Genetic Variants Associated With Intraparenchymal Hemorrhage Progression After Traumatic Brain Injury
Authors: Ruchira M. Jha, Benjamin E. Zusman, Ava M. Puccio, David O. Okonkwo, Matthew Pease, Shashvat M. Desai, Matthew Leach, Yvette P. Conley, Patrick M. Kochanek
Journal: JAMA Network Open (2021)

IMPORTANCE Intracerebral hemorrhage progression is associated with unfavorable outcome after traumatic brain injury (TBI).No effective treatments are currently available.This secondary injury process reflects an extreme form of vasogenic edema and blood-brain barrier breakdown.The sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) cation channel is a key underlying mechanism.A phase 2 trial of SUR1-TRPM4 inhibition in contusional TBI is ongoing, and a phase 3 trial is being designed.Targeted identification of patients at increased risk for hemorrhage progression may inform prognostication, trial design (including patient selection), and ultimately treatment response.OBJECTIVE To determine whether ABCC8 (SUR1) and TRPM4 genetic variability are associated with intraparenchymal hemorrhage (IPH) progression after severe TBI, based on the putative involvement of the SUR1-TRPM4 channel in this pathophysiology. DESIGN, SETTING, AND PARTICIPANTSIn this genetic association study, DNA was extracted from 416 patients with severe TBI prospectively enrolled from a level I trauma academic medical center from May 9, 2002, to August 8, 2014.Forty ABCC8 and TRPM4 single-nucleotide variants (SNVs) were genotyped (multiplex, unbiased).Data were analyzed from January 7, 2020, to May 3, 2021. MAIN OUTCOMES AND MEASURESPrimary analyses addressed IPH progression at 6, 24, and 120 hours in patients without acute craniectomy (n = 321).Multivariable regressions and receiver operating characteristic curves assessed SNV and haplotype associations with progression.Spatial modeling and functional predictions were determined using standard software. RESULTSOf the 321 patients included in the analysis (mean [SD] age, 37.0 [16.3] years; 247 [76.9%] male), IPH progression occurred in 102.Four ABCC8 SNVs were associated with markedly increased odds of progression (rs2237982 [odds ratio (OR), 2.60-3.80;95% CI, 1.14-5.90 to 1.80-8.02;P = .02to P < .001],rs2283261 [OR, 3.37-4.77;95% CI, 1.07-10.77to 1.89-12.07;P = .04to P = .001],rs3819521 [OR, 2.96-3.92;95% CI, 1.13-7.75 to 1.42-10.87;P = .03to P = .009],and rs8192695 [OR, 3.06-4.95;95% CI, 1.02-9.12 to 1.67-14.68];P = .03-.004).These are brain-specific expression quantitative trait loci (eQTL) associated with increased ABCC8 messenger RNA levels.Regulatory annotations revealed promoter and enhancer marks and strong and/or active brain-tissue transcription, directionally consistent with increased progression.Three SNVs (rs2283261, rs2237982, and rs3819521) in this cohort have been associated with intracranial hypertension.Four TRPM4 SNVs were associated with decreased IPH progression (rs3760666 [OR, 0.40-0.49;95% CI, 0.19-0.86 to 0.27-0.89;P = .02to P = .009],rs1477363 [OR, 0.40-0.43;95% CI, 0.18-0.88 to 0.23-0.81;P = .02to P = .006],rs10410857 [OR, 0.36-0.41;95% CI, 0.20-0.67 to 0.20-0.85;P = .02to P = .001],and rs909010 [OR, 0.27-0.40;95% CI, 0.12-0.62 to 0.16-0.58;P = .002to P < .001]).Significant SNVs in both genes cluster downstream, flanking exons encoding the receptor site and (continued) Key Points Question Is genetic variation in a key channel of secondary injury after traumatic brain injury (TBI) associated with patients' risk of intraparenchymal hemorrhage (IPH) progression, a major contributor to unfavorable outcome?Findings In this genetic association study of a prospective cohort of 321 patients with severe TBI, 8 spatially clustered ABCC8 (sulfonylurea receptor 1) and TRPM4 sequence variants, all brain-specific expression quantitative trait loci, were associated with IPH progression and improved clinical models; regulatory annotations further suggest biological plausibility.ABCC8 variants that increase brain tissue ABCC8 messenger RNA expression were associated with increased IPH progression risk, whereas variant TRPM4 was protective.Meaning The findings suggest that identifying patients with risk-altering genotypes of a pivotal channel in IPH progression may guide risk stratification, prognostication, patient selection, and upcoming trial design for targeted sulfonylurea receptor 1 inhibition.