Pleiotropic and epistatic effects in sickle cell anemia

Abstract

Sickle cell anemia is the first monogenic disease ever described, and it became the paradigm for a disease traceable to a single mutation in a single gene. Pauling's concept of "molecular disease," based on this discovery, opened a new chapter in the history of medicine. Nevertheless, at the phenotypic level, sickle cell anemia is not a monogenic disease; it is a multigenic disease. The latter is the product of pleiotropic genes (involved in secondary pathophysiologic events) and epistatic genes (same gene but with significant pathophysiologic consequences among individual=polymorphism). These secondary events are an important part of the phenotype and explain the intense interindividual differences in the severity of the disease, in spite of all the patients having the same sickle globin gene in the homozygote form. In the last decade a number of epistatic genes and pleiotropic genes have been defined, and many others are potential candidates. CHIP technology and high-throughput sequencing promise to accelerate our full multigenic understanding of this disease, contributing to a more individualized concept of disease in conjunction as we enter the new millennium.