Gene:

ABCB1

ATP-binding cassette, sub-family B (MDR/TAP), member 1

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ABCB1 Description
ABCB1 (MDR1) is one of many ubiquitous adenosine triphosphate (ATP)-binding cassette (ABC) genes present in all kingdoms of life that is responsible for cellular homeostasis [PMID: 15052411, 9099718, 7765321]. ABC genes encode transporter and channel proteins possessing multiple membrane-spanning domains that form a pore, and intracellular nucleotide-binding domains for ATP-dependent translocation of substrates or ions across the cell membrane [PMID: 15052411, 12045106, 10331089]. Although bacterial ABC proteins function as both importers and exporters [PMID: 14630327], all eukaryotic ABC proteins are efflux pumps [PMID: 15052411, 11907151]. ABCB1 is one of forty-nine putative members in the superfamily of human ABC transporters [PMID: 1869973, 18154452] within sub-family B (MDR/TAP), which is one of seven phylogenetically distinct sub-families [PMID: 12045106] with overlapping substrate specificity [PMID: 18668431] (see Wageningen University website: www.nutrigene.4t.com/humanabc.htm).

Molecular and protein structure
ABCB1 was first cloned by Riordan and colleagues in 1985 [PMID: 2863759]. The gene lies less than 25 kilobases (kb) from ABCB4 on chromosome 7q21.12 (UCSC Genome Browser, March 2006 Assembly (hg18)). Analysis of human cell lines, liver tissue, and lymphocytes consistently show ABCB1 to contain 29 exons in a genomic region spanning 209.6 kb [PMID: 16146331] (Entrez GeneID: 5243, GenBank accession NT_007933). The two most 5' exons are untranslated. Two primary transcriptional start regions exist: a proximal promoter in exon 1 and intron 1 for constitutive expression, and a cryptic distal promoter that is active in drug-selected cell lines and cancer patient samples for overexpression of the protein product. The ABCB1 promoter region contains a few low-frequency polymorphisms and is relatively invariant compared to other genes in the genome [PMID: 16608921].

The messenger RNA (mRNA) is 4872 base pairs in length, including the 5' untranslated region (UTR) (RefSeq accession NM_000927.3), which gives rise to a protein that is 1280 amino acids in length, named P-glycoprotein (P-gp) [PMID: 16146331]. The secondary structure of P-gp reveals two homologous halves to the protein, each containing six transmembrane domains and a nucleotide-binding domain (see image per Fung et al. [PMID: 19285158] as adapted from Ambudkar et al. [PMID: 10331089]). The existence and number of putative splice variants is undetermined [PMID: 16146331]. Alternative transcripts for ABCB1 have been predicted from sequence alignments with human complementary DNA (cDNA) (see ABCB1 in AceView), protein sequences, and expressed sequence tags [PMID: 16708052]. P-gp is post-translationally modified by phosphorylation and N-glycosylation. Differential phosphorylation of P-gp by kinases have been shown to influence P-gp activity [PMID: 10790147, 16309179].

A number of mechanistic observations have been made from low-resolution crystal structures for P-gp in bacteria [PMID: 12777401] and Chinese hamster ovary cells [PMID: 9099718], and from a high-resolution structure of the mouse homolog with 87% sequence identity to humans (see Protein Data Bank accession 3G60, 3G5U, and 3G61) [PMID: 19325113]. The twelve transmembrane helices form a toroidal protein with an aqueous pore (see image from Higgins et al. [PMID: 9099718]). Two nucleotide-binding domains for the protein lie in the cytoplasm. The pore is lined with hydrophobic and aromatic amino acids at the extracellular-facing half of the pore, while the cytosolic-facing portion of the pore contains polar, charged residues [PMID: 19325113]. Structural analysis reveals two openings in the protein that open into the lipid bilayer and permit extraction of substrates directly from the membrane upon the passive diffusion of substrates into the cell (see image from Aller et al. [PMID: 19325113]) [PMID: 9099718, 12777401]. Several highly conserved residues within the pore are able to recognize a diverse range of substrates. The protein exhibits high conformational flexibility to allow for structural rearrangements in binding and effluxing substrates [PMID: 19325113]. Substrate-bound images reveal the capacity to distinguish stereoisomers and simultaneously bind multiple substrates at overlapping binding sites. The ability to bind substrates in close proximity to one another provides a mechanistic rationale for observed functional interactions between co-administered substrates (e.g. allosteric, competitive and non-competitive inhibition, and cooperativity) [PMID: 9300798, 18668431, 19325102].

Tissue distribution and function
P-gp is expressed in a polarized manner in the plasma membrane of cells in barrier and elimination organs, where it has protective and excretory function [PMID: 11913728]. It plays an important role in the first-pass elimination of orally administered drugs to limit their bioavailability by effluxing them at the lumen-facing epithelia of the small intestine and colon, and the bile-facing canaliculi of the liver. It eliminates substrates from the systemic circulation at the urine-facing side of the brush border membrane of proximal tubules in the kidney, and again via biliary excretion. It restricts permeability of drugs into 'sanctuary' organs from the apical or serosal side of blood-tissue barriers (e.g. blood-brain, blood-cerebral spinal fluid, blood-placenta, blood-testis barriers) [PMID: 15276711]. P-gp expression in the adrenal cortex is thought to play a role in hormone transport and homeostasis, and glucorcorticoid resistance [PMID: 12844331, 10331089]. In lymphocytes and other immunological and blood components P-gp putatively plays a role in viral resistance and in trafficking cytokines and enveloped viruses [PMID: 10331089, 8765502, 10698966]. P-gp is also thought to be important for steroid partitioning and lipid homeostasis in the periphery and central nervous system [PMID: 12379510, 19285054, 12844331]. Intracellular P-gp has been detected in the endoplasmic reticulum, vesicles, and the nuclear envelope, and has been associated with cell trafficking machinery with unknown function [PMID: 18560012]. Relevant to the clinical challenge of multi-drug resistance, P-gp is overexpressed in numerous tissues transformed by cancer.

Physiological role
P-gp was discovered in 1970 by Biedler and colleagues who observed the phenomenon of multi-drug resistance (MDR) conferred by a cell surface protein in mammalian cell lines. This membrane protein conferred up to a 2500-fold increase in drug resistance to actinomycin D and cross-resistance to a single exposure of mithramycin, vinblastine, vincristine, puromycin, daunomycin, demecolcine, and mitomycin C [PMID: 5533992]. The 170 kilo Dalton (kD) phospho-glycoprotein, or 'permeability' glycoprotein, was identified as the cause for reduced cellular drug exposure [PMID: 990323] by its active extrusion of drugs from the cell [PMID: 1203765, 2900833]. The physiological impact of this multi-drug efflux pump was appreciated in 1994 by Schinkel and colleagues who observed a 100-fold increase in the brain penetration of antiparasitic medication, ivermectin, in genetically engineered mice lacking abcb1 [PMID: 7910522]. Animals naturally deficient for abcb1 were also found to exhibit neurological and fetal drug toxicity due to a breach in the blood-brain and blood-placenta barriers where P-gp is normally active [PMID: 9299600, 19171022]. A 4-base pair deletion (ABCB1-1 Delta) was subsequently identified as the cause of the non-functioning allele in dogs [PMID: 19171022], which led to proposed dosing changes in veterinary medicine [PMID: 9934933, 19411645]. In humans, spontaneous deletion of ABCB1 has not been described, but a nonfunctional variant was found in two heterozygous individuals in which a single nucleotide polymorphism (SNP), T3587G, results in an isoleucine to serine change at residue 1196 in the second ATP-binding domain of P-gp [PMID: 16648557]. However, in one heterozygous subject tested, the SNP was not shown to affect the clearance of the P-gp substrate, SN-38, after parenteral irinotecan administration [PMID: 16648557, 14646693]. The frequency of the 3587 G allele was 1:300 in a Japanese population, thus homozygotes with two copies of the non-functioning 1196Ser allele would be very rare (1:100,000).

Numerous common coding variants in ABCB1 have been studied for their potential influence on P-gp expression, function, and disease risk. Genetic associations with molecular or clinical phenotypes have largely been inconsistent [PMID: 12406646, 14749689, 16969364]. As a result, no adjustments in drug dosing have been recommended for individuals carrying sequence variants of ABCB1 in humans, and replication studies are needed to understand the influence of ABCB1 genetics on disease susceptibility. Current clinical considerations for P-gp are therefore related to its important role in (1) multi-drug resistance, and (2) drug-drug interactions, derived primarily from its broad substrate specificity and variable intrinsic and drug-induced expression [PMID: 17933685].

Compounds that interact with P-gp
P-gp recognizes and effluxes a multitude of structurally and biochemically unrelated substrates (cyclic, linear, basic, uncharged, zwitterionic, negatively charged, hydrophobic, aromatic, non-aromatic, amphipathic), from 250 to 4,000 molecular weight [ISBN: 9780123695208, PMID: 18560012, 15072439], sufficiently indeterminate to predict in drug design [PMID: 11907151]. Substrates include xenobiotics, endogenous compounds (e.g. peptides (including beta-amyloids), steroid hormones, lipids, phospholipids, cholesterol, and cytokines) [PMID: 9300798], pharmaceuticals [PMID: 16454744], neutraceuticals (e.g. St. John's wort), dietary compounds (e.g. grapefruit juice, green tea) [ISBN: 9781588293138, PMID: 15072439] , and other compounds, which may also modulate P-gp activity [PMID: 19545213] (see Drugs/Substrates). P-gp compounds can act as substrates, inhibitors, inducers, and repressors; and citations refer to P-gp compounds as being in more than one category, depending upon the circumstance [PMID: 18668431]. Modulation of ABCB1 gene expression and/or P-gp activity by various mechanisms consequently influences P-gp-mediated drug disposition.

Repressors of P-gp, including certain antineoplastic agents that act at nuclear receptors [PMID: 17048260], or endotoxin [PMID: 14709616], cobalamin (1, 2) [PMID: 17982279], and atorvastatin [PMID: 18156365, 19543298], potentiate the action of substrates; while rifampin (rifampicin) [PMID: 10411543] and cell stress signals induce P-gp-mediated drug resistance [PMID: 17982279, 18156365, 18560012]. Another mechanism for P-gp-related pharmacoresistance to cytotoxic agents is hypothesized to relate to the cell stress signals they induce [PMID: 18699730, 19638996]. Upregulation of ABCB1 gene expression can occur at gene promoter sequences via transactivation [PMID: 15072439, 18668431, 19460946], for example, by the pregnane X receptor (NR1I2, PXR) gene in response to substrates that may have overlapping specificity for P-gp [PMID: 18560012]; or induction can occur independent of nuclear receptors [PMID: 15258100]. Alternatively, epigenetic inactivation of P-gp can occur by DNA methylation at specific nucleotide sequences within the promoter sequence, called CpG islands, as has been observed in some cancer tissues [PMID: 15326379]; or downregulation of P-gp can also occur by mechanisms other than by DNA methylation, for example, in response to cobalamin (1, 2), a vitamin B-12 derivative [PMID: 17982279].

Drug interactions
Many studies have characterized the interactions between P-gp compounds, since concomitant administration can substantially alter the pharmacokinetics of the compounds involved [PMID: 17933685]. Research has focused on both the deleterious and beneficial effects of interactions between P-gp compounds: (1) interactions that potentially affect drug safety and efficacy [PMID: 9300798], and (2) interactions exploited to optimize drug delivery (see Multi-drug resistance).

Drug safety and efficacy are major health concerns, particulary for drugs with a narrow therapeutic index and/or large clinical effect [PMID: 17168768]. A number of drug interactions of clinical relevance are cited as warnings in the drug labels. For example, the drug label for the contraceptive, Trinessa (1, 2) (Watson Pharma, Inc.), warns against potential drug inefficacy when coadministered with compounds that induce P-gp (e.g. rifampin, St. John's wort, protease inhibitors, carbamazepine, and barbiturates). The drug label for the antidiarrheal, loperamide (Imodium, McNeil Consumer Healthcare), warns against neurotoxic side effects when coadministered with P-gp inhibitors (e.g. quinidine, ritonavir) since this gut-targeted optiate relies upon P-gp to prohibit intestinal absorption and entry into the central nervous system [PMID: 19372478].

Interactions between compounds are substrate-specific, concentration-dependent [PMID: 9300798], and tissue-specific [PMID: 16537797]. For example, unlike the drug-potentiating interaction between quinine [PMID: 11014404, 14583678] or ritonavir [PMID: 16304151] on loperamide, the potent P-gp inhibitor, tariquidar, does not produce the same analgesic effects, despite its efficient inhibition of P-gp in lymphocytes. This is presumably due to tissue-specific factors [PMID: 16537797]. Concentration is another important determinant of drug interactions. For example, at the therapeutic concentration for the beta blocker and P-gp substrate, propranolol (Innopran Xl, Reliant Pharmaceuticals, Inc.), propranolol disposition is not affected by modulation of P-gp by other compounds. Other influences include key pharmacokinetic genes that affect the disposition of substrates for P-gp. For example, P-gp and cytochrome P450 3A4 metabolizing enzyme (CYP3A4) overlap in tissue distribution and specificity for a substantial number of substrates, inducers, and inhibitors [PMID: 7619215, 15276711]. Furthermore, genes responsible for the disposition of a drug can act synergistically [PMID: 16435171]. Marchetti et al. cite clinically relevant drug interactions influenced by the interplay of ABCB1 with other genes in the disposition of P-gp compounds, such as paclitaxel and cyclosporine A (CsA) (via CYP3A4 inhibition), digoxin and rifampin (via CYP3A4 induction), and topotecan and elacridar (via ABCG2 inhibition) [PMID: 17766652].

Multi-drug resistance
Drug resistance by multiple mechanisms [PMID: 2892943, 12712010, 15641020, 16454744, 18699730] accounts for more than 90% treatment failure in metastatic cancer [PMID: 15641020, 18286284]. Multi-drug resistance from intrinsic (drug-naive) and acquired (drug-induced) over-expression of P-gp [PMID: 2892943] is a notable impediment to brain-targeted therapies (e.g. antiepileptics, neuro-antiretrovirals) and chemotherapies [ISBN: 9781402059636, PMID: 16011870, 11907151, 17048260, 18627414]. P-gp expression predicts between 30 to 40% of treatment failure in epilepsy [PMID: 10331089, 15072439, 18199522] and is correlated with drug non-response in acute myeloid leukemia [PMID: 18056183], childhood neuroblastoma [PMID: 1682809] and sarcoma [PMID: 1968964], and other cancers [PMID: 8504063]. The relationship between P-gp expression with non-response to chemotherapy and drug-induced upregulation of P-gp according to tumor type is nicely reviewed by Takara et al. [PMID: 16454744].

Known interactions between substrates and modulators of P-gp have been exploited in drug development and treatment protocols to overcome low drug delivery. Inhibitors of P-gp, such as formulary excipients (e.g. tocopherol (vitamin E preparation, TPGS 1000) and Cremophor EL) [PMID: 8118035, 9520143, 17367162] and approved drugs, are clinically used to enhance the delivery of P-gp substrates. Verapamil and cyclosporine A (CsA) are examples of the first-generation of 'P-gp reversal agents' [PMID: 16454744] used in combination with antineoplastic agents, such as doxorubicin, vincristine, and paclitaxel to enhance bioavailability [PMID: 1676918, 8725386, 12454106, 16969354, 18510173]. However, dose-limiting toxicity of early reversal agents and formulary excipients has led to the development of second-generation antagonists of P-gp, such as valspodar (PSC833), with ten-fold greater potency for P-gp and less side effects [PMID: 19949935, 1346494, 12712010].

Substrate interactions with other pharmacokinetic genes affecting the absorption, distribution, metabolism, elimination (ADME) of drugs play a significant role in the effectiveness of P-gp reversal agents. Substrate specificity for multiple ADME genes can be advantageous or disadvantageous in adjunct therapy. For example, the mechanism by which both cyclosporine A and valspodar enhance the bioavailability of paclitaxel is owed in part to their inhibition of CYP3A4 [PMID: 9698296, 10589748], ABCC2 [PMID: 17062689], and other elimination-pathway genes (e.g. CYP2J2) [PMID: 19923256] for paclitaxel. On the other hand, non-specific inhibition of multiple elimination-pathway genes involved in drug clearance can lead to side effects associated with the prolonged half life of the primary drug. As more is known about the gene expression profile of specific pathological conditions, P-gp reversal agent use can be optimized. For example, where redundant drug resistance mechanisms are operant, as with ABCB1, ABCC1 (MRP1), and ABCG2 (BCRP) in acute myeloid leukemia [PMID: 14617793, 18699730], inhibition of multiple drug resistance genes can be beneficial. Characterization of the genes responsible for pharmacoresistance in a particular disease or disease stage is used to inform drug treatment (see P-gp-guided therapy). Also, third-generation P-gp reversal agents (e.g. tariquidar (XR9576), zosuquidar (LY335979), laniquidar (R101933), and OC144-093 (ONT093)) with greater specificity for P-gp and less affinity for other ADME genes, have been developed [PMID: 10975553, 12712010]. A number of the newer-generation P-gp reversal agents (e.g. tariquidar, valspodar (PSC833), zosuquidar, OC144-093, elacridar (GF120918, GG918), and CBT-1) have shown promise in in vitro and early trials for treatment of epilepsy and cancer [PMID: 12712010, 18234154, 15565444, 18234154, 18627414].

P-gp-guided therapy
Techniques to characterize the mechanisms of drug resistance that are operant in individual patients inform treatment with P-gp antagonists as adjuncts in the appropriate case. Single photon emission computed tomography (SPECT) analysis of the P-gp substrate, Tc-99m sestamibi, is used to probe P-gp-positive cells as a way to predict pharmacoresistance to antiepileptics [PMID: 18627414] and antitumor drugs [PMID: 9815718, 19390941]. This technique is shown to be a cost-effective method for pre-selecting responders to lung cancer treatment [PMID: 19223414]. Tc-99m sestamibi is also used to monitor the efficacy of P-gp reversal agents in sensitizing pharmacoresistant cells to P-gp substrates [PMID: 15269145]. A phase I clinical trial using vinblastine plus valspodar reversal agent, and Tc-99m sestamibi imaging to monitor the sensitization of P-gp-positive cells, showed increased Tc-99m sestamibi retention in tumor cells of metastatic renal carcinoma patients (and thus presumably, cytotoxic agent, vinblastine) [PMID: 9815718]. Tariquidar/taxane/anthracycline polytherapy guided by serial Tc-99m sestamibi tumor scans was tried in a phase II clinical trial for breast cancer with acquired pharmacoresistance (Clinical trial ID: NCT00048633 at http://clinicaltrials.gov

). Results to date show that cancers exhibiting de novo pharmacoresistance (drug naive), such as leukemias, myeloma, lymphomas, and breast and ovarian cancers, are the most amenable to P-gp modulation with reversal agents as adjunct therapy.

Genetic associations
Disease-causing mutations in fourteen of the ABC superfamily members have been described, as in CFTR (ABCC7) for cystic fibrosis, ABCA4 for macular degeneration, ABCC2 and ABCB11 for biliary dysfunction, and ABCA1, ABCG5, ABCG8, and ABCD1 for fatty acid/lipid disorders [PMID: 12045106]. A large corpus of literature about sequence variations for ABCB1 exists, however there is no clear consensus regarding the contribution of ABCB1 variation to disease risk [PMID: 16969364, 17661727, 18370231]; and despite evidence for inter-individual variability in ABCB1 expression and P-gp function [PMID: 7473127, 14965248, 19285158], the genetic contribution is unclear [PMID: 16969364]. A great number of studies has been carried out to establish the role of ABCB1 genetics in various phenotypes such as P-gp expression, function, drug response, and disease susceptibility with little consensus. Most genotype-phenotype associations are not substantiated by study replication, meaningful sample size, and appropriate multitesting correction. See helpful reviews [PMID: 12505329, 12406646, 14749689, 15212152], including a detailed summary by Leschziner et al. of the discordant literature regarding genetic association of ABCB1 SNPs and haplotypes with P-gp expression, activity, drug response, and disease risk [PMID: 16969364].

Despite much work to ascertain the genetic contribution of ABCB1 on drug disposition and disease susceptibility, the accumulation of studies to date are unclear. Until data is amassed to form a consensus about the role of genetics in P-gp-related phenotypes, the primary clinical focus on P-gp relates to its role in (1) multi-drug resistance, and (2) drug-drug interactions [PMID: 17933685].

ABCB1 variants
As of April 30, 2009 for build 130 of the Single Nucleotide Polymorphism database (dbSNP), there are 1279 SNPs in the ABCB1 gene region, 62 of which are coding (22 synonymous, 41 non-synonymous, and 1 in the start codon). The number and frequency of SNPs observed varies by ethnicity. Excluding SNPs below 5% allele frequency, there are approximately 124 SNPs observed in Caucasians, 134 in African Americans, 153 in Chinese, and 166 in Japanese (see ABCB1 in HapMap at www.hapmap.org). Additional information is available at the University of California, San Francisco Pharmacogenetics of Membrane Transporters Database (see ABCB1 at http://pharmacogenetics.ucsf.edu).

About 2.6 times fewer (n = 4) SNPs occur in the transmembrane domains compared to the intracellular and extracellular regions of the protein. None of the three prime untranslated region (3'UTR) SNPs are reported to alter mRNA stability [PMID: 19285158]. The three most common SNPs in the protein coding region are rs1128503 (1236T>C, Gly412Gly), rs2032582 (2677T>G/A, Ser893Ala/Thr), and rs1045642 (3435T>C, Ile1145Ile) [PMID: 16141795], according to build 130 of (dbSNP). These three SNPs have been the focus of many pharmacokinetic and disease association studies with controversial results [PMID: 16969364] (see Important Variants). Other less frequent variants include -129C>T (5'-UTR), 61A>G (Asn21Asp), and 1199G>A (Ser400Asn), which have been studied in vivo and in vitro. (See coding SNP locations on the secondary structure of P-gp per Fung et al. [PMID: 19285158] as adapted from Ambudkar et al. [PMID: 10331089].)

ABCB1 haplotypes
Closely positioned sequence variants tend not to segregate independently with each generation due to linkage disequilibrium (LD). As a result, multiple variant alleles are inherited together on the same physical chromatid in a particular pattern. That is to say that for linked variant alleles, the occurance of one variant allele informs the valence other alleles with a certain level of predictability. For example, alleles from the three most common coding SNPs at nucleotides 1236, 2677, and 3435, are in high LD [PMID: 16708052] and are observed most frequently as the 893Ala-containing CGC haplotype and 893Ser-containing TTT haplotype in most ethnic groups [PMID: 11503014, 12172212, 12893986, 14976162]. Other observed haplotypes extend beyond the exonic region of ABCB1 [PMID: 16255080]. Leschziner et al. observed LD extending 75 kilobases, linking 3' variant alleles of ABCB1 to coding variant alleles of the adjacent ABC transporter gene, ABCB4 [PMID: 16708052].

Haplotype structure relates to the location of recombination hot spots and ancestry-specific patterns of LD [PMID: 16255080, 18288195]. Tang et al. observed ethnic-specific LD blocks at the ABCB1 locus that are 80, 60, and 40 kilobase in length and distinguish Chinese, Malay, and Indian populations, respectively [PMID: 12172212]. Similarly, comparison of the mutation rate between Beninese Africans (1 variant per 224 basepairs) and American Africans (1 variant per 172 bp) reflects admixture in the U.S. cohort that differentiates the ABCB1 haplotype structure in these populations [PMID: 15692830]. Accordingly, haplotype frequencies differ by ethnic group. For example, the 893Ser-containing TTT haplotype occurs relatively infrequently in African Americans compared to Caucasians [PMID: 11503014, 12893986] and Asians [PMID: 12172212].

A haplotype by definition is not bound by a gene region, but gene-specific haplotypes can acquire allelic designations in the literature. Sequence analysis of ABCB1 in different ethnic groups has been performed [PMID: 11503014, 12172212, 12893986, 14646693, 15692830, 16708052, 17187507] and led to the designation of "star alleles" [PMID: 14646693, 11503014, 12893986], as explained by Robarge et al. [PMID: 17700589] (see Important Haplotypes). Briefly, the designation of ABCB1 star alleles follows rules established by the Cytochrome P450 Allele Nomenclature Committee and others for naming haplotypes observed for cytochrome P450 (CYP450), uridinediphosphate-glucuronosyltransferase (UGT), N-acetyltransferase (NAT), and aldehyde dehydrogenase (ALDH) [PMID: 10862518, 17700589] genes. Star alleles are defined relative to an arbitrarily established reference sequence, denoted *1. ABCB1*1 contains 1236C, 2677G (893Ala), and 3435C. Many star allele designations for ABCB1 are currently not harmonization in the literature. To illustrate, ABCB1*2, as defined by Kim et al., harbors three coding variants, namely 1236T, 2677T (893Ser), and 3435T [PMID: 11503014]; while ABCB1*2, as defined by Kroetz et al., contains 3435T (and is reference for 1236C and 2677G (893Ala)) [PMID: 12893986]. ABCB1*13 per Kroetz et al. (1236T, 2677T (893Ser), 3435T, and 3 intronic SNPs) [PMID: 12893986] is most similar to ABCB1*2 defined by Kim et al. [PMID: 11503014] as they are indistinguishable in terms of the coding region and amino acid sequence.

To investigate the regulatory impact of promoter variants on functional phenotypes, haplotype analysis of the promoter region has also been performed [PMID: 15280437, 16907707, 16608921, 19072639]. Wang et al. observed a haplotype formed from eight low-frequency variants (<5% minor allele frequency) in the promoter region that accounted for 85% of all haplotypes observed in five ethnic groups [PMID: 16608921]. They functionally characterized promoter haplotypes observed in Chinese, Malays, Indians, European Americans, and African Americans using an in vitro reporter assay and found significant ethnic-specific differences in promoter activity, although activity differed by the cell line used in the assay (presumably due to cell-specific regulatory factors). Other work has been done to understand the relationship between regulatory and coding variants for ABCB1 and their potential association with endophenotypes. Takane et al. showed that variation in promoter haplotype activity was independent of variation at the synonymous 3435 SNP, and the methylation status of the proximal promoter did not correlate with ABCB1 mRNA expression [PMID: 15280437] (see Molecular and protein structure, and Compounds that interact with P-gp). Jiang et al. found an association between the promoter methylation status and variation in coding SNPs for ABCB1. They showed that lower promoter methylation was associated with the 3435 TT and 893Ala-containing 2677 genotypes, while the 893Ser-containing TTT (1236, 2677, 3435) haplotype was associated with higher methylation 19072639. More research is needed to elucidate the functional relevance of regulatory variants for ABCB1 and their potential value to predicting P-gp-related phenotypes.

In-Depth Annotations ()

1. rs1045642 at chr7:86976581 in ABCB1
   This SNP is well-studied but there is no clear consensus on its significance for drug disposition, response or toxicity.

   Variant Name:

   ABCB1:3435C>T

   Evidence:

   http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforABCB1-3435
   

2. rs1045642 at chr7:86976581 in ABCB1
   Risk or phenotype-associated allele: TT genotype. Phenotype: Increased cellular rhodamine levels in leukocytes isolated from subjects (p < 0.05), but no association with fexofenadine plasma levels in the subjects. Study size: 20. Study population/ethnicity: Caucasian volunteers from Germany. Significance metric(s): p < 0.05 Type of association: GN; PK; FA.

   Variant Name:

   ABCB1:3435T>C, Ile1145Ile

   Related Drugs:

   fexofenadine, rhodamine 123

   Evidence:

   PMID:11994059
   http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforABCB1-3435
   

3. rs1045642 at chr7:86976581 in ABCB1
   Risk or phenotype-associated allele: TT genotype. Phenotype: Decreased or no ABCB1 (P-gp) expression in mammary and ovarian carcinoma cell lines. Study size: < 40. Study population/ethnicity: not stated. Significance metric(s): p = 0.0448. Type of association: GN; FA.

   Variant Name:

   ABCB1:3435T>C, Ile1145Ile

   Related Diseases:

   Carcinoma

   Evidence:

   PMID:12142082
   http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforABCB1-3435
   

4. rs1045642 at chr7:86976581 in ABCB1
   Risk or phenotype-associated allele: CC genotype. Phenotype: Increased time to wean from steroid treatment in pediatric heart transplantation. Study size: 69. Study population/ethnicity: Pediatric heart transplant patients from the Children's Hospital of Pittsburgh, Pennsylvania, USA. Significance metric(s): p = 0.04. Type of association: GN; PD.

   Variant Name:

   ABCB1:3435T>C, Ile1145Ile

   Related Drugs:

   prednisone

   Related Diseases:

   Drug Resistance, Organ Transplantation

   Evidence:

   PMID:12175731
   http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforABCB1-3435
   

5. rs1045642 at chr7:86976581 in ABCB1
   Risk or phenotype-associated allele: none. Phenotype: No association with digoxin disposition (AUC, C(max), T(max)) after a single oral dose. Study size: 50. Study population/ethnicity: Healthy, unrelated, white male non-smokers, aged 18-40, from Berlin, Germany. Significance metric(s): p >= 0.3. Type of association: GN; PK.

   Variant Name:

   ABCB1:3435T>C, Ile1145Ile

   Related Drugs:

   digoxin

   Evidence:

   PMID:12492608
   http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforABCB1-3435
   

6. rs1045642 at chr7:86976581 in ABCB1
   Risk or phenotype-associated allele: TT genotype. Phenotype: Increased drug response to anthracyclines and taxanes in breast cancer. Study size: 68. Study population/ethnicity: Locally advanced stage breast cancer patients undergoing preoperative chemotherapy. Significance metric(s): p = 0.029. Type of association: GN; PD.

   Variant Name:

   ABCB1:3435T>C, Ile1145Ile

   Related Drugs:

   anthracyclines and related substances, taxanes

   Related Diseases:

   Breast Neoplasms

   Evidence:

   PMID:12684679
   http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforABCB1-3435
   

7. rs1045642 at chr7:86976581 in ABCB1
   Risk or phenotype-associated allele: CC genotype. Phenotype: Increased antiepileptic drug resistance. Study size: 315 (200 drug-resistant, 115 drug-responsive). Study population/ethnicity: Epilepsy patients from England, classified as drug-resistant or drug-responsive. Significance metric(s): OR = 2.66; p = 0.006. Type of association: GN; PD.

   Variant Name:

   ABCB1:3435T>C, Ile1145Ile

   Related Diseases:

   Drug Resistance, Epilepsy

   Evidence:

   PMID:12686700
   http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforABCB1-3435
   

8. rs1045642 at chr7:86976581 in ABCB1
   Risk or phenotype-associated allele: TT genotype. Phenotype: Decreased digoxin absorption after direct delivery to the surface of the duodenum by endoscope. Study size: 11 (5 CC genotype, 6 TT genotype). Study population/ethnicity: Unrelated, healthy subjects from Kobe, Japan. Significance metric(s): p = 0.007. Type of association: GN; PK.

   Variant Name:

   ABCB1:3435T>C, Ile1145Ile

   Related Drugs:

   digoxin

   Evidence:

   PMID:12739761
   http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforABCB1-3435
   

9. rs1045642 at chr7:86976581 in ABCB1
   Risk or phenotype-associated allele: CC genotype. Phenotype: Increased etoposide clearance. Study size: 109 (104 whites, 42 blacks). Study population/ethnicity: Black and white children, newly diagnosed with acute lymphoblastic leukemia, from the USA. Significance metric(s): p = 0.027. Type of association: GN; PK.

   Variant Name:

   ABCB1:3435T>C, Ile1145Ile

   Related Drugs:

   etoposide

   Related Diseases:

   Precursor Cell Lymphoblastic Leukemia-Lymphoma

   Evidence:

   PMID:12969965
   http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforABCB1-3435
   

10. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: TT genotype. Phenotype: Decreased tacrolimus levels in a subset of 29 post-operative kidney transplant patients (p < 0.01), and lower incidence of steroid-induced osteonecrosis in 136 patients (OR = 0.1; p = 0.034). Study size: 136 (30 osteonecrosis cases, 106 without osteonecrosis for 2 years post-transplant). Study population/ethnicity: Post-operative kidney transplant patients from Japan. Significance metric(s): OR = 0.10, p = 0.034 (osteonecrosis incidence); p < 0.01 (tacrolimus levels). Type of association: GN; PK; ADR.

    Variant Name:

    ABCB1:3435T>C, Ile1145Ile

    Related Drugs:

    tacrolimus

    Related Diseases:

    Organ Transplantation

    Evidence:

    PMID:14583680
    http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforABCB1-3435
    

11. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: none. Phenotype: No association with plasma levels after a single dose of loperamide, nor drug-induced respiratory depression (pharmacodynamic evidence of brain penetration as an unintended drug target). Study size: 16 (8 TT genotype, 8 CC genotype). Study population/ethnicity: Healthy Caucasians from San Francisco, California, USA. Significance metric(s): p > 0.05. Type of association: GN; PK; ADR.

    Variant Name:

    ABCB1:3435T>C, Ile1145Ile

    Related Drugs:

    loperamide

    Evidence:

    PMID:14586389
    http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforABCB1-3435
    

12. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: T allele. Phenotype: Decreased drug-induced neurotoxicity (e.g. convulsion, tremor, leukoencephalopathy) in recipients of liver transplantation associated with the T allele in combination with other factors (e.g. ABCB1:2677G>T/A, tacrolimus trough concentration, aspartate aminotransferase, ratio of graft weight-to-recipient's standard liver volume). Study size: 17 (6 with and 11 without neurotoxicity). Study population/ethnicity: Liver transplant patients from Kyushu University Hospital in Japan. Significance metric(s): chi-squared = 7.91; p < 0.005. Type of association: GN; PK; PD; TOX; ADR.

    Variant Name:

    ABCB1:3435T>C, Ile1145Ile

    Related Drugs:

    tacrolimus

    Related Diseases:

    Drug Toxicity, liver transplantation

    Evidence:

    PMID:12352921
    http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforABCB1-3435
    

13. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: T allele, TT genotype. Phenotype: Association with decreased virologic failure (p = 0.05, TT vs. CC/CT), decreased drug resistance (OR = 0.56, p = 0.05), and increased toxicity-related treatment failure (p = 0.05) with efavirenz (EFV); however, no association with nelfinavir (NLF) or efavirenz response (e.g. increase in CD4 T cell count) (p > 0.1) nor nelfinavir or efavirenz exposure. Study size: 504 (340 efavirenz, 348 nelfinavir, 184 both drugs). Study population/ethnicity: Subset of larger study of 504 (49% whites, 31% blacks, 19% Hispanics from the USA and Italy) randomized antiretroviral-naive HIV-1 patients who were administered efavirenz plus two nucleoside analogues. Significance metric(s): p = 0.05 (ERV: less virologic failure, drug resistance, tox-related Tx failure); p > 0.1 (EFV/NLF response); not significant (EFV/NLF exposure). Type of association: GN; PK; PD; TOX; ADR.

    Variant Name:

    ABCB1:3435T>C, Ile1145Ile

    Related Drugs:

    efavirenz, nelfinavir

    Related Diseases:

    HIV

    Evidence:

    PMID:16267764
    http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforABCB1-3435
    

14. rs2032582 at chr7:86998554 in ABCB1
    This SNP is well-studied but there is no clear consensus on its significance for drug disposition, response or toxicity.

    Variant Name:

    ABCB1:2677G>A/T

    Evidence:

    http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforABCB1-2677
    

15. rs1128503 at chr7:87017537 in ABCB1
    This SNP is well known, but there is no clear consensus on its significance for drug disposition, response or toxicity.

    Variant Name:

    ABCB1:1236C>T

    Evidence:

    http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforABCB1-1236
    

Curated Annotations ()

1. rs1045642 at chr7:86976581 in ABCB1
   rs1045642 is associated with altered inhibition by verapamil and cyclosporin A of substrate uptake in vitro.

   Variant Name:

   ABCB1:C3435T

   Related Drugs:

   cyclosporine, verapamil

   Evidence:

   PMID:17185560
   

2. rs1045642 at chr7:86976581 in ABCB1
   Individuals that are homozygotes for 3435T alleles of ABCB1 have increased risk of developing nortriptyline-induced postural hypotension.This variant is also associated with expression level and in vivo function of ABCB1.

   Variant Name:

   ABCB1: 3435C>T

   Related Drugs:

   nortriptyline

   Related Diseases:

   Depression, Depressive Disorder, Depressive Disorder, Major, Hypotension

   Evidence:

   PMID:12082591
   

3. rs1045642 at chr7:86976581 in ABCB1
   The T allele of this SNP is associated with nortriptyline-induced postural hypotension in patients treated for major depression. This SNP is not associated with response to treatment with nortriptyline or fluoxetine.

   Variant Name:

   ABCB1:3435C>T

   Related Drugs:

   nortriptyline

   Related Diseases:

   Hypotension, Orthostatic

   Evidence:

   PMID:12082591
   

4. rs1045642 at chr7:86976581 in ABCB1
   Indian rheumatoid arthritis patients heterozygous for this SNP (CT genotype) had about double the risk of non-response to methotrexate.

   Variant Name:

   ABCB1:C3435T, MDR1:C3435T

   Related Drugs:

   methotrexate

   Related Diseases:

   Arthritis, Rheumatoid

   Evidence:

   PMID:19093297
   

5. rs1045642 at chr7:86976581 in ABCB1
   The C3435T variant (rs1045642) at exon 26 in the ABCB1 was showed to influence clopidogrel absorption in patients with a cardiovascular disease. Plasma concentrations of clopidogrel and its active metabolite were reduced in patients carrying the TT genotype.

   Variant Name:

   ABCB1: C3435T

   Related Drugs:

   clopidogrel

   Related Diseases:

   Cardiovascular Diseases

   Evidence:

   PMID:17112805
   PMID:19106083
   

6. rs1045642 at chr7:86976581 in ABCB1
   (R)-lansoprazole concentrations significantly increased in CYP2C19 extensive metabolizers with the ABCB1 C3435T C allele, but not TT genotype, after renal transplantation and treatment with tacrolimus and lansoprazole.

   Variant Name:

   ABCB1:3435C>T

   Related Drugs:

   lansoprazole, tacrolimus

   Related Diseases:

   Gastroesophageal Reflux, Transplantation

   Evidence:

   PMID:17190370
   

7. rs1045642 at chr7:86976581 in ABCB1
   In a study of HIV patients in South Africa, participants who experienced hepatotoxicity were less likely to have at least one T allele of the variant ABCB1:3435C>T.

   Variant Name:

   ABCB1:3435C>T, MDR1 3435C>T

   Related Drugs:

   efavirenz

   Related Diseases:

   HIV

   Evidence:

   PMID:16912957
   

8. rs1045642 at chr7:86976581 in ABCB1
   Decreased risk of hepatotoxicity was associated with ABCB1:3435C>T in a study of HIV patients receiving either efavirenz- or nevirapine-containing drug regimens.

   Variant Name:

   ABCB1:3435C>T, MDR1 3435C>T

   Related Drugs:

   efavirenz, nevirapine

   Related Diseases:

   HIV

   Evidence:

   PMID:16912956
   

9. rs1045642 at chr7:86976581 in ABCB1
   Patients with this variant with metastatic breast cancer treated with palitaxel showed a significantly lower disease control rate and lower overall survival rate than the CC variant allele.

   Variant Name:

   ABCB1:3435 C>T

   Related Drugs:

   paclitaxel

   Related Diseases:

   Breast Neoplasms

   Evidence:

   PMID:18836089
   

10. rs1045642 at chr7:86976581 in ABCB1
    Patients with both rs1045642 and rs2032582 variants have been associated with neutropenia from paclitaxel.

    Variant Name:

    ABCB1:3435 C>T

    Related Drugs:

    paclitaxel

    Related Diseases:

    Neutropenia

    Evidence:

    PMID:16950614
    

11. rs1045642 at chr7:86976581 in ABCB1
    In Slovak (White) breast cancer patients (n=221) receiving anthracycline-based chemotherapy, the CC genotype of ABCB1:3435C>T was associated with longer time to progression.

    Variant Name:

    ABCB1:3435C>T; MDR1 C3435T

    Related Drugs:

    doxorubicin, epirubicin

    Related Diseases:

    Breast Neoplasms

    Evidence:

    PMID:19752884
    

12. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: T. Phenotype: In subjects carrying one or two T alleles of this variant, the plasma olanzapine level alone was positively associated with percent change in Brief Psychiatric Rating Scale (BPRS) score. As olanzapine plasma levels increased, the BPRS score increased. Study size: 41. Study population/ethnicity: Patients with schizophrenia; > 90% Caucasian. Significance metric(s): p = 0.02. Type of association: CO.

    Variant Name:

    PGP C3435T; ABCB1:3435C>T

    Related Drugs:

    olanzapine

    Related Diseases:

    Schizophrenia

    Evidence:

    PMID:17038883
    

13. rs1045642 at chr7:86976581 in ABCB1
    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.

    Variant Name:

    ABCB1: c.3435C>T, mRNA 3853C>T

    Related Drugs:

    cyclosporine, digoxin, verapamil, vinblastine

    Evidence:

    PMID:12781336
    

14. rs1045642 at chr7:86976581 in ABCB1
    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.

    Variant Name:

    ABCB1: c.3435C>T, mRNA 3853C>T, p.Ile1145Ile

    Related Drugs:

    cyclosporine, digoxin, verapamil, vinblastine

    Evidence:

    PMID:12781336
    

15. rs1045642 at chr7:86976581 in ABCB1
    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.

    Variant Name:

    ABCB1: c.3435C>T, mRNA 3853C>T, p.Ile1145Ile

    Related Drugs:

    ritonavir

    Evidence:

    PMID:14600574
    

16. rs1045642 at chr7:86976581 in ABCB1
    Haplotypes derived from the SNPs 2677G > T (rs2032582) and 3435C > T (rs1045642) do not influence the pharmacokinetics of tacrolimus in renal transplant patients

    Variant Name:

    ABCB1: c.3435C>T, mRNA 3853C>T

    Related Drugs:

    tacrolimus

    Related Diseases:

    Transplantation

    Evidence:

    PMID:15521904
    

17. rs1045642 at chr7:86976581 in ABCB1
    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+.

    Variant Name:

    ABCB1:3435C>T, mRNA 3853C>T, Ile1145Ile

    Related Drugs:

    rifampin, verapamil

    Evidence:

    PMID:12914549
    

18. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: None. Phenotype: Efflux of P-glycoprotein substrates (verapamil; digoxin; vinblastine; cyclosporin A) in vitro were not significantly affected by combined mutations for rs1128503 (2677G>T/A) and rs1045642 (3435C>T) in LLC-PK1 cell lines. Study size: Triplicate cell assays. Study population/ethnicity: N/A. Significance metric(s): Not significant, p > 0.05. Type of association: FA

    Variant Name:

    ABCB1:3435C>T, mRNA 3853C>T, Ile1145Ile

    Related Drugs:

    cyclosporine, digoxin, verapamil, vinblastine

    Evidence:

    PMID:12781336
    

19. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: 3435 CT and TT genotypes. Phenotype: ABCB1 polymorphisms were associated with risk for coronary artery disease (CAD) (p<0.05). 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). 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

    Variant Name:

    ABCB1:3435C>T, mRNA 3853C>T, Ile1145Ile

    Related Drugs:

    atorvastatin

    Related Diseases:

    Coronary Artery Disease, Hypercholesterolemia

    Evidence:

    PMID:18851956
    

20. rs1045642 at chr7:86976581 in ABCB1
    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).

    Variant Name:

    ABCB1:3435C>T, mRNA 3853C>T, p.Ile1145Ile

    Related Drugs:

    cytarabine, idarubicin

    Related Diseases:

    Leukemia, Myeloid, Acute

    Evidence:

    PMID:16331627
    

21. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: none. Phenotype: There was no significant association between systemic exposure of tipifarnib (AUC levels) and rs1045642 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

    Variant Name:

    ABCB1: c.3435C>T, mRNA 3853C>T, p.Ile1145Ile; ABCB1*6

    Related Drugs:

    Tipifarnib

    Evidence:

    PMID:15122075
    

22. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: C. Phenotype: This variant is associated with nevirapine-induced hepatotoxicity in patients from Mozambique, with the T allele showing a protective effect. Study size: 156 (78 with nevirapine-induced hepatotoxicity and 78 without adverse events). Study population/ethnicity: HIV infected patients from Mozambique. Significance metric(s): p = 0.038; odds ratio: 0.42. Type of association: GN; CO

    Variant Name:

    c.3435C>T

    Related Drugs:

    nevirapine

    Related Diseases:

    Drug Toxicity, HIV Infections

    Evidence:

    PMID:20017669
    

23. rs1045642 at chr7:86976581 in ABCB1
    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.

    Variant Name:

    ABCB1:3435C>T

    Related Drugs:

    doxorubicin

    Related Diseases:

    Breast Neoplasms

    Evidence:

    PMID:18377430
    

24. rs1045642 at chr7:86976581 in ABCB1
    3435TT homozygotes showed statistically different fenofexadine area under the concentration curve (AUC) values for 0-4 hours (p = 0.036) than CC homozygotes.

    Variant Name:

    ABCB1:3435C>T, mRNA 3853C>T, Ile1145Ile

    Related Drugs:

    fexofenadine

    Evidence:

    PMID:11503014
    

25. rs1045642 at chr7:86976581 in ABCB1
    There was no significant association between the genotype C3435T distribution and the risk of Cyclosporin A failure in steroid resistance ulcerative colitis (p = 0.23).

    Variant Name:

    ABCB1:3435C>T, mRNA 3853C>T, Ile1145Ile

    Related Drugs:

    cyclosporine

    Related Diseases:

    Colitis, Ulcerative

    Evidence:

    PMID:17206635
    

26. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: TT genotype. Phenotype: Decreased expression of intestinal ABCB1 (P-gp) (p = 0.056, n = 21), and increased plasma levels of digoxin relative to the CC genotype (p = 0.006, n = 14). Study size: 21 duodenum samples, and 14 PK subjects. Study population/ethnicity: Caucasians from Germany. Significance metric(s): p = 0.006 - 0.056. Type of association: GN; PK; FA.

    Variant Name:

    ABCB1:3435T>C, Ile1145Ile

    Related Drugs:

    digoxin

    Evidence:

    PMID:10716719
    

27. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: TT genotype. Phenotype: Decreased ABCB1 (P-gp) expression in leukocytes isolated from subjects, and increased in vitro rhodamine exposure in peripheral blood cells isolated from subjects. Study size: 31. Study population/ethnicity: Caucasians from Germany. Significance metric(s): p < 0.01. Type of association: GN; FA.

    Variant Name:

    ABCB1:3435T>C, Ile1145Ile

    Related Drugs:

    rhodamine 123

    Evidence:

    PMID:11434506
    

28. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: TT allele. Phenotype: Increased efavirenz and nelfinavir response after 6 months treatment. Study size: 123. Study population/ethnicity: White HIV patients. Significance metric(s): p = 0.0001. Type of association: GN; PD.

    Variant Name:

    ABCB1:3435T>C, Ile1145Ile

    Related Drugs:

    efavirenz, nelfinavir

    Related Diseases:

    HIV

    Evidence:

    PMID:11809184
    

29. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: none. Phenotype: Efavirenz and lopinavir plasma levels. Study size: 67. Study population/ethnicity: HIV patients. Significance metric(s): not available from abstract. Type of association: GN; PK.

    Variant Name:

    ABCB1:3435T>C, Ile1145Ile

    Related Drugs:

    efavirenz, lopinavir

    Evidence:

    PMID:14711599
    

30. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: CC genotype. Phenotype: CC genotype associated with decreased tacrolimus levels after 1 and 3 months (p < 0.05), but no genotypic association at 6, 9, and 12 months (p > 0.05) post-transplantation immunosuppressive therapy. Study size: 83. Study population/ethnicity: Adult lung transplant recipients, from the USA. Significance metric(s): p < 0.05 (1, 3 months Tx); p > 0.05 (6, 9, 12 months Tx). Type of association: GN; PK.

    Variant Name:

    ABCB1:3435T>C, Ile1145Ile

    Related Drugs:

    tacrolimus

    Related Diseases:

    Transplantation

    Evidence:

    PMID:14747421
    

31. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: TT genotype. Phenotype: Decreased ABCB1 (P-gp) expression in placenta and liver. Study size: 115 (96 placental and 19 liver tissue samples). Study population/ethnicity: Japanese. Significance metric(s): p < 0.05. Type of association: GN; FA.

    Variant Name:

    ABCB1:3435T>C, Ile1145Ile

    Evidence:

    PMID:15280437
    

32. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: TT gentoype and T allele. Phenotype: Risk of antiepileptic drug resistance (refractory epilepsy) is not associated with the 3435 SNP, although the T allele (p = 0.013) and TT gentoype (OR = 2.67; p = 0.026) were associated with temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) compared to TLE without HS in a subgroup. Study size: 609 (401 drug-resistant and 208 drug-responsive); 226 TLE subgroup (116 with HS, 110 without HS). Study population/ethnicity: Ethnically-matched drug-resistant and drug-responsive epilepsy patients. Significance metric(s): p = 0.013 (allelic); OR = 2.67, p = 0.026 (genotypic). Type of association: GN; CO.

    Variant Name:

    ABCB1:3435T>C, Ile1145Ile

    Related Diseases:

    Drug Resistance, Epilepsy

    Evidence:

    PMID:15452306
    

33. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: none. Phenotype: No genetic association with dicloxacillin pharmacokinetics given 1g dicloxacillin prior to or after 600 mg rifampin (ABCB1 (P-gp) inducer). Study size: 18 (13 male). Study population/ethnicity: Healthy volunteers (12 Caucasian, 5 Asian, 1 African American, 1 subject undetermined) from San Francisco, California, USA. Significance metric(s): not significant. Type of association: GN; PK.

    Variant Name:

    ABCB1:3435T>C, Ile1145Ile

    Related Drugs:

    dicloxacillin, rifampin

    Evidence:

    PMID:15778422
    

34. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated allele: none. Phenotype: No association with dicloxacillan pharmacokinetics given 1g dicloxacillan prior to or after 600 mg rifampin (ABCB1 (P-gp) inducer). Study size: 18 (13 male). Study population/ethnicity: Healthy volunteers (12 Caucasian, 5 Asian, 1 African American, 1 subject undetermined) from San Francisco, California, USA. Significance metric(s): not significant. Type of association: GN; PK.

    Variant Name:

    ABCB1:3435T>C, Ile1145Ile

    Related Drugs:

    dicloxacillin, rifampin

    Evidence:

    PMID:15778422
    

35. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated genotype: TT. Phenotype: ABCB1 3435C>T genotype was significantly associated with the risk of cardiovascular death, myocardial infarction, or stroke (p=0.0064). ABCB1 3435 TT homozygotes had a 72% increased risk of cardiovascular death, myocardial infarction, or stroke compared with CT/CC individuals HR 1.72, 95% CI 1.22-2.44, p=0.002). CT heterozygotes were at similar risk to CC individuals (HR 0.94, 0.58-1.51). Study size/population: 1471 patients with acute coronary syndromes taking clopidogrel. Type of association: CO; GN; ADR

    Variant Name:

    ABCB1: 3435C>T

    Related Drugs:

    clopidogrel

    Related Diseases:

    Cardiovascular Diseases, Death, Sudden, Cardiac, Myocardial Infarction, Stroke

    Evidence:

    PMID:20801494
    

36. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated genotype: CC. Phenotype: In patients with or without ST-elevation acute coronary syndrome a higher rate of of ischaemic events were observed for patients with the ABCB1 3435 CC genotype (high-expression group) than for those with polymorphisms of intermediate (CT) or low expression (TT) who were on clopidogrel. Study size: 5148 patients receiving 75 mg clopidogrel once daily Study population/ethnicity: predominantly white (98%) Type of association: GN

    Related Drugs:

    clopidogrel

    Evidence:

    PMID:20801498
    

37. rs72552784 at chr7:86983850 in ABCB1
    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.

    Variant Name:

    ABCB1: c.2995G>A, mRNA 3413G>A, p.Ala999Thr

    Related Drugs:

    bisantrene, calcein, forskolin, prazosin, verapamil, vinblastine

    Evidence:

    PMID:12065748
    

38. rs4148740 at chr7:86990039 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.

    Related Drugs:

    amitriptyline, citalopram, paroxetine, venlafaxine

    Related Diseases:

    Depression

    Evidence:

    PMID:18215618
    

39. rs10280101 at chr7:86991521 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.

    Related Drugs:

    amitriptyline, citalopram, paroxetine, venlafaxine

    Related Diseases:

    Depression

    Evidence:

    PMID:18215618
    

40. rs7787082 at chr7:86994987 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.

    Related Drugs:

    amitriptyline, citalopram, paroxetine, venlafaxine

    Related Diseases:

    Depression

    Evidence:

    PMID:18215618
    

41. rs2032583 at chr7:86998497 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.

    Related Drugs:

    amitriptyline, citalopram, paroxetine, venlafaxine

    Related Diseases:

    Depression

    Evidence:

    PMID:18215618
    

42. rs2032582 at chr7:86998554 in ABCB1
    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.

    Variant Name:

    MDR1 G2677T/A, MDR1 (2677G, 893 Ala), MDR1 (2677T, 893 Ser), MDR1 (2677A, 893 Thr)

    Related Drugs:

    dexamethasone, doxorubicin, vincristine

    Related Diseases:

    Multiple Myeloma

    Evidence:

    PMID:18408561
    

43. rs2032582 at chr7:86998554 in ABCB1
    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.

    Related Drugs:

    paroxetine

    Related Diseases:

    Depression

    Evidence:

    PMID:17913323
    

44. rs2032582 at chr7:86998554 in ABCB1
    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.

    Variant Name:

    ABCB1: G2677T/A; Ala893Ser/Thr

    Related Drugs:

    paclitaxel

    Related Diseases:

    Ovarian Neoplasms

    Evidence:

    PMID:19143748
    

45. rs2032582 at chr7:86998554 in ABCB1
    This variant maybe associated with drug resistance in chinese epilepsy patients. Sample size: 464 chinese epilepsy patients (270 drug responsive, 194 drug resistant).

    Variant Name:

    ABCB1: 2677T/A>G

    Related Drugs:

    carbamazepine, clobazam, clonazepam, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, topiramate, valproic acid, vigabatrin

    Related Diseases:

    Epilepsy

    Evidence:

    PMID:19450124
    

46. rs2032582 at chr7:86998554 in ABCB1
    This variant have been associated with response to palitaxel.

    Variant Name:

    ABCB1: 2677G>T/A

    Related Drugs:

    paclitaxel

    Evidence:

    PMID:16467099
    

47. rs2032582 at chr7:86998554 in ABCB1
    Patients with epithelial ovarian cancer, with this variant, have been associated with response to taxane- and platinum-based therapy and gastrointestinal toxicity.

    Variant Name:

    ABCB1: 2677G>T/A

    Related Drugs:

    carboplatin, cisplatin, docetaxel, paclitaxel, taxanes

    Related Diseases:

    Ovarian Neoplasms

    Evidence:

    PMID:19203783
    

48. rs2032582 at chr7:86998554 in ABCB1
    Patients with both rs1045642 and rs2032582 variants have been associated with neutropenia from paclitaxel.

    Variant Name:

    ABCB1: 2677G>T/A

    Related Drugs:

    paclitaxel

    Related Diseases:

    Neutropenia

    Evidence:

    PMID:16950614
    

49. rs2032582 at chr7:86998554 in ABCB1
    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.

    Variant Name:

    ABCB1: c.2677G>T/A, mRNA 3095G>T/A, p.Ala893Ser/Thr

    Related Drugs:

    bisantrene, calcein, forskolin, prazosin, verapamil, vinblastine

    Evidence:

    PMID:12065748
    

50. rs2032582 at chr7:86998554 in ABCB1
    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.

    Variant Name:

    ABCB1: c.2677G>T/A, mRNA 3095G>T/A, p.Ala893Ser/Thr

    Related Drugs:

    cyclosporine, digoxin, verapamil, vinblastine

    Evidence:

    PMID:12781336
    

51. rs2032582 at chr7:86998554 in ABCB1
    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.

    Variant Name:

    ABCB1: c.2677G>T/A, mRNA 3095G>T/A, p.Ala893Ser/Thr

    Related Drugs:

    ritonavir

    Evidence:

    PMID:14600574
    

52. rs2032582 at chr7:86998554 in ABCB1
    Haplotypes derived from the SNPs 2677G > T (rs2032582) and 3435C > T (rs1045642) do not influence the pharmacokinetics of tacrolimus in renal transplant patients

    Variant Name:

    ABCB1: c.2677G>T/A, mRNA 3095G>T/A, p.Ala893Ser/Thr

    Related Drugs:

    tacrolimus

    Related Diseases:

    Transplantation

    Evidence:

    PMID:15521904
    

53. rs2032582 at chr7:86998554 in ABCB1
    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

    Variant Name:

    ABCB1:2677G>T/A, mRNA 3095G>T/A, Ala893Ser/Thr

    Related Drugs:

    cyclosporine

    Related Diseases:

    Myasthenia Gravis

    Evidence:

    PMID:18717915
    

54. rs2032582 at chr7:86998554 in ABCB1
    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+.

    Variant Name:

    ABCB1:2677G>T/A, mRNA 3095G>T/A, Ala893Ser/Thr

    Related Drugs:

    rhodamine 123, rifampin, verapamil

    Evidence:

    PMID:12914549
    

55. rs2032582 at chr7:86998554 in ABCB1
    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

    Variant Name:

    ABCB1:2677G>T/A, 3095G>T/A, Ala893Ser/Thr

    Related Drugs:

    atorvastatin

    Related Diseases:

    Coronary Artery Disease, Hypercholesterolemia

    Evidence:

    PMID:18851956
    

56. rs2032582 at chr7:86998554 in ABCB1
    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).

    Variant Name:

    ABCB1:2677G>T/A, mRNA 3095G>T/A, p.Ala893Ser/Thr

    Related Drugs:

    cytarabine, idarubicin

    Related Diseases:

    Leukemia, Myeloid, Acute

    Evidence:

    PMID:16331627
    

57. rs2032582 at chr7:86998554 in ABCB1
    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

    Variant Name:

    ABCB1: c.2677G>T/A, mRNA 3095G>T/A, p.Ala893Ser/Thr; ABCB1*7

    Related Drugs:

    Tipifarnib

    Evidence:

    PMID:15122075
    

58. rs2032582 at chr7:86998554 in ABCB1
    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.

    Variant Name:

    ABCB1: c.2677G>T/A, mRNA 3095G>T/A, p.Ala893Ser/Thr

    Related Drugs:

    cyclosporine, digoxin, verapamil, vinblastine

    Evidence:

    PMID:12781336
    

59. rs2032582 at chr7:86998554 in ABCB1
    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.

    Variant Name:

    ABCB1:2677G>A/T

    Related Drugs:

    doxorubicin

    Related Diseases:

    Breast Neoplasms

    Evidence:

    PMID:18377430
    

60. rs2032582 at chr7:86998554 in ABCB1
    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.

    Variant Name:

    ABCB1:2677G>T/A, mRNA 3095G>T/A, Ala893Ser/Thr

    Related Drugs:

    digoxin, fexofenadine

    Evidence:

    PMID:11503014
    

61. rs2032582 at chr7:86998554 in ABCB1
    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).

    Variant Name:

    ABCB1:2677G>T/A, mRNA 3095G>T/A, Ala893Ser/Thr

    Related Drugs:

    cyclosporine

    Related Diseases:

    Colitis, Ulcerative

    Evidence:

    PMID:17206635
    

62. rs4148739 at chr7:86998985 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.

    Related Drugs:

    amitriptyline, citalopram, paroxetine, venlafaxine

    Related Diseases:

    Depression

    Evidence:

    PMID:18215618
    

63. rs11983225 at chr7:86999456 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.

    Related Drugs:

    amitriptyline, citalopram, paroxetine, venlafaxine

    Related Diseases:

    Depression

    Evidence:

    PMID:18215618
    

64. rs10248420 at chr7:87002922 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.

    Related Drugs:

    amitriptyline, citalopram, paroxetine, venlafaxine

    Related Diseases:

    Depression

    Evidence:

    PMID:18215618
    

65. rs2235040 at chr7:87003686 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.

    Related Drugs:

    amitriptyline, citalopram, paroxetine, venlafaxine

    Related Diseases:

    Depression

    Evidence:

    PMID:18215618
    

66. rs12720067 at chr7:87007292 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.

    Related Drugs:

    amitriptyline, citalopram, paroxetine, venlafaxine

    Related Diseases:

    Depression

    Evidence:

    PMID:18215618
    

67. rs1128503 at chr7:87017537 in ABCB1
    peak blood concentration of cyclosporin A (CsA) was significantly lower in myasthenia gravis patients harboring the 1236 T allele; and trough CsA levels were significantly greater in 1236 TT homozygotes versus CC homozygotes

    Variant Name:

    ABCB1:1236T>C, mRNA 1654T>C, Gly412Gly

    Related Drugs:

    cyclosporine

    Related Diseases:

    Myasthenia Gravis

    Evidence:

    PMID:18717915
    

68. rs1128503 at chr7:87017537 in ABCB1
    Risk or phenotype-associated allele: None. Phenotype: Efflux of P-glycoprotein substrates (verapamil; digoxin; vinblastine; cyclosporin A) in vitro were not significantly affected by combined mutations for rs1128503 (2677G>T/A) and rs1045642 (3435C>T) in LLC-PK1 cell lines. Study size: Triplicate cell assays. Study population/ethnicity: N/A. Significance metric(s): Not significant, p > 0.05. Type of association: FA

    Variant Name:

    ABCB1:2677G>T/A, mRNA 3095G>T/A, Ala893Ser/Thr

    Related Drugs:

    cyclosporine, digoxin, verapamil, vinblastine

    Evidence:

    PMID:12781336
    

69. rs1128503 at chr7:87017537 in ABCB1
    Risk or phenotype-associated allele: rs1128503 TT genotype. Phenotype: Systemic exposure of tipifarnib, based on plasma AUC levels, were 46.5% higher for patients homozygous for ABCB1*8 (3435TT) compared to the CT and CC genotypes. Study size: 28 (16 male). Study population/ethnicity: Caucasian cancer patients, aged 34-75. Significance metric(s): p = 0.047. Type of association: GN; PK

    Variant Name:

    ABCB1: c.1236T>C, mRNA 1654T>C, p.Gly412Gly; ABCB1*8

    Related Drugs:

    Tipifarnib

    Evidence:

    PMID:15122075
    

70. rs1128503 at chr7:87017537 in ABCB1
    Risk or phenotype-associated allele: T Phenotype: Carriers of the T variant of ABCB1:1236C>T had lower Autism Treatment Evaluation Checklist (ATEC) scores, indicating improved symptoms and response to risperidone, than CC homozygotes. Study size: 45 Study population/ethnicity: Children with Autism receiving risperidone Significance metric(s): p = 0.002 Type of association: PD

    Variant Name:

    ABCB1 1236C>T, ABCB1:1236C>T

    Related Drugs:

    risperidone

    Related Diseases:

    Autistic Disorder

    Evidence:

    PMID:19997080
    

71. rs1128503 at chr7:87017537 in ABCB1
    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.

    Variant Name:

    ABCB1:1236C>T

    Related Drugs:

    doxorubicin

    Related Diseases:

    Breast Neoplasms

    Evidence:

    PMID:18377430
    

72. rs2229109 at chr7:87017745 in ABCB1
    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.

    Variant Name:

    ABCB1: c.1199G>A, mRNA 1617G>A, p.Ser400Asn

    Related Drugs:

    bisantrene, calcein, forskolin, prazosin, verapamil, vinblastine

    Evidence:

    PMID:12065748
    

73. rs2235015 at chr7:87037500 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.

    Related Drugs:

    amitriptyline, citalopram, paroxetine, venlafaxine

    Related Diseases:

    Depression

    Evidence:

    PMID:18215618
    

74. rs3789243 at chr7:87058822 in ABCB1
    This variant maybe associated with drug resistance in chinese epilepsy patients. Sample size: 464 chinese epilepsy patients (270 drug responsive, 194 drug resistant).

    Related Drugs:

    carbamazepine, clobazam, clonazepam, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, topiramate, valproic acid, vigabatrin

    Related Diseases:

    Epilepsy

    Evidence:

    PMID:19450124
    

75. rs9282564 at chr7:87067376 in ABCB1
    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.

    Variant Name:

    ABCB1: c.61A>G, mRNA 479A>G, p.Asn21Asp

    Related Drugs:

    bisantrene, calcein, forskolin, prazosin, verapamil, vinblastine

    Evidence:

    PMID:12065748
    

76. rs3213619 at chr7:87068129 in ABCB1
    This variant is in exon 1b of ABCB1 and may be associated with tacrolimus pharmacokinetics in renal transplant recipients. It was also associated with lower ABCB1 mRNA expression and possibly being an useful invasive marker predicting poorly-differentiated colorectal adenocarcinomas and thereby the poor prognosis of the Japanese patients in the study.

    Variant Name:

    ABCB1:T-129C

    Evidence:

    PMID:16819187
    PMID:16906020
    PMID:17548681
    PMID:17635180
    PMID:19285054
    

Non-Curated Annotations ()

1. rs28364274 at chr7:86971587 in ABCB1
   (i) Decreased intracellular calcein levels (increased function), (ii) increased intracellular BODIPy-FL- paclitaxel levels (decreased function), in transfected cells

   Variant Name:

   ABCB1: V1251I

   Related Drugs:

   calcein, paclitaxel

   Evidence:

   PMID:19940846
   

2. rs2229107 at chr7:86976595 in ABCB1
   Increased resistance to daunorubicin, doxorubicin, valinomycin, or actinomycin D in transformed yeast

   Variant Name:

   ABCB: S1141T

   Related Drugs:

   Actinomycines, daunorubicin, doxorubicin, valinomycin

   Evidence:

   PMID:19940846
   

3. rs35730308 at chr7:86976694 in ABCB1
   Decreased resistance to daunorubicin, doxorubicin, valinomycin, or actinomycin D in transformed yeast

   Variant Name:

   ABCB1: W1108R

   Related Drugs:

   Actinomycines, daunorubicin, doxorubicin, valinomycin

   Evidence:

   PMID:19940846
   

4. rs2032582 at chr7:86998554 in ABCB1
   Decreased intracellular calcein levels (increased function) in transfected cells

   Variant Name:

   ABCB1:A893T

   Related Drugs:

   calcein

   Evidence:

   PMID:19940846
   

5. rs2032582 at chr7:86998554 in ABCB1
   Increased intracellular BODIPy-FL- paclitaxel levels (decreased function) in transfected cells

   Variant Name:

   ABCB1: A893S

   Related Drugs:

   paclitaxel

   Evidence:

   PMID:19940846
   

6. rs35023033 at chr7:87012134 in ABCB1
   Increased resistance to daunorubicin, doxorubicin, valinomycin, or actinomycin D in transformed yeast

   Variant Name:

   ABCB1: R669C

   Related Drugs:

   Actinomycines, daunorubicin, doxorubicin, valinomycin

   Evidence:

   PMID:19940846
   

7. rs10276036 at chr7:87018134 in ABCB1
   The AUCs of irinotecan, SN-38, SN-38 glucuronide, and APC are influenced by rs3740066, rs2306283, rs35605, rs10276036, and rs717620 .

   Variant Name:

   ABCB1: IVS9 ¿44a>G

   Related Drugs:

   irinotecan, SN-38

   Evidence:

   PMID:19940846
   

8. rs35810889 at chr7:87052784 in ABCB1
   Increased resistance to daunorubicin, doxorubicin, valinomycin, or actinomycin D in transformed yeast

   Variant Name:

   ABCB1: M89T

   Related Drugs:

   Actinomycines, daunorubicin, doxorubicin, valinomycin

   Evidence:

   PMID:19940846
   

Curated Information

The following genes are in curated knowledge about this gene.

	Gene	Relationship	Evidence
	NR1I2	PK FA	Publications
	NR1I3	PK FA	Publications

Non-Curated Information

A list of non-curated publications that mention this gene along with other genes is available.

PharmGKB Curated Pathways

• Antiplatelet Drug Clopidogrel Pathway (PK)
• Citalopram Pathway (PK)
• Codeine and Morphine Pathway (PK)
• Doxorubicin (Cancer PD)
• Doxorubicin (PK)
• Erlotinib Pathway (PK)
• Etoposide Pathway
• Gefitinib Pathway (PK)
• Imatinib Pathway
• Irinotecan Pathway (Cancer)
• Irinotecan Pathway (liver)
• Methotrexate Pathway
• Proton Pump Inhibitor (PK)
• Statin Pathway (Atorvastatin, Lovastatin and Simvastatin PK)
• Statin Pathway (PK)
• Statin Pathway (Pravastatin PK)
• Taxane Pathway
• Vinca Alkaloids Pathway (PK)
• Warfarin Pathway (PK)

BioCarta Pathways†

• hypoxia and p53 in the cardiovascular system - (BioCarta via Pathway Interaction Database)
• multi-drug resistance factors - (BioCarta via Pathway Interaction Database)

PID Pathways†

• HIF-1-alpha transcription factor network - (Pathway Interaction Database NCI-Nature Curated)

Curated Information

The following drugs are in curated knowledge about this gene.

	Drug Class	Relationship	Evidence
	anthracyclines and related substances		Variants
	antidepressants	PD       GN	Publications
	antineoplastic agents	GN	Publications
	calcium channel blockers	CO    PK    GN	Publications
	corticosteroids	CO          GN	Publications
	farnesyltransferase inhibitors	PK    GN	Publications
	hmg coa reductase inhibitors	CO          GN	Publications
	non-nucleoside reverse transcriptase inhibitors	PD PK	Publications
	nucleosides and nucleotides excl. reverse transcriptase inhibitors	FA	Publications
	pesticides	PD       GN	Publications
	protease inhibitors	PD PK	Publications
	Pyrimidine analogues	CO PD       GN	Publications
	taxanes		Variants
	vitamin d and analogues	PK FA	Publications
	xenobiotics	PK FA GN	Publications

	Drug	Relationship	Evidence
	abacavir	PK	Publications
	acetaminophen	PD PK    GN	Publications
	aldosterone	PK FA	Publications
	alitretinoin	FA	Publications
	amiodarone	FA	Publications
	amitriptyline	PK FA	Publications, Variants
	amlodipine	PK    GN	Publications
	amprenavir	PK FA	Publications
	arsenic trioxide	FA	Publications
	arsenite	PD       GN	Publications
	asparaginase	CO PD PK    GN	Publications
	astemizole	FA	Publications
	atazanavir	PK    GN	Publications
	atorvastatin	PD PK FA GN	Publications, Variants
	azathioprine	CO    PK    GN	Publications
	azithromycin	PK FA GN	Publications
	bepridil	FA	Publications
	bevacizumab	CO PD	Publications
	Biricodar	FA	Publications
	bisantrene		Variants
	bromocriptine	FA	Publications
	Bromperidol	PK	Publications
	budesonide	PK    GN	Publications
	caffeine	PK	Publications
	calcein	FA GN	Publications, Variants
	carbamazepine	CO PD PK FA GN	Publications, Variants
	carboplatin	CO PD PK    GN	Publications, Variants
	carvedilol	FA	Publications
	Celiprolol	PK FA	Publications
	cerivastatin	PD PK	Publications
	chlorambucil	FA	Publications
	chlorpromazine	PK FA	Publications
	cimetidine	PK FA	Publications
	cisplatin	CO       FA GN	Publications, Variants
	citalopram	PK    GN	Publications, Variants
	clarithromycin	FA	Publications
	clobazam		Variants
	clonazepam		Variants
	clopidogrel	CO    PK FA GN	Publications, Variants
	clotrimazole	FA	Publications
	clozapine	CO          GN	Publications
	codeine	PK	Publications
	colchicine	PK FA	Publications
	cyclophosphamide	CO PD PK    GN	Publications
	cyclosporine	CO PD PK FA GN	Publications, Variants
	cytarabine	CO PD PK    GN	Publications, Variants
	dactinomycin	PK FA	Publications
	daunorubicin	CO PD PK FA GN	Publications
	dexamethasone	CO PD PK FA GN	Publications, Variants
	dextromethorphan	PK	Publications
	dicloxacillin		Variants
	digoxin	CO PD PK FA GN	Publications, Variants
	diltiazem	PD PK FA	Publications
	dipyridamole	FA	Publications
	disulfiram	FA	Publications
	docetaxel	CO    PK FA GN	Publications, Variants
	domperidone	PK FA	Publications
	doxycycline	PK FA	Publications
	efavirenz	PK    GN	Publications, Variants
	Elacridar	FA	Publications
	epirubicin	CO       FA GN	Publications, Variants
	erlotinib	PK FA GN	Publications
	erythromycin	PD PK FA	Publications
	esomeprazole	FA	Publications
	etoposide	CO PD PK FA GN	Publications, Variants
	ezetimibe	PD PK    GN	Publications
	felodipine	FA	Publications
	fentanyl	PD       GN	Publications
	fexofenadine	PK FA	Publications, Variants
	fluconazole	PK FA GN	Publications
	fluorouracil	CO PD PK FA GN	Publications
	fluoxetine	PD    FA	Publications
	fluvastatin	PD PK	Publications
	folic acid	CO       FA GN	Publications
	forskolin		Variants
	gabapentin	PK FA GN	Publications, Variants
	gefitinib	PD PK FA GN	Publications
	gemcitabine	FA	Publications
	gemfibrozil	PD PK	Publications
	glibenclamide	PK FA	Publications
	granisetron	PD       GN	Publications
	grapefruit juice	PK FA	Publications
	heroin	PD PK    GN	Publications
	hydrocortisone	PK FA	Publications
	hydroxyurea	FA	Publications
	ibutilide	PK    GN	Publications
	idarubicin		Variants
	imatinib	CO    PK FA GN	Publications
	indinavir	PK FA	Publications
	insulin glargine recombinant	FA	Publications
	insulin lyspro recombinant	FA	Publications
	insulin recombinant	FA	Publications
	insulin, porcine	FA	Publications
	insulin-aspart	FA	Publications
	insulin-detemir	FA	Publications
	insulin-glargine	FA	Publications
	insulin-glulisine	FA	Publications
	insulin-lispro	FA	Publications
	irinotecan	CO PD PK FA GN	Publications
	itraconazole	PD PK FA	Publications
	ivermectin	PK FA	Publications
	ketoconazole	PD PK FA	Publications
	lamotrigine	PK FA GN	Publications, Variants
	lansoprazole	PD PK FA	Publications, Variants
	leucovorin	CO PD PK    GN	Publications
	levetiracetam	PK FA GN	Publications, Variants
	levofloxacin	PK FA	Publications
	levothyroxine	PK	Publications
	loperamide	PK FA	Publications, Variants
	lopinavir	GN	Publications, Variants
	losartan	PK FA	Publications
	lovastatin	PD PK	Publications
	mefloquine	PD       GN	Publications
	melphalan	PK	Publications
	mercaptopurine	CO PD PK FA GN	Publications
	metformin	PK FA	Publications
	methadone	PD PK    GN	Publications
	methotrexate	CO PD PK FA GN	Publications, Variants
	methylprednisolone	PK FA	Publications
	midazolam	PK FA GN	Publications
	mitomycin	PK FA	Publications
	mitoxantrone	CO    PK FA GN	Publications
	morphine	PD PK FA GN	Publications
	mycophenolate mofetil	CO          GN	Publications
	nelfinavir	PK FA GN	Publications, Variants
	nevirapine	CO    PK    GN	Publications, Variants
	nicardipine	FA	Publications
	nifedipine	FA	Publications
	nitrendipine	FA	Publications
	nortriptyline	PD	Publications, Variants
	OC144-093	FA	Publications
	olanzapine	CO PD       GN	Publications
	omeprazole	PK FA	Publications
	ondansetron	PK FA	Publications
	oseltamivir	FA	Publications
	oxaliplatin	CO PD	Publications
	oxycodone	GN	Publications
	paclitaxel	CO    PK FA GN	Publications, Variants
	pantoprazole	PK FA	Publications
	paroxetine	FA	Publications, Variants
	pentazocine	PK FA	Publications
	phenobarbital	PK FA GN	Publications, Variants
	phenytoin	CO PD PK FA GN	Publications, Variants
	pitavastatin	PD PK	Publications
	pravastatin	PD PK	Publications
	prazosin		Variants
	prednisone	CO PD PK    GN	Publications, Variants
	probenecid	FA	Publications
	progesterone	FA	Publications
	promazine	FA	Publications
	propafenone	FA	Publications
	propranolol	PK	Publications
	quinidine	PK FA	Publications
	quinine	FA	Publications
	R101933	FA	Publications
	ranitidine	PK FA	Publications
	reserpine	FA	Publications
	rhodamine 123		Variants
	rifampin	PD PK FA GN	Publications, Variants
	risperidone	CO PD PK    GN	Publications, Variants
	ritonavir	PD PK FA GN	Publications, Variants
	rosiglitazone	PK FA	Publications
	rosuvastatin	PD PK	Publications
	saquinavir	PK FA GN	Publications
	sertraline	FA	Publications
	simvastatin	CO PD PK    GN	Publications
	sirolimus	PD PK FA GN	Publications
	SJG-136	PK    GN	Publications
	SN-38	FA	Publications
	sparfloxacin	PK FA	Publications
	st. john's wort	FA	Publications
	tacrolimus	CO PD PK FA GN	Publications, Variants
	talinolol	PD PK FA GN	Publications
	tamoxifen	FA	Publications
	teniposide	PK FA	Publications
	terfenadine	PK FA	Publications
	testosterone		Publications
	tetrabenazine	FA	Publications
	tetracycline	PK FA	Publications
	thioguanine	FA	Publications
	Tipifarnib	PK    GN	Publications, Variants
	tipranavir	PK FA	Publications
	topiramate		Variants
	topotecan	PK FA	Publications
	tretinoin	FA	Publications
	valinomycin	FA	Publications
	valproic acid	PK FA GN	Publications, Variants
	Valspodar	PK FA	Publications
	vecuronium	PK FA	Publications
	venlafaxine		Variants
	verapamil	PD PK FA GN	Publications, Variants
	vigabatrin		Variants
	vinblastine	PK FA GN	Publications, Variants
	vincristine	CO PD PK FA GN	Publications, Variants
	warfarin	CO    PK    GN	Publications
	XR9051	FA	Publications
	yohimbine	FA	Publications
	Zosuquidar	PK FA	Publications

Non-Curated Information

A list of non-curated publications that mention this gene along with other drugs is available.

Curated Information

The following diseases are in curated knowledge about this gene.

	Disease	Relationship	Evidence
	Adenocarcinoma	PD    FA	Publications
	Anemia	PK    GN	Publications
	Anemia, Sickle Cell	PD PK    GN	Publications
	Arrhythmias, Cardiac	CO PD PK    GN	Publications
	Arthritis, Rheumatoid	CO PD PK    GN	Publications, Variants
	Atrial Fibrillation	PK    GN	Publications
	Autism Spectrum Disorder	PD       GN	Publications
	Autistic Disorder		Variants
	Bipolar Disorder	PK    GN	Publications
	Blood Coagulation Disorders	CO          GN	Publications
	Brain Neoplasms	PD    FA	Publications
	Carcinoma		Variants
	Carcinoma, Non-Small-Cell Lung	CO PD PK    GN	Publications
	Carcinoma, Renal Cell	FA GN	Publications
	Cardiovascular Diseases		Variants
	Carotid Artery Diseases	PD PK	Publications
	Colitis, Ulcerative	CO          GN	Publications, Variants
	Colonic Neoplasms	PD    FA	Publications
	Colorectal Neoplasms	CO PD PK FA GN	Publications
	Coronary Artery Disease	PD PK FA GN	Publications, Variants
	Crohn Disease	CO          GN	Publications
	Death, Sudden, Cardiac	CO          GN	Publications, Variants
	Depression	CO PD PK    GN	Publications, Variants
	Depressive Disorder		Variants
	Depressive Disorder, Major	PD	Publications, Variants
	Diabetes Mellitus, Type 2	PK FA	Publications
	Drug interaction with drug	PK FA	Publications
	Drug Resistance	FA	Publications, Variants
	Drug Toxicity	CO PD PK    GN	Publications, Variants
	Epilepsy	CO PD PK FA GN	Publications, Variants
	Gastroesophageal Reflux		Variants
	Gastrointestinal Stromal Tumors	PK    GN	Publications
	Gingival Hyperplasia	CO    PK    GN	Publications
	Graft vs Host Disease	CO PD PK	Publications
	Head and Neck Neoplasms	CO          GN	Publications
	Heart Failure	CO PD PK    GN	Publications
	HIV	CO    PK    GN	Publications, Variants
	HIV Infections	CO PD PK    GN	Publications, Variants
	Hypercholesterolemia	PD    FA GN	Publications, Variants
	Hyperlipidemias	CO          GN	Publications
	Hypertension	CO          GN	Publications
	Hypotension		Variants
	Hypotension, Orthostatic		Variants
	Hypoxia-Ischemia, Brain	CO          GN	Publications
	Inflammatory Bowel Diseases	PK    GN	Publications
	Influenza, Human	FA	Publications
	Kidney Neoplasms		Publications
	Leukemia	FA	Publications
	Leukemia, Myelogenous, Chronic, BCR-ABL Positive	CO    PK FA GN	Publications
	Leukemia, Myeloid	PK    GN	Publications
	Leukemia, Myeloid, Acute	CO    PK FA GN	Publications, Variants
	Leukopenia	PK    GN	Publications
	liver transplantation	CO    PK FA GN	Publications, Variants
	Lung Neoplasms	CO          GN	Publications
	Lymphoma	PD    FA	Publications
	Malaria	PD       GN	Publications
	Melanoma	PD    FA	Publications
	Metabolic Diseases	PD       GN	Publications
	Metabolic Syndrome X	PD       GN	Publications
	Multiple Myeloma	CO          GN	Publications, Variants
	Myasthenia Gravis		Variants
	Myocardial Infarction	CO          GN	Publications, Variants
	Nephritis, Interstitial	CO          GN	Publications
	Nephrotic Syndrome	CO          GN	Publications
	Neurotoxicity Syndromes	CO    PK    GN	Publications
	Neutropenia	CO PD PK    GN	Publications, Variants
	Opioid-Related Disorders	PD PK    GN	Publications
	Organ Transplantation	CO    PK    GN	Publications, Variants
	Osteosarcoma	FA	Publications
	Ovarian Neoplasms	PD PK FA GN	Publications, Variants
	Pain	PD PK    GN	Publications
	Parkinson Disease	PD       GN	Publications
	Peripheral Nervous System Diseases	CO    PK    GN	Publications
	Prostatic Neoplasms	PD    FA	Publications
	Psychotic Disorders	CO          GN	Publications
	Rectal Neoplasms	CO PD       GN	Publications
	Rhabdomyolysis	PD PK	Publications
	Schizophrenia	CO PD       GN	Publications
	Stroke	CO          GN	Publications, Variants
	Thrombocytopenia	PK    GN	Publications
	Transplantation	CO PD PK    GN	Publications, Variants
	Vomiting	PD       GN	Publications