Sickle cell disease (SCD) is the most common genetic disease in the United States inherited as an autosomal recessive disorder, where approximately 70,000 individuals have sickle cell disease. Acute painful vaso-occlusive crisis (VOCs) is one of the common complications of SCD that influences overall survival (Platt, Thorington et al. 1991). Pain, is also the most common cause of SCD morbidity, which has a negative impact on quality of life of these individuals and their families. There is significant inter-individual variation in the frequency and course of severe VOCs that result in hospital based treatment, the reasons for which have not been clearly elucidated. Vaso-occlusion of irreversibly sickle red cells within the microcirculation is believed to be the proximate cause of painful VOCs, however it is likely that other non-SCD related factors affecting pain perception and sensitivity to pain will also contribute to individuals susceptibility to pain and therefore contribute to the observed inter-individual variability in the course of VOC. Early identification of individuals who are at high risk for developing severe pain related morbidity and chronic pain syndromes is crucial since early multimodal interventions might have the potential to minimize both the morbidity and mortality associated with VOCs.
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Patients with SCD are hypothesized to have lower nitric oxide (NO) bioavailability due to NO scavenging by cell free hemoglobin released into plasma during red cell hemolysis. NO deficiency has been identified as a key factor in development vascular dysfunction in SCD. NO has also recently been identified as a key mediator in processing nociceptive signals and modulation of pain in non-SCD models. Thus, low NO is associated with lower pain perception (Meller, Dykstra et al. 1992; Tegeder, Costigan et al. 2006). GTP cyclohydrolase (GCH1) is the rate-limiting enzyme for synthesis of an essential cofactor for both NO production and metabolism of aromatic amino acids, namely tetrahydrobiopterin (BH4). Therefore it is hypothesized that genetic variants in the GCH1 gene will affect BH4 levels and which will have a secondary impact on vascular dysfunction and sensitivity to pain in SCD.
The primary goal of this protocol is to establish patterns of sensitivity to experimental pain among subjects with SCD compared to healthy African American controls. In addition, an exploratory analysis will determine if increased sensitivity to experimental pain correlates with the frequency and intensity of clinical pain in those with SCD. Once an expected pattern of experimental pain phenotypes are established for a cohort with SCD, we will then further explore the role of GCH1 genetic variants in experimental pain perception and vascular function. If successful, a longer term secondary objective is to establish a sufficiently large patient cohort with experimental pain phenotypes for future exploratory genetic studies to investigate the role of other loci that might influence sensitivity to experimental pain and vascular function in SCD.
