Regionally clustered ABCC8 polymorphisms in a prospective cohort predict cerebral oedema and outcome in severe traumatic brain injury

Abstract

This study identifies four tag SNPs associated with cerebral oedema and/or outcome in TBI, tagging a region including 33 polymorphisms. In polymorphisms predictive of oedema, variant alleles/genotypes confer increased risk. Different variant polymorphisms were associated with favourable outcome, potentially suggesting distinct mechanisms. Significant polymorphisms spatially clustered flanking exons encoding the sulfonylurea receptor site and transmembrane domain 0/loop 0 (juxtaposing the channel pore/binding site). This, if validated, may help build a foundation for developing future strategies that may guide individualised care, treatment response, prognosis and patient selection for clinical trials.

Neuroprotective effects of FK866 against traumatic brain injury: Involvement of p38/ERK pathway

“…TBI refers to the impairment of brain function resulting from an external force such as impact or penetration 20 . Brain edema following TBI is an important factor which contributes to the evolution of brain injury and is associated with significant morbidity and mortality 21,22 . It is classified as vasogenic or cytotoxic edema according to BBB disruption or dysfunction of cellular ionic pumps.…”

A Precision Medicine Approach to Cerebral Edema and Intracranial Hypertension after Severe Traumatic Brain Injury: Quo Vadis?

“…Similar to other biomarkers where longitudinal trajectories appear relevant (glutamate, Vascular endothelial growth factor (VEGF), MMP-9), no patients with declining Sur1 levels between 48 and 72 h had any episodes of intracranial hypertension. Spatially clustered ABCC8 (encoding Sur1) polymorphisms contained within a region of DNA encoding the Sur1-receptor site and Trpm4-pore interface have been reported to predict measures of cerebral edema (radiographic, mean/peak ICP, ICP trajectories) and outcome after severe TBI [30, 200, 201]. In the same cohort, clustered TRPM4 polymorphisms (contained within a region of DNA encoding the channel pore) also predicted intracranial hypertension after TBI and had important interactions with ABCC8 polymorphisms [202].…”

“…With the advent of precision medicine, there is an increasing recognition of the likely inadequacy of a “one-size -fits-all” approach, particularly in a heterogenous disease like TBI [1•, 24•, 25]. Advances in research increasingly suggest the potential benefits of incorporating mechanistic endophenotypes in the care of TBI patients, including biomarkers, genetic information, radiographic nuances, and advanced neuromonitoring [14, 25-30]. Although this review discusses current monitoring and management of cerebral edema in TBI, the primary focus is on how translational strategies are evolving towards targeting molecular processes and individualizing patient-care.…”

“Take a Number”—Precision Monitoring Directs Precision Therapy

“…We seek to define the patients most likely to swell, and those who may benefit most from specific therapies targeting brain edema. We have been interested in augmenting conventional monitoring with specific edema-linked CSF biomarkers [20], along with edema-relevant genotyping [21][22][23]. We also recently explored the use of trajectory analysis of ICP with the hope of ultimately rapidly defining those who may benefit most from specific targeted interventions to block brain swelling [24].…”

“…Such an approach should also be developed to leverage the recently completed ADAPT trial in 1000 pediatric severe TBI cases with ICP-directed therapy [33]. Such paradigms might also likely benefit from biomarker and genetic data, and germane to ICP-directed therapy, specifically from biomarkers and geneticslinked to brain edema [20][21][22][23]. Studies such as "BOOST III" inquiring whether adding therapies targeting additional "thresholds, " such as for PbO 2 [34], or more recent approaches in development to continuously assess brain compliance, refining the classic vision and approach of Anthony Marmarou [35][36][37], are also welcome steps forward.…”