Influence of ATP-Binding Cassette Polymorphisms on Neurological Outcome After Traumatic Brain Injury

Abstract

Background As important mediators of solute transport at the blood–brain and blood–cerebrospinal fluid barriers, ATP-binding cassette (ABC) transporters (including ABCB1, ABCC1, and ABCC2), impact the bioavailability of drugs and endogenous substrates in the brain. While several ABCB1, ABCC1, and ABCC2 single nucleotide polymorphisms (SNPs) have been identified, their impact on outcome after traumatic brain injury (TBI) is unknown. Hypothesis ABCB1, ABCC1, and ABCC2 SNPs are associated with Glasgow Outcome Scale (GOS) score after TBI. Methods DNA samples from 305 adult patients with severe TBI (Glasgow Coma Scale, GCS score ≤ 8) were genotyped for tagging SNPs of ABCB1 (rs1045642; rs1128503), ABCC1 (rs212093; rs35621; rs4148382), and ABCC2 (rs2273697). For each SNP, patients were dichotomized based on presence of variant allele for multivariate analysis to determine associations with GOS assigned at 6 months adjusting for GCS, Injury Severity score, age, and patient sex. Results For ABCB1 rs1045642, patients homozygous for the T allele were less likely to be assigned poor outcome versus those possessing the C allele [CT/CC; odds of unfavorable GOS = 0.71(0.55−0.92)]. For ABCC1 rs4148382, patients homozygous for the G allele were less likely to be assigned poor outcome versus those possessing the A allele [AG/AA; odds of unfavorable GOS = 0.73(0.55−0.98)]. Conclusions In this single-center study, patients homozygous for the T allele of ABCB1 rs1045642 or the G allele of ABCC1 rs4148382 were found to have better outcome after severe TBI. Further study is necessary to replicate these very preliminary findings and to determine whether these associations are due to central nervous system bioavailability of ABC transporter drug substrates commonly used in the management of TBI, brain efflux of endogenous solutes, or both.

Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans

“…30,31 In addition, a single nucleotide polymorphism (SNP) for ABCC1 has been shown to be associated with neurological outcome after TBI, 32 although whether this represents a gain or loss of function (or neither) SNP is unknown.…”

Effect of single nucleotide polymorphisms in the ATP-binding cassette B1 gene on the clini­cal outcome of traumatic brain injury

“…Cousar et al (2013) reported that the C allele of ABCB1 C3435T was associated with a better outcome of TBI patients compared with those carrying the T allele. However, Seven et al (2014) reported that the MDR1 C3435T and G2677T/A polymorphisms were not associated with antiepileptic drug resistance in Turkish epileptic patients.…”

“…Several studies have investigated the association between ABCB1 polymorphisms and neurological disease (Liang et al, 2013;Cousar et al, 2013;Emich-Widera et al, 2013;Seven et al, 2014). Cousar et al (2013) reported that the C allele of ABCB1 C3435T was associated with a better outcome of TBI patients compared with those carrying the T allele.…”

Tackling the Challenges of Clinical Trials for Severe Traumatic Brain Injury in Children

“…For example, polymorphisms of the antiexcitotoxic adenosine A1 receptor are strongly associated with the development of posttraumatic seizures in adults with TBI and may help guide anticonvulsant therapy (19). Similarly, adenosine triphosphate (ATP)-binding cassette polymorphisms are associated with outcome after TBI in children (20). ATP-binding cassette proteins are drug transporters at the blood-brain barrier and impact dosing and efficacy.…”