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 58 annotations for this variant. Register or sign in to see them.
There are 14 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 triallelic, thymine (T) - guanine (G) - adenine (A) point mutation at nucleotide 2677 in exon 22 of ABCB1 (per ENST00000265724;vdb=variation;vf=10286490] in Ensembl) results in a non-synonymous codon change (TCT serine, GCT alanine, ACT threonine) at residue 893 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, with the T (893Ser) and G (893Ala) alleles being the most common. The 893 serine-bearing T allele frequency varies as much as 2% to 65% among world populations, according to data from the International HapMap project (www.hapmap.org). The frequency of 893Ala/Ala homozygotes (2677 GG genotype) is greater than 81% in African populations, compared to 10% to 32% in American Indians, Mexicans, Italians, Asians, and Caucasians. According to dbSNP, the 893 threonine-bearing 2677 A allele is relatively uncommon [Articles:11240981, 12352921], ranging from 0% to 17% in different ethnic populations.
Despite a large number of studies testing potential phenotypic associations with this missense SNP, the literature is inconclusive [Articles:16969364, 12359865, 16969364]. To illustrate briefly, evidence exists in favor of [Articles:11503014, 15228162] and against [Articles:11369657, 15752383] the association of the 893Ser allele with altered P-gp activity and expression [Article:16969364]; and 893Ser has been associated with an increase [Articles:12352921, 19545213], decrease [Article:11503014], and no change [Articles:14600574, 12893986, 12781336, 12914549, 15521904, 19207033] in drug exposure and drug effect [Article:16969364]. Studies for clinical outcome and disease risk are similarly discordant [Article:16969364]. As a brief example, research in drug treatment and disease risk for the related conditions of inflammatory bowel disease, Crohn disease, and ulcerative colitis, have implicated the 893Ala allele [Article:14610718], the 893Ser/Ser genotype [Article:17206635], or showed no genotypic effect with regard to rs2032582 [Articles:17505995, 18819034].
The rs2032582 T (893 serine) allele is reference, and the G (893 alanine) and A (893 threonine) alleles are 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: | 65241 is reference A on AC005068 (hg18 plus strand) |
|---|---|
| mRNA Variant & GenBank ID: | 3095 is reference T on NM_000927.3 (hg18 minus strand) |
| Protein Variant & GenBank ID: | 893 is reference serine on NP_000918.2 (hg18 minus strand) |
| GoldenPath Position: | chr7:86998554 (hg18) |
Positive and negative findings for drugs/substrates:
| Drug/substrate | Positive findings | Negative findings |
|---|---|---|
| Antiepileptics | T allele of this variant (2677 SNP) associated with increased drug resistance in refractory epilepsy [Article:17924830] | |
| Atorvastatin | The non-GG genotypes of this variant (2677 SNP) associated with decreased ABCB1 (P-glycoprotein) expression in response to drug treatment [Article:18851956] | |
| Bisantrene | This variant (2677 SNP) not associated with drug substrate specificity for P-glycoprotein [Article:12065748] | |
| Calcein AM | (1) This variant (2677 SNP) not associated with drug levels (PharmGKB data set: PA129411303) [Article:12893986] (2) This variant (2677 SNP) not associated with drug substrate specificity for P-glycoprotein [Article:12065748] | |
| Cyclosporine A | (1) The TT genotype of this variant (2677 SNP) associated with increased drug levels in myasthenia gravis [Article:18717915] (2) The TT genotype of this variant (2677 SNP) associated with decreased drug response in steroid resistant ulcerative colitis [Article:17206635] | This variant (2677 SNP) not associated with drug levels in cells in vitro [Article:12781336] |
| Cytarabine | The GG genotype of this variant (2677 SNP) associated with increased drug response in acute myeloid leukemia given idarubicin and cytarabine[Article:16331627] | |
| Digoxin | The T allele of this variant (2677 SNP) associated with decreased drug levels in cells in vitro [Article:11503014] | This variant (2677 SNP) not associated with drug levels in cells in vitro [Article:12781336] |
| Fexofenadine | The TT genotype of this variant (2677 SNP) associated with decreased drug levels [Article:11503014] | |
| Forskolin | This variant (2677 SNP) not associated with drug substrate specificity for P-glycoprotein [Article:12065748] | |
| Idarubicin | The GG genotype of this variant (2677 SNP) associated with increased drug response in acute myeloid leukemia given idarubicin and cytarabine [Article:16331627] | |
| Lopinavir | This variant (2677 SNP) not associated with drug levels in HIV [Article:19207033] | |
| Paroxetine | This variant (2677 SNP) not associated with drug response in major depression [Article:18550244] | |
| Prazosin | This variant (2677 SNP) not associated with drug substrate specificity for P-glycoprotein [Article:12065748] | |
| Prednisone | The GG genotype of this variant (2677 SNP) associated with decreased drug weaning after heart transplantation (PharmGKB data set: PA133888800) [Article:12175731] | |
| Rhodamine 123 | This variant (2677 SNP) not associated with drug levels in lymphocytes in vitro [Article:12914549] | |
| Ritonavir | (1) This variant (2677 SNP) not associated with drug levels in HIV [Article:19207033] (2) This variant (2677 SNP) not associated with drug levels or pharmacokinetics in HIV [Article:14600574] | |
| Tacrolimus | (1) This variant (2677 SNP) associated with drug levels in adult lung transplantation (PharmGKB data set: PA133888947) [Article:14747421] (2) The A and T alleles of this variant (2677 SNP) associated with increased neurological drug toxicity with liver transplantation [Article:12352921] | This variant (2677 SNP) not associated with pharmacokinetics [Article:15521904] |
| Verapamil | (1) This variant (2677 SNP) not associated with drug substrate specificity for P-glycoprotein [Article:12065748] (2) This variant (2677 SNP) not associated with drug levels in cells in vitro [Article:12781336] | |
| Vinblastine | (1) This variant (2677 SNP) not associated with drug levels in cells in vitro [Article:12781336] (2) This variant (2677 SNP) not associated with drug substrate specificity for P-glycoprotein [Article:12065748] |
Key Phenotypes/Diseases: Positive findings
| Coronary artery disease: The non-GG genotypes of this variant (2677 SNP) associated with increased likelihood of family history of disease [Article:18851956] |
| Lung cancer: The T allele of this variant (2677 SNP) associated with increased disease risk [Article:17120199] |
Key Phenotypes/Diseases: Negative findings
| Childhood acute lymphoblastic leukemia: This variant (2677 SNP) not associated with disease risk [Article:18243305] |
| Crohn disease: (1) This variant (2677 SNP) not associated with disease risk in Hungarians [Article:17505995] (2) This variant (2677 SNP) not associated with disease risk in Danes [Article:18819034] |
| Drug resistance: This variant (2677 SNP) not associated in drug response in pediatric epilepsy in Indians [Article:19571437] |
| Molecular phentoype: (1) This variant (2677 SNP) not associated with hepatic ABCB1 (P-glycoprotein) expression [Article:15752383] (2) This variant (2677 SNP) not associated with ABCB1 (P-glycoprotein) expression or activity in lymphocytes in acute myeloid leukemia [Article:11369657] |
| Osteonecrosis : This variant (2677 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 (2677 SNP) not associated with disease risk in Indians [Article:19571437] |
| Sporadic colorectal cancer: This variant (2677 SNP) not associated with disease risk in Bulgarians [Article:17674045] |
| Systemic lupus erythematosus: This variant (2677 SNP) not associated with disease risk [Article:18820766] |
| Ulcerative colitis: (1) This variant (2677 SNP) not associated with disease risk in Hungarians [Article:17505995] (2) This variant (2677 SNP) not associated with disease risk in Danes [Article:18819034] |
ABCB1 haplotypes
Variant alleles in the common coding SNPs at nucleotides 1236 (rs1128503), 2677 (rs2032582), and 3435 (rs1045642) are in high linkage disequilibrium [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 rs2032582 at chr7:87160618: 51
Cross-References
- UCSC Golden Path:
- chr7:87160618
- dbSNP:
- rs2032582
- HapMap:
- rs2032582
- JSNP:
- ssj0007866
Platform Availability
- Illumina