digoxin, vinblastine or cyclosporin A.
    www.ncbi.nlm.nih.gov/pubmed/12781336
  • [Transplantation]
    [tacrolimus]
    Haplotypes derived from the SNPs 2677G > T (rs2032582) and 3435C > T (rs1045642) do not influence the pharmacokinetics of tacrolimus in renal transplant patients
    www.ncbi.nlm.nih.gov/pubmed/15521904
  • [ritonavir]
    No significant association between allelic ABCB1 variants, C3435T (rs1045642) and G2677T/A (Ala893Ser) (rs2032582), and phase 1 or phase 2 viral decay, changes in lymphocyte subsets over time, or plasma trough ritonavir concentrations among 31 HIV-infected individuals initiating antiretroviral therapy.
    www.ncbi.nlm.nih.gov/pubmed/14600574

Other in silico analyses
 

  • NBLOSUM100 score = –1
  • GET-Evidence autoscore = 1

Edit history
 

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