Genetic Modulation on the Phenotypic Diversity of Sickle Cell Disease

Sickle cell hemoglobin is a b chain structural variant where valine is substituted for glutamic acid in the sixth amino acid position. A point mutation (A--->T) in codon 6 of the b globin gene which is located on the short arm of chromosome 11 is responsible for this abnormality. Despite the fact that all sickle cell disease patients have an identical single base change in their DNA, the severity in the clinical manifestations varies between and within different population groups. Advances in DNA technology have enabled us to characterize the bS mutation by restriction fragment length polymorphism (RFLP) and also became possible to identify many variations (DNA polymorphism) in the non coding regions of globin genes. Studies in different population groups have revealed that the clinical severity may be ameliorated by higher fetal hemoglobin (HbF) expression, inheritance of a particular bS haplotype along with some other DNA sequence polymorphisms in the b-globin gene cluster and the co-inheritance of associated a-thalassemia. Our study in the tribal and non-tribal population groups of western India with a diverse clinical manifestations revealed that the bS gene was linked to the typical Arab-Indian haplotype with a higher HbF levels in those who were homozygous for Arab-Indian haplotype. However, homozygosity for Arab-Indian haplotype had no effect on the clinical severity. The presence of other polymorphisms like b-silencer and b LCR motif within the Arab-Indian haplotype in each of these populations were found to be identical. The prevalence of a-thalassemia was found to very high and varied between 24 to 97 % in these groups. The clinical manifestations were less frequent in the patients with homozygous a-thalassemia as compared to normal a-globin gene. It is interesting to note that the presence of excess a genes (aaa 3.7 / aa) in sickle heterozygotes resulted in unusually severe clinical symptoms. Hence, the phenotypic expression of sickle cell disease linked to the Arab-India haplotype is not uniformly mild and a-thalassemia is a powerful and additional genetic factor in ameliorating the severity of the disease