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

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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.

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Acknowledgments

The authors would like to thank Sandra Deslouches for expert technical assistance. This work is supported by University of Pittsburgh School of Medicine Clinical Scientist Training Program (JLC); NINDS R01 NS069247 (RSBC, PEE), P50 NS30318 (DOO, AMP, YPC, PMK, RSBC); NICHD T32 HD40686 (AAS); NCATS KL2 TR000146 (PEE); and NINR R01 NR008424 (YPC).

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Correspondence to Robert S. B. Clark.

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Cousar, J.L., Conley, Y.P., Willyerd, F.A. et al. Influence of ATP-Binding Cassette Polymorphisms on Neurological Outcome After Traumatic Brain Injury. Neurocrit Care 19, 192–198 (2013). https://doi.org/10.1007/s12028-013-9881-7

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