DownstreamTRPM4Polymorphisms Are Associated with Intracranial Hypertension and Statistically Interact withABCC8Polymorphisms in a Prospective Cohort of Severe Traumatic Brain Injury

Abstract

Sulfonylurea-receptor-1(SUR1) and its associated transient-receptor-potential cation channel subfamily-M (TRPM4) channel are key contributors to cerebral edema and intracranial hypertension in traumatic brain injury (TBI) and other neurological disorders. Channel inhibition by glyburide is clinically promising. ABCC8 (encoding SUR1) singlenucleotide polymorphisms (SNPs) are reported as predictors of raised intracranial pressure (ICP). This project evaluated whether TRPM4 SNPs predicted ICP and TBI outcome. DNA was extracted from 435 consecutively enrolled severe TBI patients. Without a priori selection, all 11 TRPM4 SNPs available on the multiplex platform (Illumina:Human-Core-Exome v1.0) were genotyped spanning the 25 exon gene. A total of 385 patients were analyzed after quality control. Outcomes included ICP and 6 month Glasgow Outcome Scale (GOS) score. Proxy SNPs, spatial modeling, and functional predictions were determined using established software programs. rs8104571 (intron-20) and rs150391806 (exon-24) were predictors of ICP. rs8104571 heterozygotes predicted higher average ICP (b = 10.3 mm Hg, p = 0.00000029), peak ICP (b = 19.6 mm Hg, p = 0.0007), and proportion ICP >25 mm Hg (b = 0.16 p = 0.004). rs150391806 heterozygotes had higher mean (b = 7.2 mm Hg, p = 0.042) and peak (b = 28.9 mm Hg, p = 0.0015) ICPs. rs8104571, rs150391806, and 34 associated proxy SNPs in linkage-disequilibrium clustered downstream. This region encodes TRPM4's channel pore and a region postulated to juxtapose SUR1 sequences encoded by an ABCC8 DNA segment containing previously identified relevant SNPs. There was an interaction effect on ICP between rs8104571 and a cluster of predictive ABCC8 SNPs (rs2237982, rs2283261, rs11024286). Although not significant in univariable or a basic multivariable model, in an expanded model additionally accounting for injury pattern, computed tomographic (CT) appearance, and intracranial hypertension, heterozygous rs8104571 was associated with favorable 6 month GOS (odds ratio [OR] = 16.7, p = 0.007951). This trend persisted in a survivor-only subcohort (OR = 20.67, p = 0.0168). In this cohort, two TRPM4 SNPs predicted increased ICP with large effect sizes. Both clustered downstream, spanning a region encoding the channel pore and interacting with SUR1. If validated, this may guide risk stratification and eventually inform treatment-responder classification for SUR1-TRPM4 inhibition in TBI. Larger studies are warranted.

Role of Sulfonylurea Receptor 1 and Glibenclamide in Traumatic Brain Injury: A Review of the Evidence

“…Targeted investigations into the impact of ABCC8 and TRPM4 genetic variation on cerebral edema, intracranial hypertension, and outcome after TBI have been performed in 385-485 patients with severe TBI from a single-center [28,[122][123][124]. Genotyped ABCC8 single nucleotide polymorphisms (SNPs) were distributed across the length of the gene with good coverage ( Figure 5A) [122,123].…”

CT‐Based Classification of Acute Cerebral Edema: Association with Intracranial Pressure and Outcome

“…3 Research on factors contributing to cerebral edema use ICP as proxy. 10 The proposed CT-based classification of cerebral edema could be proven as a valid and feasible method for quantification of cerebral edema after various acute cerebral lesions. CT-based extent of edema significantly correlated with simultaneously measured ICP in focal and global brain edema, independent of the type and extension of acute cerebral lesion.…”

Toward a Global and Reproducible Science for Brain Imaging in Neurotrauma: The ENIGMA Adult Moderate/Severe Traumatic Brain Injury Working Group

“…Much existing literature has focused on the impact of genetics in mild injury (McFayden et al, 2019;Nielson et al, 2017; or on global clinical outcome (Conley et al, 2014;Dardiotis et al, 2014;Failla, Kumar, et al, 2015). However, (other) reports in msTBI have explored the relationships between genetics (particularly single nucleotide polymorphisms) and more granular pathophysiology-based outcomes such as cognition (Ariza et al, 2006;Failla, Myrga, et al, 2015;Isoniemi et al, 2006;Koponen et al, 2004;Krueger et al, 2011;Markos et al, 2017;McFadyen et al, 2019;Nicoll et al, 1995;Amy K. Wagner et al, 2012), seizures (Darrah et al, 2013;Diamond et al, 2015;Diaz-Arrastia et al, 2003;Ritter, Kammerer, Brooks, Conley, & Wagner, 2016;Wagner et al, 2010;Wang et al, 2017), cerebral autoregulation and blood flow Robertson et al, 2011), cerebral edema (Jha et al, 2019(Jha et al, , 2018(Jha et al, , 2017, and contusion expansion (Hadjigeorgiou et al, 2005;Liaquat et al, 2002). While many of these genetic association analyses have used neuroimaging metrics, the more common use of structural and functional neuroimaging as endophenotypes of outcome (Coughlin et al, 2017(Coughlin et al, , 2015De Simoni et al, 2016;Hong et al, 2014;Lutkenhoff et al, 2015;Newcombe et al, , 2013Schnakers et al, 2019;Scott et al, 2016;…”