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Genetic variation reduced hospitalizations in children with sickle cell disease
Shorter alleles in heme oxygenase-1 were associated with a significant reduction in hospitalizations for acute chest syndrome in a cohort of children with sickle cell disease, according to study results.
Sickle cell disease often is linked to complications that include vaso-occlusive episodes, acute chest syndrome, pain and stroke.
In the current study, researchers defined heme oxygenase-1 (HMOX1 gene; HO-1 protein) as the “inducible, rate-limiting enzyme in the catabolism of heme.” The enzyme may have the ability to attenuate the severity of outcomes from vaso-occlusive and hemolytic crises.
Within the promoter region of the HMOX1 gene is a dinucleotide repeat that, because of its long repeat lengths, may be associated with decreased activity and inducibility.
The researchers analyzed this polymorphism to test the hypothesis that short alleles are associated with decreased risk for adverse outcomes, such as hospitalization for pain or acute chest syndrome.
The analysis involved 942 children with sickle cell disease. The range of alleles among these children was 13 to 45 repeats. Alleles also had a trimodal distribution.
After adjusting for sex, age, asthma, percentage of fetal hemoglobin and alpha-globin gene deletion, children with two shorter alleles (4%; ≤25 repeats) experienced lower hospitalization rates for acute chest syndrome than children with longer allele lengths (incidence rate ratio=0.28; 95% CI, 0.1-0.81).
“To our knowledge, this is the first study to examine the role of genetic variation in HMOX1 in sickle cell disease,” the researchers wrote. “Our results implicate a role for the heme oxygenase-heme axis in the etiology of acute chest syndrome and highlight the need for future studies to interrogate genetic variation in this pathway as one of potential mechanisms for acute lung injury. Acute chest syndrome is a leading cause of death among individuals with sickle cell disease. Greater understanding of the role of the HMOX1 response in the setting of an exacerbation of chronic hemolysis may elucidate targeted strategies to prevent or attenuate life threatening acute chest syndrome episodes.”
Perspective
Back to TopThe results are important because they give another insight into why some patients with sickle cell disease are less likely to have acute chest syndrome, one of the major complications of the disease. Research in the past several years has generated new insights into the pathophysiology of sickle cell disease. We have known for a long time that vasocclusion secondary to polymerization of hemoglobin and distortion of the red cell shape is the central event in this disease. In the last few years, there has been a better understanding of the role played by hemolysis and plasma free hemoglobin on vascular homeostasis on the pathophysiology of sickle cell disease. This paper provides evidence of a relationship between the metabolism of plasma free hemoglobin and risk for acute chest syndrome. If proven by further studies that include plasma hemooxygenase levels in patients with or without the polymorphism, these data suggest a molecular basis for variability in risk for acute chest syndrome in patients with sickle cell disease. These mechanistic insights are important in developing prediction models for risk for complications in sickle cell disease and potentially in the development of novel, targeted therapies.
Perspective
Back to TopThe findings of Bean and colleagues highlight the importance of the pro-inflammatory molecule heme in the pathogenesis of acute chest syndrome in sickle cell disease. Hemolysis and the release of hemoglobin and heme may be critical in vaso-occlusion and vasculopathy of sickle cell disease. Hemoglobin and heme removal by haptoglobin and hemopexin is compromised in sickle cell disease. Heme detoxification by HO-1 with the concomitant release of anti-inflammatory biliverdin/bilirubin and CO can prevent vascular stasis in murine models of sickle cell disease as shown by Belcher and colleagues (Belcher JD. J Clin Invest. 2006;116:808-816). These studies by Bean and colleagues support the concept that enhanced heme degradation by inducible HO-1 is associated with a decrease in acute chest syndrome in children with sickle cell disease. These observations may explain some of the phenotypic variability of the severity of sickle cell disease in patients. Unfortunately, only 4% of the children were homozygous for the protective short (GT)n genotype. However, the low prevalence of the protective genotype underscores the intriguing opportunity of HO-1 induction as a pharmacologic target in sickle cell disease.