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

ABCC8 encodes sulfonylurea receptor 1, a key regulatory protein of cerebral oedema in many neurological disorders including traumatic brain injury (TBI). Sulfonylurea-receptor-1 inhibition has been promising in ameliorating cerebral oedema in clinical trials. We evaluated whether ABCC8 tag single-nucleotide polymorphisms predicted oedema and outcome in TBI. DNA was extracted from 485 prospectively enrolled patients with severe TBI. 410 were analysed after quality control. ABCC8 tag single-nucleotide polymorphisms (SNPs) were identified (Hapmap, r2>0.8, minor-allele frequency >0.20) and sequenced (iPlex-Gold, MassArray). Outcomes included radiographic oedema, intracranial pressure (ICP) and 3-month Glasgow Outcome Scale (GOS) score. Proxy SNPs, spatial modelling, amino acid topology and functional predictions were determined using established software programs. Wild-type rs7105832 and rs2237982 alleles and genotypes were associated with lower average ICP (β=-2.91, p=0.001; β=-2.28, p=0.003) and decreased radiographic oedema (OR 0.42, p=0.012; OR 0.52, p=0.017). Wild-type rs2237982 also increased favourable 3-month GOS (OR 2.45, p=0.006); this was partially mediated by oedema (p=0.03). Different polymorphisms predicted 3-month outcome: variant rs11024286 increased (OR 1.84, p=0.006) and wild-type rs4148622 decreased (OR 0.40, p=0.01) the odds of favourable outcome. Significant tag and concordant proxy SNPs regionally span introns/exons 2-15 of the 39-exon gene. This study identifies four ABCC8 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.

Jha RM ，Koleck TA ，Puccio AM ，Okonkwo DO ，Park SY ，Zusman BE ，Clark RSB ，Shutter LA ，Wallisch JS ，Empey PE ，Kochanek PM ，Conley YP ... -  《-》

Downstream TRPM4 Polymorphisms Are Associated with Intracranial Hypertension and Statistically Interact with ABCC8 Polymorphisms in a Prospective Cohort of Severe Traumatic Brain Injury.

Jha RM ，Desai SM ，Zusman BE ，Koleck TA ，Puccio AM ，Okonkwo DO ，Park SY ，Shutter LA ，Kochanek PM ，Conley YP ... -  《-》

ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI.

Jha RM ，Puccio AM ，Okonkwo DO ，Zusman BE ，Park SY ，Wallisch J ，Empey PE ，Shutter LA ，Clark RS ，Kochanek PM ，Conley YP ... -  《-》

Genetic Variants Associated With Intraparenchymal Hemorrhage Progression After Traumatic Brain Injury.

Jha RM ，Zusman BE ，Puccio AM ，Okonkwo DO ，Pease M ，Desai SM ，Leach M ，Conley YP ，Kochanek PM ... -  《JAMA Network Open》

Intracranial Pressure Trajectories: A Novel Approach to Informing Severe Traumatic Brain Injury Phenotypes.

Jha RM ，Elmer J ，Zusman BE ，Desai S ，Puccio AM ，Okonkwo DO ，Park SY ，Shutter LA ，Wallisch JS ，Conley YP ，Kochanek PM ... -  《-》