FUNCTIONAL GENOMICS IN HUMAN BRAIN ISCHEMIA

William Andrew Kofke , Ren Y, Augoustides J, Li H, Nathanson K, Siman R, Meng Q, Bu W, Yandrawatthana S

Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA, USA

Abstract

Background: Neuroprotection studies are generally directed to single pathophysiologic pathways of unknown relative importance. The purpose of this research was to demonstrate, using functional genomics, that the pathogenesis of perioperative human ischaemic brain damage involves multiple variably weighted proteins involving several pathways. METHODS: Ninety-four patients undergoing deep hypothermic circulatory arrest(DHCA) and/or aortic valve replacement surgery had biomarkers of brain damage, S100ß and neurofilament H (NFH), assessed at baseline, 1, & 24 hours post-cardiopulmonary bypass(CPB) with analysis for association with 92 single nucleotide polymorphisms (SNPs) related to important proteins involved pathogenesis of cerebral ischaemia. Results: At the nominal significance level of 0.05, changes in S100ß and in NFH at 1 & 24 hours post-CPB were associated with multiple SNPs involving several prospectively determined pathophysiologic pathways, but were not significant after multiple comparison adjustments. Regression analysis suggests that the most important associating genes early post-DHCA /CPB are CAPN10, NPPB, SERPINE1, SOD2, CALM2, MDM2, and NFKB1, and that the most important associating genes 24 hours post-DHCA/CPB are dissimilar: ADRA2A, SELE, BAX, SUMO4, IL11, ADRB2, SOD2, SLC4A7, HSPA1B, FGA, CAPN10, ROCK2, and EPO. Conclusions: Association SNP data suggest specific disparate proteins may be more important than others with variation at different post-insult times after human brain ischaemia. Such information may allow weighting of various pathophysiologic factors in rational design of time-sensitive multifaceted neuroprotective therapies.

Keywords: Brain Ischaemia [C10.228.140.300.150] Cardiopulmonary Bypass [E04.292.413] Genomics [H01.158.273.180.350] Neuroprotection [G11.561.645] Polymorphism, Single Nucleotide [G05.365.795.598].