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 December 27, 2009 at 4:09pm by Genome Importing Robot.

Short summary

 

Variant evidence
Computational -
Functional -
Case/Control -
Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Insufficiently evaluated not reviewed

(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
 

Genomes
 

Added in this revision:

NA12878

 

snp-2

 

Other external references
 

    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
 

Gene search

"GENE" or "GENE A123C":

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