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

Journal of neurotrauma, 2019-06, Vol.36 (11), p.1804-1817 [Peer Reviewed Journal]

Copyright 2019, Mary Ann Liebert, Inc., publishers ;Copyright 2019, Mary Ann Liebert, Inc., publishers 2019 ;ISSN: 0897-7151 ;EISSN: 1557-9042 ;DOI: 10.1089/neu.2018.6124 ;PMID: 30484364

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Title:
Downstream TRPM4 Polymorphisms Are Associated with Intracranial Hypertension and Statistically Interact with ABCC8 Polymorphisms in a Prospective Cohort of Severe Traumatic Brain Injury
Author: Jha, Ruchira M ; Desai, Shashvat M ; Zusman, Benjamin E ; Koleck, Theresa A ; Puccio, Ava M ; Okonkwo, David O ; Park, Seo-Young ; Shutter, Lori A ; Kochanek, Patrick M ; Conley, Yvette P
Subjects: Adolescent ; Adult ; Aged ; Brain Edema - genetics ; Brain Injuries, Traumatic - complications ; Brain research ; Clinical trials ; Computed tomography ; Deoxyribonucleic acid ; DNA ; Edema ; Female ; Genetics ; Genotype ; Heterozygotes ; Humans ; Hypertension ; Hypotheses ; Intracranial Hypertension - genetics ; Male ; Medicine ; Middle Aged ; Neurological diseases ; Nucleotide sequence ; Nursing schools ; Original ; Patients ; Polymorphism, Single Nucleotide ; Prospective Studies ; Public health ; Quality control ; Single-nucleotide polymorphism ; Sulfonylurea ; Sulfonylurea Receptors - genetics ; Transient receptor potential proteins ; Traumatic brain injury ; TRPM Cation Channels - genetics ; Young Adult
Is Part Of: Journal of neurotrauma, 2019-06, Vol.36 (11), p.1804-1817
Description: 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. (encoding SUR1) single-nucleotide polymorphisms (SNPs) are reported as predictors of raised intracranial pressure (ICP). This project evaluated whether SNPs predicted ICP and TBI outcome. DNA was extracted from 435 consecutively enrolled severe TBI patients. Without selection, all 11 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 (β = 10.3 mm Hg, = 0.00000029), peak ICP (β = 19.6 mm Hg, = 0.0007), and proportion ICP >25 mm Hg (β = 0.16 = 0.004). rs150391806 heterozygotes had higher mean (β = 7.2 mm Hg, = 0.042) and peak (β = 28.9 mm Hg, = 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 DNA segment containing previously identified relevant SNPs. There was an interaction effect on ICP between rs8104571 and a cluster of predictive 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, = 0.007951). This trend persisted in a survivor-only subcohort (OR = 20.67, = 0.0168). In this cohort, two 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.
Publisher: United States: Mary Ann Liebert, Inc
Language: English
Identifier: ISSN: 0897-7151
EISSN: 1557-9042
DOI: 10.1089/neu.2018.6124
PMID: 30484364
Source: ProQuest One Psychology
AUTh Library subscriptions: ProQuest Central
MEDLINE
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Downstream TRPM4 Polymorphisms Are Associated with Intracranial Hypertension and Statistically Interact with ABCC8 Polymorphisms in a Prospective Cohort of Severe Traumatic Brain Injury

Copyright 2019, Mary Ann Liebert, Inc., publishers ;Copyright 2019, Mary Ann Liebert, Inc., publishers 2019 ;ISSN: 0897-7151 ;EISSN: 1557-9042 ;DOI: 10.1089/neu.2018.6124 ;PMID: 30484364

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