Blood, 15 December 2002, Vol. 100, No. 13, pp. 4255-4255
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.
George J. Dover
Johns Hopkins University School of
Medicine
