Sickle cell disease: a multigenic perspective of a single gene disorder

The phenotypic heterogeneity of sickle cell disease continues to puzzle clinicians and investigators more than half a century after the elucidation of its molecular basis. Although advances have been made in understanding the influences of globin gene-related factors such as alpha-thalassemia (thal) and high Hb F determinants, these are far from providing a satisfactory explanation to the variation and clinical diversity of sickle cell disease in many cases. The sequencing of the human genome and the development of novel technologies such as high throughput genotyping and analysis of gene expression through cDNA microarrays has made it possible to investigate this diversity with these approaches and identify novel genetic modifiers of sickle cell disease. This brief review focuses on the recent advances in our understanding of the impact of non globin genetic modifiers on the phenotypic diversity of the disease.