rs1045642(T;T)

altered drug metabolism and bioavailability; moderately increased risk for certain cancers

Is a	genotype
of	rs1045642
Gene	ABCB1
Chromosome	7
Position	87,509,329
mentioned	by

Magnitude

3

Repute

Bad

Geno	Mag	Summary
(C;C)	1	increased risk of cannabis dependence, lower (normal) cancer risk
(C;T)	2	Slower metaboliser for some drugs
(T;T)	3	altered drug metabolism and bioavailability; moderately increased risk for certain cancers

This is the homozygous variant of C3435T, on the gene encoding P-glycoprotein (called MDR1 or ABCB1). P-glycoprotein is a protein involved in pumping foreign substances out of cells. It mainly affects areas of the body that have a barrier or excretory function: blood-tissue barrier, the gastrointestinal tract, liver and kidney. Poor functioning of this cellular defense mechanism can affect elimination of carcinogens and movement of drugs in the system.

Drug Treatment Response & Toxicity

ABCB1 polymorphism as prognostic factor in breast cancer patients treated with docetaxel and doxorubicin neoadjuvant chemotherapy. (2014). Among 216 patients, those with the 3435TT genotype had a longer overall survival than CC/CT. ABCB1 3435TT genotype had a higher blood concentration than CC/CT for docetaxel. These higher values in the C3435TT were associated with increased toxicities of neutropenia (low count of a type of white blood cell) and diarrhea. This study showed that the genetic polymorphism of ABCB1 C3435T might be associated with a longer overall survival. Our results also suggest that the prediction of docetaxel toxicity might be possible for C3435T polymorphism.

Effect of polymorphisms within methotrexate pathway genes on methotrexate toxicity and plasma levels in adults with hematological malignancies. (2014). [1] Individuals respond differently to the cancer drug methotrexate (MTX) and experience differences in toxicity. The authors evaluated the impact of SNPs within the MTX pathway genes on MTX-induced toxicity and MTX plasma levels at 48 hours following treatment in Asian adults with acute lymphoblastic leukemia or non-Hodgkin lymphoma. Patients with MTHFR C677T and ABCB1 C3435T polymorphisms appear to have significantly higher MTX plasma concentrations (p < 0.05). Hepatic toxicity was associated with SLC19A1 G80A and ABCB1 C3435T.

SNPWatch: Variants Associated with Clopidogrel Efficacy and Stent Thrombosis. [2] 2.6 times higher odds of developing early stent thrombosis in patients with a stent taking the anti-clotting drug Clopidogrel, due to slow metabolism of Clopidogrel.

With the increasing incidence of coronary artery disease, knowledge of variations in anticoagulant metabolism may have in impact on drug therapy. This is particularly important in those undergoing stent placement. Variants in the CYP2C19 gene affect how people metabolize clopidogrel and those that those who metabolize clopidogrel faster were less likely to develop early stent thrombosis.

ABCB1 gene encodes a protein that effects clopidogrel absorption; rs individuals with the AA genotype at rs1045642 in the ABCB1 gene had 2.6 times higher odds of developing early stent thrombosis over individuals with the AG or GG genotypes. [PMID 22028352]

ABCB1 C3435T Polymorphism and Response to Clopidogrel Treatment in Coronary Artery Disease (CAD) Patients: A Meta-Analysis (2012). The C3435T genotype influences the impaired function of P-glycoprotein which can hinder the absorption of clopidogrel.

ABCB1 polymorphism predicts escitalopram dose needed for remission in major depression. (2012). [3] The study was based on the reasoning that polymorphisms of ABCB1 may influence central nervous system bioavailability of antidepressants. Single-nucleotide polymorphisms (SNPs) at rs1045642 (C3435T) of ABCB1 have been associated with efflux pump efficiency. Results: People with TT genotype of C3435T required significantly less medication (escitalopram or venlafaxine) to achieve remission.

Cancer

The association between polymorphisms in the MDR1 gene and risk of cancer: a systematic review and pooled analysis of 52 case–control studies. (2013). [4] This meta-analysis suggests that the 3435C > T polymorphism is associated with increased cancer risk; however, when stratified by cancer type, the only cancer showing a statistically significant increase was acute lymphoblastic leukemia (ALL).

MDR1 (C3435T) polymorphism: relation to the risk of breast cancer and therapeutic outcome. (2010).[5] Statistically significant higher C3435T allele frequency found in breast cancer patients (n=221) than in controls (n=113), implying slight increase in risk. Poorer therapeutic outcome after chemotherapy and shorter time to progression after anthracycline-based chemotherapy was observed in TT homozygotes.

Alzheimer's Disease

Blood–brain barrier P-glycoprotein function in healthy subjects and Alzheimer's disease patients: effect of polymorphisms in the ABCB1 gene.(2012). [6] Single-nucleotide polymorphisms in ... C3435T are related to changes in blood-brain barrier P-glycoprotein function in Alzheimer's patients, but not in healthy controls. In Alzheimer's patients, genetic variations in ABCB1 might contribute to the progression of amyloid-beta deposition in the brain.

Major Depressive Disorder

Association between the functional polymorphism (C3435T) of the gene encoding P-glycoprotein (ABCB1) and major depressive disorder in the Japanese population. (2012). [7] Results suggest that the T3435 allele or carrying two copies of this allele confers slightly increased susceptibility to MDD in the Japanese population.