rs2032583 is a SNP in the ABCB1 gene (also known as the MDR1 gene), which encodes a protein that transports certain molecules across the blood-brain barrier. SNPs in ABCB1 may thus influence the intracerebral concentrations of certain drugs and their efficacy or potential for adverse side effects. Clinical studies on antidepressant drug dosage, plasma medication levels and treatment outcome suggest monotonic associations for tricyclic antidepressant drugs [PMID 3881999] and threshold models or higher order relationships for selective serotonin reuptake inhibitors [PMID 28648553] and newer antidepressant drugs [PMID 25188033],[PMID 30611837]. However, the link between the increased brain concentrations of antidepressants and a clinically significant response is to be confirmed.
A study of ~400 of German psychiatric inpatients with depression conducted in 2007 by Uhr et al 10.1016/j.neuron.2007.11.017 found that rs2032583(C) carriers treated with ABCB1 substrates had better chances on remission. However,could not be reproduced in a large (~900) -trial with outpatient with major depression treated with the ABCB1 substrate citalopram (STAR-D study, level 1). According to a recent meta analysis [PMID 25847751], the significant association of antidepressant treatment outcome among all studies with this SNP becomes insignificant after Bonferroni correction for multiple comparisons. However, the association remained significant after Bonferroni-correction in a subgroup-analysis of all inpatients.
rs2032583 is one of 9 SNPs found within a tight linkage block (r2 >= 0.8 ) such that the minor allele at any one of them predicts (with ~80%+ accuracy) that the other SNPs will also be the minor allele. The 9 SNPs in the linkage block identified are 10.1016/j.neuron.2007.11.017:
In contrast, [PMID 25487678] reported on two SNPs from the block, rs2032583 and rs2235040, that these SNPs are close to Hardy–Weinberg equilibrium (not inherited together) in their 81% white population. Other results from [PMID 25487678] are unreliable because they picked an antidepressant sertraline, which is, likely, not an ABCB1 substrate [PMID 27918249], as an example of an ABCB1 substrate and treated a majority of patients in the study with it.
[PMID 15197162] Identifying candidate causal variants responsible for altered activity of the ABCB1 multidrug resistance gene.
[PMID 18424454] ABCB1 (MDR1) genetic variants are associated with methadone doses required for effective treatment of heroin dependence.
[PMID 19844206] Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans.
[PMID 21172166] Pharmacogenetics of antidepressant response.
[PMID 21827404] The clinical impact of ABCB1 polymorphisms on the treatment of psychiatric diseases.
[PMID 21987299] Associations between variants in the ABCB1 (MDR1) gene and corticosteroid dependence in children with Crohn's disease.
[PMID 22641028] ABCB1 gene variants influence tolerance to selective serotonin reuptake inhibitors in a large sample of Dutch cases with major depressive disorder.
[PMID 22672924] Polymorphisms of the drug transporter gene ABCB1 predict side effects of treatment with cabergoline in patients with PRL adenomas
[PMID 23093106] Detection of frequent ABCB1 polymorphisms by high-resolution melting curve analysis and their effect on breast carcinoma prognosis
[PMID 3881999] Tricyclic antidepressants--blood level measurements and clinical outcome: an APA Task Force report. Task Force on the Use of Laboratory Tests in Psychiatry
[PMID 28648553] Escitalopram plasma levels and antidepressant response
[PMID 25188033] Venlafaxine and O-desmethylvenlafaxine concentrations in plasma and cerebrospinal fluid
[PMID 30611837] Duloxetine plasma level and antidepressant response