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Original Investigation
July 2018

Association of Sickle Cell Trait With Ischemic Stroke Among African Americans: A Meta-analysis

Author Affiliations
  • 1Aflac Cancer and Blood Disorder Center, Emory Children’s Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
  • 2Women’s Health Initiative, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 3Department of Mathematics and Statistics, Hal Marcus College of Science and Engineering, University of West Florida, Pensacola
  • 4Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham
  • 5Division of Hematology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
  • 6Division of Public Health Science, Wake Forest University, Winston-Salem, North Carolina
  • 7Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington
  • 8Department of Pathology and Laboratory Medicine, Larner College of Medicine at the University of Vermont, Burlington
  • 9Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson
  • 10Department of Nephrology, University of North Carolina, Chapel Hill
  • 11Basic Science Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, National Cancer Institute, Frederick, Maryland
  • 12National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
  • 13Stroke Center, Department of Neurology, Medical University of South Carolina, Charleston
  • 14Departments of Neurology and Epidemiology, University of Washington, Seattle
  • 15Division of General Internal Medicine, Medical College of Wisconsin, Milwaukee
  • 16Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia
  • 17Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 18Division of Preventive Medicine, Department of Family Medicine and Public Health, University of California, San Diego
  • 19Department of Pediatrics, Morehouse School of Medicine, Atlanta, Georgia
  • 20Jackson Heart Study, University of Mississippi Medical Center, Jackson
  • 21Division of General Internal Medicine, Weill Cornell Medicine, New York, New York
  • 22College of Public Health, University of Kentucky College of Public Health, Lexington
  • 23Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham
  • 24Fred Hutchinson Cancer Research Center, University of Washington, Seattle
JAMA Neurol. 2018;75(7):802-807. doi:10.1001/jamaneurol.2018.0571
Key Points

Questions  Is sickle cell trait a genetic risk factor for increased risk of ischemic stroke among African Americans?

Findings  In this meta-analysis of 4 studies with 19 464 African American participants, no association was found between heterozygosity for the sickle cell mutation or sickle cell trait and incidence of ischemic stroke among African Americans.

Meaning  Among African Americans, sickle cell trait may not be a genetic risk factor for ischemic stroke.

Abstract

Importance  African Americans and individuals of African ancestry have a higher risk of stroke compared with non-Hispanic white individuals. Identifying the source of this disparity could provide an opportunity for clinical stroke risk stratification and more targeted therapy. Whether sickle cell trait (SCT) is an indicator of increased risk of ischemic stroke among African Americans is still unclear.

Objective  To examine whether SCT is associated with a higher risk of incident ischemic stroke among African Americans.

Design, Setting, and Participants  This meta-analysis assessed the association of SCT with the risk of incident ischemic stroke. Four large, prospective, population-based studies with African American cohorts were assessed: Jackson Heart Study (September 1, 2005, through December 31, 2012), Multi-Ethnic Study of Atherosclerosis (July 1, 2002, through December 31, 2012), Reasons for Geographic and Racial Differences in Stroke (January 1, 2003, through December 31, 2014), and Women’s Health Initiative (October 1, 1998, through December 31, 2012). Using a Cox proportional hazards regression model adjusted for major stroke risk factors, this study estimated the hazard ratio for incident ischemic stroke associated with SCT. Data analysis was performed from July 10, 2016, to February 2, 2017.

Interventions or Exposures  Participants’ SCT status determined by polymerase chain reaction assay genotyping or a combination of whole-exome sequencing and imputation.

Main Outcomes and Measures  Incident ischemic stroke.

Results  This meta-analysis included 19 464 African American individuals (1520 with SCT, 17 944 without SCT, and 620 with ischemic stroke) from 4 studies, with a mean (SD) age of 60.0 (13.0) years (5257 [27.0%] men and 14 207 [73.0%] women). No differences were found in the distribution of risk factors for ischemic stroke comparing participants with and those without SCT at study visit 1 in each cohort. The crude incidence of ischemic stroke was 2.9 per 1000 person-years (95% CI, 2.2-4.0 per 1000 person-years) among those with SCT and 3.2 per 1000 person-years (95% CI, 2.7-3.8 per 1000 person-years) among those without SCT. After stroke risk factors were adjusted for, the hazard ratio of incident ischemic stroke independently associated with SCT in the meta-analysis of all 4 cohorts was 0.80 (95% CI, 0.47-1.35; P = .82). The results of the meta-analysis were similar to those of individual cohorts, in which the results were also similar.

Conclusions and Relevance  Sickle cell trait may not be associated with incidence of ischemic stroke among African Americans. The results of this study suggest performing a more thorough clinical evaluation of a stroke patient with SCT rather than assuming that SCT is the etiologic factor for the stroke.

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