A study evaluated 108 SNPs in 39 candidate genes in 1398 individuals with SCD using bayesian networks and found that 31 SNPs in 12 genes interact with fetal hemoglobin to modulate the risk of stroke.577 This network of interactions includes 3 genes in the transforming growth factor- pathway and selectin P, which is associated with stroke in the general population. The model was validated in a different population, predicting the occurrence of stroke in 114 individuals with STOP data were used to confirm previous findings of associations between the tumor necrosis factor phisms and risk of large-vessel stroke in SCD.578 Consistent with prior findings, the tumor necrosis factor ( 308) GG genotype increased the risk of large-vessel disease by >3-fold also showed a previously unidentified association between the leukotriene C4-synthase ( 444) A/C variant and risk of large- The Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) study found that of the 38 candidate SNPs in 22 genes studied, 5 polymorphisms had significant influence on stroke risk; SNPs in the ANXA2, TGFBR3, and TEK genes were associated with increased stroke risk, and -thalassemia and an SNP in the ADCY9 gene were linked to decreased stroke risk.579 The SIT Trial found that 2 varia- tions in the G6PD gene that are linked to reduced enzymatic function, rs1050828 and rs1050829, were associated with vas- culopathy in male participants with SCD (OR, 2.78; 95% CI, Further validation of these findings is required before these genetic variations can be used for stroke risk prediction. Meschia et al Guidelines for the Primary Prevention of Stroke 3785 Periodic red cell transfusion is the only intervention proven in randomized trials to prevent stroke in patients with SCD. 