Genetics and Pain Severity in Sickle Cell Disease

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.

• ELIGIBILITY CRITERIA FOR ALL PARTICIPANTS:

All study participants must be of self-described African or African American ancestry. They will be at least 18 years old and must be able to provide informed, written consent for participation.

Inclusion criteria

Inclusion criteria

for Sickle Cell Patients

• Diagnosis of sickle cell disease (documentation of SS, SC, S beta + thalassemia, S beta + thalassemia by electrophoresis is required).
• If taking chronic analgesics (NSAID, acetaminophen) or opioids, study subjects should be on a stable dose for 4 weeks prior to recruitment.

Inclusion criteria

for Control Subjects

• Hemoglobin AA genotype by HPLC or hemoglobin electrophoresis.
• General good health defined as the absence of untreated major medical conditions (e.g. uncontrolled systemic hypertension, etc.).

Exclusion criteria

Exclusion criteria

for Sickle Cell Patients

• History of severe vaso-occlusive pain crisis resulting in either evaluation in an emergency department or admission to a hospital during the two weeks prior to study enrollment.
• Acute pain at the time of enrollment defined as spontaneous recent onset pain with a self rated score of 6 or higher on a scale of 0-10. (This is acute pain not the pain that subjects function at on a daily basis.)

Exclusion criteria

for Control Subjects

• Acute pain or injury at enrollment or a recent history of chronic pain (daily pain reported for at least 6 months) in the past 3 years.
• Major medical/psychiatric illness known to cause pain.
• Sickle cell trait.