Abstract 76: Genome Wide Association Study of Early Neurological Deterioration after Acute Ischemic Stroke Defines the Interferon-Stimulated Gene IFIT1 as a Neuroprotective Factor
Introduction: In the first hours after ischemic stroke, neurological deficits can be highly unstable. These early neurological changes are important due to their influence on long-term outcome. We performed a GWAS on ΔNIHSS24h (NIHSS change from baseline to 24 hours after stroke onset) in acute ischemic stroke patients.
Methods: DNA from 191 stroke patients presenting within 4.5 hours of stroke onset was genotyped using an Affymetrix Exome-chip. Single variant analysis was performed using PLINK, including age, baseline NIHSS and principal component factors as covariates. European- and African-Americans were analyzed separately, with p-values combined by meta-analysis. Gene-based analysis was performed using SKAT-O, including only non-synonymous variants. Pathway analysis was performed using ALIGATOR to identify pathways with SNPs with significant associations. IFIT1-/- and IFIT1+/+ mice underwent one-hour MCA occlusion (tMCAO) followed by 24-hour reperfusion. Brains were removed, TTC-stained, and infarcts measured.
Results: Single variant analysis did not reveal genome-wide significant associations. One gene, IFIT1 (interferon-induced protein with tetratricopeptide repeats), passed the gene-based genome-wide multiple test correction (A). All three polymorphic variants in IFIT1 associated with neurologic deterioration with an average ΔNIHSS24h 9.5 points lower in carriers versus non-carriers (B). Pathway analysis, including 21 interferon-related genes but excluding IFIT1, showed a highly significant association (p=2.30х10-3) with ΔNIHSS24h. Infarct volumes in IFIT1-/- mice were twice the size of IFIT1+/+ mice after tMCAO (C, 110.6 mm3 vs 52.8 mm3).
Conclusion: These data suggest that IFIT1 and other interferon-related genes may function in endogenous neuroprotective responses during acute ischemic stroke.
Author Disclosures: L. Heitsch: Research Grant; Significant; Emergency Medicine Foundation Career Development Grant. A. Kraft: None. K. Guilliams: None. A. Ford: None. N. Khoury: None. L. Connor: None. M.S. Diamond: None. C. Cruchaga: None. J. Lee: None.
- © 2014 by American Heart Association, Inc.