Abstract 858 Poster Session I, Saturday, 5/1 (poster 280)

Stroke is a devastatingly common complication in children with sickle cell disease (SCD) with 25% of children having evidence of cerebral infarction on MRI. Cerebral infarction generally results from progressive narrowing and occlusion of the large intracranial arteries due to endothelial injury. With the exception of transcranial doppler ultrasound, there are no predictors which permit identification of SCD patients who will ultimately develop stroke. Anecdotal studies have noted stroke in siblings with SCD and a sib-pair analysis in SCD patients with stroke documented an increased risk of stroke in siblings with SCD, supporting a genetic influence on stroke in SCD. Reports in the general population have demonstrated an association between HLA type and diseases characterized by endothelial injury, such as moyamoya disease which is histopathologically similar to the cerebral vasculopathy found in SCD. We studied 54 children with SCD to determine if HLA type is associated with stroke in SCD. HLA typing was undertaken in 23 patients with evidence of MRI-documented cerebral infarction and 31 patients with a negative MRI. Complete HLA typing, including both Class I and II loci was performed using DNA-based technology, utilizing PCr and sequence-specific oligonucleotide probe formats. HLA typing revealed that the Class II groups, DR and DQ, had significant associations with risk of stroke. Patients with a positive MRI carried the DR3 phenotype significantly more frequently than did patients with a negative MRI[43% MRI(+) vs. 10% MRI(-), OR=7.18, p=.004]. Patients carrying DR15 were more likely to have a negative MRI [17% MRI(+) vs. 45% MRI(-), OR=.26, p=.02] supporting a protective effect of this HLA type. Further allelic subtyping showed that the greatest associations were between DRB1 *0301 and (+)MRI and between DRB*1501 and (-)MRI. Analyses of DQ alleles revealed that DQB1*0201/02 was also significantly associated with stroke [56% MRI(+) vs. 23% MRI(-), OR=4.46, p=.011]. The combination of DRB1*0301 and DQB1*0201/02 is a well recognized HLA haplotype and further supports the association of HLA type with stroke. The analysis of Class I HLA alleles and stroke did not reveal any significant associations. Subclassification of MRI(+) patients by large vs. small vessel involvement, presence or absence of stenosis on MRA, or overt vs. clinically silent stroke did not localize the observed HLA association to any particular MRI/MRA findings. These preliminary findings support a causal relationship between HLA type and risk of stroke in SCD, suggesting a genetic component to this manifestation. Further studies will be necessary to determine if the association is with HLA genes, in particular, or with another gene in linkage with the HLA genes. Most importantly, HLA typing may serve as a useful marker in identifying SCD patients at higher risk for stroke, thereby allowing for early or preventive interventions.