Genetics and Pain Severity in Sickle Cell Disease
Condition: Genotype; Pain; Genetic Variation; Quantitative Sensory Testing (QST); GCH1
MeSH terms: Anemia, Sickle Cell
Study type: Observational

Summary: 
      Background:

      - Pain is the most common symptom of sickle cell disease. Episodes of severe sickle cell pain
      are known as "crises." High rates of pain crises are associated with a higher risk of early
      death. Some people with sickle cell disease have many severe pain crises while others
      experience fewer crises. This difference in pain crisis may be caused by sensitivity to pain.
      People with high sensitivity to pain may have more pain crises. Many factors, including a
      person's genetic makeup, determine sensitivity to pain. Comparing genetic information from
      people with sickle cell disease and healthy volunteers may provide more information on pain
      and sickle cell disease.

      Objectives:

      - To study genetics and pain sensitivity in sickle cell disease.

      Eligibility:

        -  African or African American individuals at least 18 years of age with sickle cell
           disease.

        -  Healthy African or African American volunteers at least 18 years of age.

      Design:

        -  Participants will be screened with a medical history and physical exam. They will also
           provide blood and urine samples.

        -  Participants will have the following tests:

        -  Quantitative sensory testing to measure sensitivity to pressure, heat, cold, and
           mechanical pain.

        -  EndoPat test to measure blood vessel function and reaction.

        -  Questionnaires about mood, evidence of depression, pain, quality of sleep, and sleep
           disturbances.

        -  Measures of daily pain, whether or not related to sickle cell disease.

        -  After the first visit, those in the study will have monthly study visits for 6 months.
           The above tests will be repeated at these visits.
    

Detailed description: 
      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.

      <TAB>

      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.
    

Observational model: Case-Control
Time perspective: Other
Sampling method: Non-Probability Sample
Study population: 
        primary clinical
      
Keywords: GCH1; Pain Sensitivity; Quantitative Sensory Testing (QST); Genetic Variation; Sickle Cell Anemia