Abstract WMP113: Genetic Influences on Early Neurological Instability After Acute Ischemic Stroke

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Following acute ischemic stroke (AIS) onset, neurological deficits can be highly unstable. Early neurological change within the first 24 hours, defined here as ΔNIHSS24h (NIHSSbaseline-NIHSS24hours), substantially influences long-term outcome. While several mechanisms, such as hemorrhagic transformation and recanalization, may impact ΔNIHSS24h, little is known about genetic influences. Genetic variants associated with ΔNIHSS24h may identify genes involved in mechanisms of early neurological outcome after AIS. AIS patients were prospectively enrolled between 2008-2014 at two sites (St Louis and BCN; Table 1). NIHSS scores were obtained within 6 hours and again at 24 hours after stroke onset. Genome-wide genotyping was generated for rare and common variants, imputing up to 6 million single nucleotide polymorphisms (SNPs) for all subjects (N=891). ΔNIHSS24h was used as a quantitative trait to measure early improvement/deterioration. Genome-wide complex trait analysis (GCTA) was performed. An association model was done, using NIHSSbaseline, age, gender, glucose, PCA1 and PCA2 as covariates. All samples were analyzed together and then separately by ethnicity (Spanish, European-American (EA), and African-American (AA)). GCTA indicates that common variants account for 23-28% of ΔNIHSS24h variability. VAV3 rs72689643 (p=8.21x10-8) was associated with ΔNIHSS24h in the whole cohort analysis (Figure 1). Three additional suggestive SNPs were found: 2 intergenic SNPs (rs139950151 and rs73706194 - both p=6.1x10-7) in high LD and SNP rs10431426 (p=1.71x10-7) located in an intron. When analyzed by ethnicity, these findings did not reach GWAs significance, likely due to lack of power. Early neurological outcome after AIS is strongly influenced by genetics. Vav3 shows association with ΔNIHSS24h in the whole cohort while several other SNPs are suggestive. Rare variant analysis is underway, and we will also have an additional 800 genotypes analyzed by ISC.

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