Important Variant Information for ABCB1
Submitted by: Jason Gow, Leslie Chinn (PMT)
Reviewed by: Reviewed
Submitted date: August 11, 2006
There are Three Important Variants for ABCB1.
| Gene HGNC Name: | ABCB1 |
|---|---|
| Variant Summary: | This SNP is positioned at 1236 with respect to the translation start site. The body of work studying the effect of the 1236 C>T synonymous SNP is fairly small, with no conclusive findings to date. The majority of reports involving the 1236 SNP consider this polymorphism in its naturally occurring haplotype *13 (see below). This SNP is in exon 12. |
| Key PubMed IDs: | 15651752, 12960109 |
| Genomic Variant & GenBank ID: | 84224C>T on AC005068 |
| mRNA Variant & GenBank ID: | 1654C>T on NM_000927.3 |
| Protein Variant & GenBank ID: | NA |
| dbSNP rs#: | rs1128503 |
| GoldenPath Position: | chr7:87017537 (hg18) |
| Key Phenotypes/Diseases: | Marginal association with CD4 cell recovery after protease inhibitor treatment [PMID: 15651752]. |
| DNA Source Containing Homozygous Reference Allele(Coriell Lines): |
Coriell NA17206 (PA126721672) |
| DNA Source Containing Heterozygous Reference Allele(Coriell Lines): |
Coriell NA17204 (PA126721670) |
| DNA Source Containing Homozygous Minor Allele(Coriell Lines): |
Coriell NA17208 (PA126721674) |
| Phenotype Data Sets: | PA129966511 - 1236TT homozygous cancer patients had increased exposure to irinotecan and its metabolite SN-38 [PMID: 12960109]. |
| Key Haplotypes: | ABCB1*13 |
2. ABCB1:2677G>A/T (rs2032582)
| Gene HGNC Name: | ABCB1 |
|---|---|
| Variant Summary: | This SNP is positioned at 2677 with respect to the translation start site. The 2677 G> A/T SNP has been well studied because it is a high-frequency, non-synonymous variant. Associations between this SNP and P-gp function or expression have not been conclusively determined. Several studies have reported significant correlations between genotype and a P-gp-related phenotype (e.g. multidrug resistance), but others have found no relationship. The 2677 SNP has been extensively studied in the *13 haplotype. This SNP is in exon 21. |
| Key PubMed IDs: | 11503014, 15521904, 12914549, 12065748, 12893986, 12781336, 16331627, 12352921, 15752383, 14600574, 11369657, 15459215, 12175731 |
| Genomic Variant & GenBank ID: | 65241G>A/T on AC005068 |
| mRNA Variant & GenBank ID: | 3095G>A/T on NM_000927.3 |
| Protein Variant & GenBank ID: | Ala893Thr/Ser on NP_000918.2 |
| dbSNP rs#: | rs2032582 |
| GoldenPath Position: | chr7:86998554 (hg18) |
| Key Drugs/Substrates: | Positive findings: 2677T (Ser893) has been associated with increased efflux of digoxin in vitro [PMID: 11503014]. Negative findings: Tacrolimus (no genotype effect on PK) [PMID: 15521904]. Rho123 (no genotype effect on efflux from lymphocytes) [PMID: 12914549]. Verapamil, vinblastine, calcein AM, prazosin, bisantrene, forskolin (no genotype effect on substrate specificity) [PMID: 12065748]. Calcein AM (no genotype effect on transport) ([PMID: 12893986], PA129411303) Verapamil, digoxin, vinblastine, cyclosporin A (no genotype effect on in vitro transport and accumulation) [PMID: 12781336]. |
| Key Phenotypes/Diseases: | Positive findings: 2677GG is associated with a higher probability of complete remission and three year event-free survival in AML patients [PMID:16331627]. 2677A/T genotype is a positive predictor of tacrolimus neurotoxicity in liver transplant patients [PMID: 12352921]. 2677T allele is associated with decreased fexofenadine AUC (area under the curve) [PMID: 11503014]. Negative findings: 2677 genotype is not associated with P-gp or ABCB1 expression in liver [PMID: 15752383]. Ritonavir - no genotype effect on trough levels or PK in HIV+ patients [PMID: 14600574]. 2677 genotype is not associated with altered function or expression in lymphocytes in patients with AML [PMID: 11369657]. |
| DNA Source Containing Homozygous Reference Allele(Coriell Lines): |
Coriell NA17202 (PA126721668) |
| DNA Source Containing Heterozygous Reference Allele (Coriell Lines): |
Coriell NA17204 (PA126721670) (heterozygous for T allele), Coriell NA17212 (PA126721678) (heterozygous for A allele) |
| DNA Source Containing Homozygous Minor Allele(Coriell Lines): |
Coriell NA17203 (PA126721669) (homozygous for T allele), Coriell NA17201 (PA126721667) (homozygous for A allele) |
| Phenotype Data Sets: | PA129411303 - no 2677 genotype effect on calcein AM transport in vitro [PMID: 12893986]. PA136096708 - 2677 genotype is not a risk factor for osteonecrosis of the hip among children with leukemia [PMID: 15459215]. PA133888800 - 2677GG genotype is associated with slower steroid weaning after heart transplantation [PMID: 12175731]. PA133888947 - no 2677 genotype effect on tacrolimus exposure in adult lung transplant patients. PA126753360 - pharmacokinetics of etoposide, catechol metabolite (no genotype-phenotype analysis available). |
| Key Haplotypes: | ABCB1*13 |
| Gene HGNC Name: | ABCB1 |
|---|---|
| Variant Summary: | This SNP is positioned at 3435 with respect to the translation start site. The 3435 C>T synonymous SNP in exon 26 was first implicated in a change in P-gp function in 2000, when Hoffmeyer et al. correlated the TT genotype with lower duodenal P-gp expression and higher digoxin plasma levels than CC genotype after an oral dose [PMID: 10716719]. This report generated much interest in the 3435 SNP, and subsequent studies attempted to reproduce the Hoffmeyer paper, with varying results. The existing literature is not conclusive about the effects of this SNP, alone or in the *13 haplotype, on P-gp function or expression. |
| Key PubMed IDs: | 15651752, 14583680, 16355344, 16267764, 10716719, 12739761, 11994059, 11434506, 15521904, 14600574, 12914549, 15778422, 14711599, 14586389, 12492608, 11994059, 16331627, 12686700, 12684679, 12175731, 12142082, 11809184, 15752383, 15452306, 10716719, 15459215 |
| Genomic Variant & GenBank ID: | 43268C>T on AC005068 (this reference sequence has an A at this position because it is on the opposite strand to the gene.) |
| mRNA Variant & GenBank ID: | 3853C>T on NM_000927.3 |
| Protein Variant & GenBank ID: | NA |
| dbSNP rs#: | rs1045642 |
| GoldenPath Position: | chr7:86976581 (hg18) |
| Key Drugs/Substrates: | Positive findings: Nelfinavir -TT genotype had higher intracellular concentration in lymphocyte cell lines [PMID: 15651752]. Tacrolimus - TT genotype had higher dose/concentration ratio in renal transplant patients [PMID: 14583680]. Atazanavir - Atazanavir and bilirubin plasma levels significantly higher in HIV patients with CC genotype [PMID: 16355344]. Efavirenz - TT genotype associated with decreased virologic failure but not plasma concentration [PMID: 16267764]. Digoxin - TT genotype had higher plasma levels and lower intestinal expression [PMID: 10716719]. Digoxin -TT genotype had less duodenal absorption [PMID: 12739761]. Rho123 - TT genotype had decreased transport in CD56+ cells [PMID: 11994059]. Rho123 - CC genotype had higher transport and higher P-gp expression in CD56+ cells [PMID: 11434506]. Negative findings: Tacrolimus - no genotype effect on PK [PMID: 15521904]. Ritonavir - no genotype effect on trough levels or PK in HIV+ patients [PMID: 14600574]. Rho123 - no genotype effect on efflux from lymphocytes [PMID: 12914549]. Dicloxacillan - no genotype effect [PMID: 15778422]. Efavirenz, lopinavir - no genotype effect on plasma levels [PMID: 14711599]. Fexofenadine - no genotype effect on plasma levels or effect [PMID: 14586389]. Digoxin - no genotype effect on AUC(area under the curve), Cmax, or tmax after a single oral dose [PMID: 12492608]. Fexofenadine - no genotype effect on AUC (area under the curve) [PMID: 11994059]. |
| Key Phenotypes/Diseases: | Positive findings: 3435CC genotype associated with a higher probability of complete remission and three year event-free survival in AML patients [PMID: 16331627]. 3435CC genotype significantly associated with drug-resistant epilepsy [PMID: 12686700]. 3435TT genotype predicted response to preoperative chemotherapy for breast cancer [PMID: 12684679]. 3435CC genotype predicts longer steroid treatment in pediatric heart transplant patients [PMID: 12175731, PA133888800]. 3435TT genotype significantly associated with no or low ABCB1 expression in carcinoma cell lines [PMID: 12142082]. HIV+ patients with 3435TT genotype had a greater rise in CD4 cell count after six months on EFV or NFV treatment [PMID: 11809184]. Negative findings: 3435 genotype not associated with P-gp or ABCB1 expression in liver [PMID: 15752383]. 3435 genotype not associated with multidrug resistant epilepsy [PMID: 15452306]. |
| DNA Source Containing Homozygous Reference Allele(Coriell Lines): |
Coriell NA17212(PA126721678) |
| DNA Source Containing Heterozygous Reference Allele (Coriell Lines): |
Coriell NA17204 (PA126721670) |
| DNA Source Containing Homozygous Minor Allele(Coriell Lines): |
Coriell NA17214 (PA126721680) |
| Phenotype Data Sets: | PA136096708 - 3435 genotype is not a risk factor for osteonecrosis of the hip among children with leukemia [PMID: 15459215]. PA133888800 - 3435CC genotype is associated with slower steroid weaning after heart transplantation [PMID: 12175731]. PA133888947 - no 3435 genotype effect on tacrolimus exposure in adult lung transplant patients. PA646603 - patient responses to tamoxifen (no genotype-phenotype analysis available). PA126753360 - pharmacokinetics of etoposide, catechol metabolite (no genotype-phenotype analysis available). |
| Key Haplotypes: | ABCB1*13 |