Sickle cell disease (SCD) is a common genetic disorder in African Americans, with a major impact on health and social well-being and a life expectancy of only 42 years. Individuals with SCD are known to be at increased risk of sudden cardiac death, the basis of which is not well understood. Investigating the genetic and environmental factors that contribute to sudden cardiac death in SCD should allow development of interventions aimed at reducing this health disparity in early mortality. We have recently reported a study showing that SCN5A-1103Y interacts with hypokalemia to promote LQT in a community-based population of African Americans, within the NHLBI Jackson Heart Study (JHS). However, whether SCN5A-1103Y or other genetic variants interact with the other QT-prolonging factors present in individuals with SCD, to contribute to LQT and the risk of sudden cardiac death, has not been studied before. At the University of Mississippi Medical Center, we have large pediatric and adult SCD clinics with over 1,200 patients, drawn from the same general community as participants in the JHS. We propose to study the interaction of SCN5A-1103Y and other genetic variants, with QT-prolonging factors present in SCD, on risk of LQT. This will provide a basis for future studies of the importance of the interaction of these genetic and secondary factors on clinical outcomes and management, with the long-term goal of decreasing the health disparity in mortality in individuals with SCD.

Public Health Relevance

Sickle cell disease (SCD) is a common genetic disorder in African Americans, with a major impact on health and social well-being. There is a substantial health disparity in early mortality in individuals with SCD, due in part to an increased risk of sudden cardiac death, the basis of which is not well understood. In this proposal we will evaluate the role of common genetic factors, capable in influencing predisposition to sudden cardiac death in African Americans, and how these genetic factors interact with other predisposing factors common in SCD. Investigating the genetic and environmental factors that contribute to sudden cardiac death in SCD should allow development of interventions aimed at reducing this health disparity causing premature mortality, fulfilling the objectives of RFA-MD-13-008.

Agency
National Institute of Health (NIH)
Institute
National Institute on Minority Health and Health Disparities (NIMHD)
Type
Research Project (R01)
Project #
5R01MD009162-04
Application #
9431058
Study Section
Special Emphasis Panel (ZMD1)
Program Officer
Rajapakse, Nishadi
Project Start
2015-07-10
Project End
2020-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Mississippi Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Jacob, Seethal A; Novelli, Enrico M; Isenberg, Jeffrey S et al. (2017) Thrombospondin-1 gene polymorphism is associated with estimated pulmonary artery pressure in patients with sickle cell anemia. Am J Hematol 92:E31-E34
Kato, Gregory J; Steinberg, Martin H; Gladwin, Mark T (2017) Intravascular hemolysis and the pathophysiology of sickle cell disease. J Clin Invest 127:750-760
Kato, Gregory J (2016) New insights into sickle cell disease: mechanisms and investigational therapies. Curr Opin Hematol 23:224-32