Sickle cell disease: a multigenic perspective of a single-gene disorder.
Although significant progress has been made in our understanding of sickle cell disease (SCD) and in the development of new therapies, many questions are still unanswered, and a cure remains elusive. This is particularly evident in the clinical heterogeneity of the disease. Studies have shown the importance of high hemoglobin F determinants and alpha-thalassemia as modifiers of disease severity, but these alone do not explain the diversity that is seen. This paper focuses on recent advances on the effect of nonglobin genetic modifiers on the SCD phenotype. The roles of polymorphic variants of (1) methylenetetrahydrofolate reductase gene in the pathogenesis of avascular necrosis, (2) factor V R485K and risk of venous thrombosis, and (3) UDP glucuronosyltransferase-1 polymorphism on serum bilirubin levels in SCD are discussed. Mention is made of genetic polymorphisms that might predispose to stroke. The application of gene expression profiling to the study of SCD is very promising and some preliminary data are provided.
Kutlar
Abdullah
A
Sickle Cell Center, Medical College of Georgia, Augusta, GA 30912, USA. akutlar@mail.mcg.edu
D000755:Anemia, Sickle Cell / Q000235:genetics* / Q000628:therapy; D001663:Bilirubin / Q000097:blood; D005165:Factor V / Q000235:genetics; D020869:Gene Expression Profiling; D030342:Genetic Diseases, Inborn; D005819:Genetic Markers; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D009154:Mutation; D011110:Polymorphism, Genetic; D020521:Stroke / Q000209:etiology / Q000235:genetics
D005819:Genetic Markers; D005165:Factor V; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014453:Glucuronosyltransferase; D001663:Bilirubin