Pleiotropic and epistatic effects in sickle cell anemia

Sickle cell anemia is the first monogenic disease ever described, and it be came the paradigm for a disease traceable to a single mutation in a single gene. Pauling's concept of "molecular disease," based on this discovery, op ened a new chapter in the history of medicine. Nevertheless. at the phenoty pic level, sickle cell anemia is not a monogenic disease; it is a multigeni c disease. The latter is the product of pleiotropic genes (involved in seco ndary pathophysiologic events) and epistatic genes (same gene but with sign ificant pathophysiologic consequences among individual=polymorphism). These secondary events are an important part of the phenotype and explain the in tense interindividual differences in the severity of the disease, in spite of all the patients having the same sickle globin gene in the homozygote fo rm. In the last decade a number of epistatic genes and pleiotropic genes ha ve been defined, and many others are potential candidates. CHIP technology and high-throughput sequencing promise to accelerate our full multigenic un derstanding of this disease, contributing to a more individualized concept of disease in conjunction as we enter the new millennium. (C) 2001 Lippinco ti Williams & Wilkins, Inc.