{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T04:33:28Z","timestamp":1779165208221,"version":"3.51.4"},"reference-count":67,"publisher":"SAGE Publications","issue":"11","license":[{"start":{"date-parts":[[2019,5,22]],"date-time":"2019-05-22T00:00:00Z","timestamp":1558483200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurotrauma"],"published-print":{"date-parts":[[2019,6]]},"abstract":"<jats:p>\n                    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.\n                    <jats:italic toggle=\"yes\">ABCC8<\/jats:italic>\n                    (encoding SUR1) single-nucleotide polymorphisms (SNPs) are reported as predictors of raised intracranial pressure (ICP). This project evaluated whether\n                    <jats:italic toggle=\"yes\">TRPM4<\/jats:italic>\n                    SNPs predicted ICP and TBI outcome. DNA was extracted from 435 consecutively enrolled severe TBI patients. Without\n                    <jats:italic toggle=\"yes\">a priori<\/jats:italic>\n                    selection, all 11\n                    <jats:italic toggle=\"yes\">TRPM4<\/jats:italic>\n                    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 (\u03b2\u2009=\u200910.3\u2009mm Hg,\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    \u2009=\u20090.00000029), peak ICP (\u03b2\u2009=\u200919.6\u2009mm Hg,\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    \u2009=\u20090.0007), and proportion ICP &gt;25\u2009mm Hg (\u03b2\u2009=\u20090.16\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    \u2009=\u20090.004). rs150391806 heterozygotes had higher mean (\u03b2\u2009=\u20097.2\u2009mm Hg,\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    \u2009=\u20090.042) and peak (\u03b2\u2009=\u200928.9\u2009mm Hg,\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    \u2009=\u20090.0015) 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\n                    <jats:italic toggle=\"yes\">ABCC8<\/jats:italic>\n                    DNA segment containing previously identified relevant SNPs. There was an interaction effect on ICP between rs8104571 and a cluster of predictive\n                    <jats:italic toggle=\"yes\">ABCC8<\/jats:italic>\n                    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]\u2009=\u200916.7,\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    \u2009=\u20090.007951). This trend persisted in a survivor-only subcohort (OR\u2009=\u200920.67,\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    \u2009=\u20090.0168). In this cohort, two\n                    <jats:italic toggle=\"yes\">TRPM4<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1089\/neu.2018.6124","type":"journal-article","created":{"date-parts":[[2018,11,28]],"date-time":"2018-11-28T08:12:01Z","timestamp":1543392721000},"page":"1804-1817","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":35,"title":["Downstream\n                    <i>TRPM4<\/i>\n                    Polymorphisms Are Associated with Intracranial Hypertension and Statistically Interact with\n                    <i>ABCC8<\/i>\n                    Polymorphisms in a Prospective Cohort of Severe Traumatic Brain Injury"],"prefix":"10.1177","volume":"36","author":[{"given":"Ruchira M.","family":"Jha","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."},{"name":"Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."},{"name":"Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."},{"name":"Safar Center for Resuscitation Research, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."},{"name":"Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shashvat M.","family":"Desai","sequence":"additional","affiliation":[{"name":"Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin E.","family":"Zusman","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theresa A.","family":"Koleck","sequence":"additional","affiliation":[{"name":"School of Nursing, Columbia University, New York, New York."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ava M.","family":"Puccio","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David O.","family":"Okonkwo","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seo-Young","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."},{"name":"Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lori A.","family":"Shutter","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."},{"name":"Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."},{"name":"Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick M.","family":"Kochanek","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."},{"name":"Safar Center for Resuscitation Research, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."},{"name":"Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."},{"name":"Department of Anesthesia, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."},{"name":"Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania."},{"name":"University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yvette P.","family":"Conley","sequence":"additional","affiliation":[{"name":"Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania."},{"name":"School of Nursing, University of Pittsburgh, Pittsburgh, Pennsylvania."},{"name":"Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2019,5,22]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0036-1592109"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-016-0500-6"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-015-0437-1"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2017-317741"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12028-016-0309-z"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(17)30225-9"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.428219"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2012.91"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00457.2014"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2009.1021"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e3181fbf6d6"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12028-013-9917-z"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(16)30196-X"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000002079"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2016.4696"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2014.04.040"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2016.4491"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2014.3706"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1227\/NEU.0000000000001432"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt607"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1157"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw068"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar4510"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/28.1.235"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20084"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.12.028"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0046688"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-017-1779-6"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0974-4"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.137323.112"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv402"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10592-005-9056-y"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1916"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2010.08.053"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-77"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2017.04.016"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.wneu.2017.01.103"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMe1412951"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1212-4"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21599"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12263-017-0579-x"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-013-1250-z"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-012-2655-4"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1385\/NCC:4:1:008"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2000.17.403"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1007\/3-211-30714-1_26"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1089\/08977150150502569"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1227\/00006123-199102000-00004"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12028-014-0048-y"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000003361"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2017.5619"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2017.5275"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2015.05.006"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22581"},{"key":"e_1_3_3_57_2","doi-asserted-by":"pu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