Haptoglobin Genotypes among Pediatric and Adult Sickle Cell Patients: An Emerging Genetic Modifier?.

The role of hemolysis and its end product, cell free hemoglobin, as a Nitric Oxide (NO) scavenger in the pathogenesis of some complications of sickle cell disease (SCD) such as pulmonary hypertension has recently been recognized. Hemoglobin (Hb) released from red blood cells as a result of hemolysis complexes with haptoglobin (Hp). Hb-Hp complexes are removed from the circulation by tissue macrophages in the liver and spleen through CD163, the newly identified hemoglobin scavenger receptor expressed on the monocytes and macrophages. Hp is a polymorphic protein with two well-known alleles, Hp-1 and Hp-2 with worldwide distribution. Although the worldwide frequencies of these two allelles are approximately equal, there is significant ethnic and geographic variation in the distribution of Hp-1 and Hp-2 among different populations. Hp locus is on chromosome 16q22. each Hp monomer consists of one α-chain and one β-chain. An intragenic duplication event during evolution resulted in an elongated α-chain thus generating the Hp-2 allele. Thus individuals homozygous for the long α-2 chain express large multimeric molecules (Hp 2-2). Over the past 5 years, Hp-2 allele has emerged as a major susceptibility gene for development of vascular complications such as coronary artery restenosis and risk of cardiovascular disease, particularly in diabetic patients. It has been reported that the Hb-Hp-2 complexes have a 10-fold greater affinity for the CD163 receptor compared to Hb-Hp-1, and the interaction of Hb-Hp-2 complexes with CD163 on macrophages generates a more powerful inflammatory response with the release of pro-inflammatory cytokines such as IL-1β, IL-6, and GM-CSF. These observations led us to examine the role of Hp polymorphisms in sickle cell disease. We performed genotyping of the Hp-alleles with PCR in 21 pediatric patients (age 4 mo-10 years) and 41 adults patients (age 16–60). The results of this genotyping are shown in the table below. The Hp-1 allele frequency was 0.24 among pediatric patients and 0.52 among adults; while that of Hp-2 was 0.76 in the pediatric age group and 0.48 in adults. This difference was significant (p=0.0023). The significantly higher allele frequency of Hp-2 in pediatric patients compared to adults may indicate a selection against this genotype and suggests that Hp-1 allele may be associated with a survival advantage. This is in keeping with the deleterious effects of Hp-2 allele reported in the literature and suggests yet another mechanism whereby hemolysis may lead to adverse outcomes associated with Hp polymorphisms, in addition to the NO scavenging effects of cell free hemoglobin. Detailed studies are currently being undertaken to elucidate the mechanism whereby Hp polymorphisms may impact on the pathophysiology of SCD.