SS disease is not a single gene disorder

In SS disease CNS damage is found in a continuum of clinical settings: normal (no ischemic changes), silent strokes (MRI changes without symptoms), transient ischemic episodes, and clinical strokes (either ischemic or hemorrhagic). Four to eight percent of children with SS disease have clinical strokes, and 23% younger than 14 years have evidence of silent strokes by MRI associated with neuropsychometric deficits. It is unclear how genetic factors affect the frequency or severity of strokes. Investigators using candidate gene approaches have looked for genetic modifiers of this clinical complication. Loci at the HLA site have been associated with clinical strokes (Styles et al, Blood. 2000;95:3562-3567). Since increased adherence of sickle red cells to endothelium may be due to the expression of the VCAM1 molecule on the endothelial surface, Taylor and colleagues (page 4303) considered this gene as a possible genetic modifier. Fifty-one SS patients with a clinical history of strokes were compared with 51 matched controls. One single nucleotide polymorphism leading to a nonsynonymous coding difference was more highly associated with control patients than with the stroke patients. The authors conclude that this variant in VCAM1 is associated with a clinically useful modifier in SS disease.

The clinical role of the VCAM1 gene as a useful genetic modifier of strokes in SS patients needs additional scrutiny. First, MRI studies were not done uniformly in either the stroke or control group; thus we do not know how much of a difference in CNS pathology exists between these 2 groups. Second, since the Senegal haplotype of the beta globin region is associated with increased silent infarcts (Kinney et al, Pediatrics. 1999:103:640-645), haplotype-matched controls are needed to exclude a confounding founder effect. Finally, a functional difference in the VCAM1 molecule related to the nonsynonymous substitution that is associated with asymptomatic SS subjects would be enlightening.