Clinical Annotations
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Variant Annotations
PharmGKB variant annotations provide information about variant-drug pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.
Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.
There are 107 annotations for this variant. Register or sign in to see them.
There are 21 disease-related annotations for this variant. Register or sign in to see them.
VIP Variant in ABCB1
Note: The ABCB1 gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand, therefore the alleles within our variant annotations will differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.
A thymine (T) - cytosine ( C ) transition at nucleotide 3435 in exon 27 of ABCB1 (per ENST00000265724;vdb=variation;vf=10286490] in Ensembl) results in a synonymous change (ATT isoleucine, ATC isoleucine) at residue 1145 in a cytoplasmic loop of the ATP-dependent membrane transporter, P-glycoprotein (P-gp) (see location per Fung et al. [Article:19285158] as adapted from Ambudkar et al. [Article:10331089]). This single nucleotide polymorphism (SNP) is one of three coding SNPs in ABCB1 with a high minor allele frequency and large inter-ethnic allele frequency differences. The C allele frequency ranges between 34% to 90% across populations [Articles:12831320, 12359865, 16370938]. Among five distinct African populations, the C allele frequency ranges between 85% and 91% according to the Allele Frequency Database (ALFRED), while in most European and Hispanic populations the C allele is the minor allele, according to dbSNP.
In 2000, a study by Hoffmeyer et al. implicated the 3435 T allele with altered P-gp function, showing an association between the 3435 TT genotype and low expression of P-gp in the gut and increased plasma levels of digoxin relative to the 3435 CC genotype [Article:10716719]. This finding generated much interest in this silent mutation with regard to P-gp expression and activity, however replication studies have not borne out this and many other phenotypic associations [Article:16969364]. To illustrate briefly, studies have associated the 3435 TT genotype with decreased [Articles:11434506, 12142082, 15280437, 16141795] and increased [Article:16370938] expression of P-gp, as well as no genotypic effect [Article:15752383]. Likewise, studies have shown increased drug exposure associated with the 3435 T allele or TT genotype [Articles:11434506, 11994059, 15651752], the 3435 CC genotype [Articles:14583680, 16355344], as well as no genetic effect with regard to rs1045642 [Articles:11994059, 12492608, 14600574, 12914549, 14586389, 14711599, 15521904, 15778422]. Association studies for clinical outcomes are similarly inconclusive. As brief illustration, there is evidence for [Article:12686700] and against [Articles:17521963, 17924830] the association of 3435 CC with drug resistance in epilepsy, or no genetic effect with regard to rs1045642 [Articles:15452306, 19571437].
The rs1045642 T allele is reference, and the C allele is non-reference, on the minus strand of the sequence in UCSC Genome browser (hg18), which is in the 5' to 3' orientation of the ABCB1 gene.
Appendix
| Genomic Variant & GenBank ID: | 43268 is reference A on AC005068 (hg18 plus strand) |
|---|---|
| mRNA Variant & GenBank ID: | 3853 is reference T on NM_000927.3 (hg18 minus strand) |
| Protein Variant & GenBank ID: | 1145 is isoleucine on NP_000918.2 (hg18 minus strand) This synonymous SNP does not result in a variation in protein sequence. |
| GoldenPath Position: | chr7:86976581 (hg18) |
Positive and negative findings for drugs/substrates:
| Drug/substrate | Positive findings | Negative findings |
|---|---|---|
| Anthracyclines and taxanes | The TT genotype of this variant (3435 SNP) associated with increased drug response in breast cancer [Article:12684679] | |
| Antiepileptics | (1) The CC genotype of this variant (3435 SNP) associated with increased drug resistance in epilepsy [Article:12686700] (2) The T allele of this variant (3435 SNP) associated with increased drug resistance in epilepsy [Article:17924830] (3) The TT genotype of this variant (3435 SNP) associated with increased drug resistance in epilepsy in Chinese [Article:17521963] | This variant (3435 SNP) not associated with drug response in pediatric epilepsy in Indians [Article:19571437] |
| Antiretrovirals | The CT genotype of this variant (3435 SNP) associated with increased drug response compared to 3435 CC genotype in drug-naive HIV [Article:18547906] Atazanavir: The CC genotype of this variant (3435 SNP) associated with increased drug levels and bilirubin levels in HIV [Article:16355344] | |
| Cisplatin | The TT genotype of this variant (3435 SNP) associated with increased risk of diarrhea in small-cell lung carcinoma treatment with irinotecan plus cisplatin [Article:19349543] | |
| Dexamethasone | The T allele of this variant (3435 SNP) associated with increased drug response in multiple myeloma given DAV polytherapy (dexamethasone, doxorubicin (adryamicin), and vincristine) followed by autologous transplantation [Article:17488488] | |
| Dicloxacillan | This variant (3435 SNP) not associated with pharmacokinetics before or after induction of ABCB1 (P-glycoprotein) by rifampin [Article:15778422] | |
| Digoxin | (1) The TT genotype of this variant (3435 SNP) associated with increased drug levels and decreased intestinal ABCB1 (P-glycoprotein) expression [Article:10716719] (2) The TT genotype of this variant (3435 SNP) associated with decreased drug levels [Article:12739761] | This variant (3435 SNP) not associated with drug levels [Article:12492608] |
| Doxorubicin | The T allele of this variant (3435 SNP) associated with increased drug response in multiple myeloma given DAV polytherapy (dexamethasone, doxorubicin (adryamicin), and vincristine) followed by autologous transplantation [Article:17488488] | |
| Efavirenz | (1) The TT genotype of this variant (3435 SNP) associated with increased drug response in HIV [Article:11809184] (2) The TT genotype of this variant (3435 SNP) associated with decreased drug resistance, decreased virologic failure, and increased toxicity-related treatment failure in HIV [Article:16267764] | (1) This variant (3435 SNP) not associated with drug levels [Article:14711599] (2) This variant (3435 SNP) not associated with drug response nor drug exposure in HIV (efavirenz and nelfinavir)PMID: [16267764\] |
| Etoposide | The CC genotype of this variant (3435 SNP) associated with increased drug clearance (PharmGKB data set: PA126753360) [Article:12969965] | |
| Fexofenadine | This variant (3435 SNP) not associated with drug levels [Article:11994059] | |
| Irinotecan | The TT genotype this variant (3435 SNP) associated with increased risk of diarrhea in small-cell lung carcinoma treatment with irinotecan plus cisplatin [Article:19349543] | |
| Loperamide | This variant (3435 SNP) not associated with drug levels or drug response [Article:14586389] | |
| Lopinavir | (1) This variant (3435 SNP) not associated with drug levels [Article:14711599] (2) This variant (3435 SNP) not associated with drug levels in HIV [Article:[19207033] | |
| Methotrexate | The TT genotype of this variant (3435 SNP) associated with increased drug toxicity in rheumatoid arthritis [Article:18607581] | |
| Morphine | The TT genotype of this variant (3435 SNP) associated with increased drug response in Italians [Article:17898703] | |
| Nelfinavir | (1) The TT genotype of this variant (3435 SNP) associated with increased drug response in HIV [Article:11809184] (2) The TT genotype of this variant (3435 SNP) associated with increased drug levels in vitro [Article:15651752] | |
| Paroxetine | This variant (3435 SNP) not associated with drug response in major depression [Article:18550244] | |
| Prednisone | The CC genotype of this variant (3435 SNP) associated with decreased drug weaning after heart transplantation (PharmGKB data set: PA133888800) [Article:12175731] | |
| Rhodamine 123 | (1) The TT genotype of this variant (3435 SNP) associated with increased substrate levels in CD56\+ cells in vitro [Article:11994059] (2) The CC genotype of this variant (3435 SNP) associated with increased ABCB1 (P-glycoprotein) expression in CD56\+ cells in vitro [Article:11434506] | This variant (3435 SNP) not associated with drug levels in lymphocytes in vitro [Article:12914549] |
| Ritonavir | (1) This variant (3435 SNP) not associated with drug levels or pharmacokinetics in HIV [Article:14600574] (2) This variant (3435 SNP) not associated with drug levels in HIV [Article:19207033] | |
| Saquinavir | (1) This variant (3435 SNP) not associated with pharmacokinetics, administered with or without ritonavir [Article:17361121] (2) This variant (3435 SNP) not associated with ABCB1 (P-glycoprotein) expression and activity in peripheral blood mononuclear cells [Article:17361121] | |
| Tacrolimus | (1) The TT genotype of this variant (3435 SNP) associated with decreased drug levels in renal transplantation [Article:14583680] (2) The T allele of this variant (3435 SNP) associated with decreased drug toxicity in liver transplantation [Article:12352921] | (1) This variant (3435 SNP) not associated with drug pharmacokinetics [Article:15521904] (2) This variant (3435 SNP) not associated with pharmacokinetics after liver transplantation [Article:17875118] (3) This variant (3435 SNP) not associated with drug levels in adult lung transplantation (PharmGKB data set: PA133888947) [Article:14747421] |
| Valproic acid | This variant (3435 SNP) not associated with drug levels in bipolar disorder [Article:18165917] | |
| Vincristine | The T allele of this variant (3435 SNP) associated with increased drug response in multiple myeloma given DAV polytherapy (dexamethasone, doxorubicin (adryamicin), and vincristine) followed by autologous transplantation [Article:17488488] |
Key Phenotypes/Diseases: Positive findings
| Acute myeloid leukemia: The CC genotype of this variant (3435 SNP) associated with increased drug response [Article:16331627] |
| Coronary artery disease: The non-CC genotypes of this variant (3435 SNP) associated with increased family history of disease [Article:18851956] |
| Gastric cancer: The TT genotype of this variant (3435 SNP) associated with decreased disease risk in Japanese [Article:17608636] |
| Drug resistance: The CC genotype of this variant (3435 SNP) predicts longer steroid treatment in pediatric heart transplantation (PharmGKB data set: PA133888800 |
| Molecular phenotype: The TT genotype of this variant (3435 SNP) associated with decreased or no ABCB1 (P-glycoprotein) expression in carcinoma cell lines [Article:12142082] |
| Childhood acute lymphoblastic leukemia: The TT genotype of this variant (3435 SNP) associated with increased disease risk in Japanese [Article:17568669] |
Key Phenotypes/Diseases: Negative findings
| Breast cancer: This variant (3435 SNP) not associated with disease risk in Iranians [Article:19388849] |
| Childhood acute lymphoblastic leukemia: This variant (3435 SNP) not associated with disease risk [Article:18243305] |
| Crohn disease: (1) This variant (3435 SNP) not associated with disease risk in Hungarians [Article:[17505995] (2) This variant (3435 SNP) not associated with disease risk in Danes [Article:18819034] |
| Drug resistance: (1) This variant (3435 SNP) not associated with risk of cyclosporine A treatment failure in patients with steroid resistant ulcerative colitis [Article:17206635] (2) This variant (3435 SNP) not associated with risk of refractory epilepsy [Article:15452306] |
| Gastric cancer: This variant (3435 SNP) not associated with disease risk in Japanese [Article:18644389] |
| Kidney failure: This variant (3435 SNP) not a predisposing factor for terminal kidney failure leading to renal transplantation [Article:17556798] |
| Molecular phenotype+: 3435 not associated to hepatic ABCB1 (P-glycogprotein) expression [Article:15752383] |
| Osteonecrosis: This variant (3435 SNP) not associated with risk of osteonecrosis of the hip in childhood acute lymphoblastic leukemia patients (PharmGKB data set: PA136096708) [Article:15459215] |
| Pediatric epilepsy: This variant (3435 SNP) not associated with refractory disease in Indians [Article:19571437] |
| Peptic ulcer: This variant (3435 SNP) not associated with disease risk in Japanese [Article:[18644389] |
| Sporadic colorectal cancer: This variant (3435 SNP) not associated with disease risk in Bulgarians [Article:17674045] |
| Systemic lupus erythematosus: This variant (3435 SNP) genotype not associated with disease risk [Article:18820766] |
| Ulcerative colitis: (1) This variant (3435 SNP) not associated with disease risk in Danes [Article:18819034] (2) This variant (3435 SNP) not associated with disease risk in Hungarians [Article:17505995] |
Phenotype Data Sets:
| * PA136096708: This variant (3435 SNP) not associated with risk for osteonecrosis of the hip in childhood acute lymphoblastic leukemia patients [Article:1545921] |
| * PA133888800: The CC genotype of this variant (3435 SNP) associated with decreased prednisone] weaning after heart transplantation [Article:12175731] |
| * PA133888947: This variant (3435 SNP) not associated with tacrolimus drug levels in adult lung transplantation [Article:14747421] |
| * PA126753360: The CC genotype of this variant (3435 SNP) associated with increased clearance of etoposide, catechol metabolite [Article:12969965@pmid] |
| * PA646603: drug response to tamoxifen (no genotype-phenotype analysis available) |
| * PA145069449, PA150799043: The genotype of this variant (3435 SNP) and lymphocyte ABCB1 (P-gp) content not associated with liver CYP3A4 activity, intestinal CYP3A4 content, or intestinal P-gp content. Intestinal P-gp levels not associated with baseline saquinavir pharmacokinetics. [Article:16338276] |
| * PA145069438: Haplotype formed from the C allele of this variant (3435 SNP) and the G allele of rs2032582 (ABCB1:2677 SNP) associated with increased hepatic ABCB1 (P-gp) mRNA expression [Article:16490813] |
ABCB1 haplotypes
Variant alleles in the common coding SNPs at nucleotides 1236 (rs1128503), 2677 (rs2032582), and 3435 (rs1045642) are in high linkage disequilibrium [PMID: [Article:16708052], and are observed as common haplotypes in the population [Articles:11503014, 12893986, 19072639]. Variant alleles for 1236-2677-3435 commonly occur as the 893Ala-containing CGC haplotype and the 893Ser-containing TTT haplotype in most ethnic groups [Articles:11503014, 12172212, 12893986]. The vast majority of haplotypic studies for ABCB1 do not take into account all segregating sites that are used to distinguish ABCB1 star alleles (see below), but interrogate a select few variants.
ABCB1 star alleles
Sequence analysis of ABCB1 in different ethnic groups has been performed [Articles:11503014, 12172212, 12893986, 14646693, 15692830, 16708052, 17187507] and led to the designation of "star alleles" [Articles:14646693, 11503014, 12893986], as explained by Robarge et al. [Article:17700589]. ABCB1 star allele designations are currently not harmonized in the literature, and thus are specific to the citation referenced.
Connected Drugs
Connected Drug Classes
Connected Diseases
Publications related to rs1045642 at chr7:87138645: 96
Cross-References
- UCSC Golden Path:
- chr7:87138645
- dbSNP:
- rs1045642
- HapMap:
- rs1045642
- JSNP:
- ssj0000047
Platform Availability
- Affymetrix
- Illumina