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Sickle Cell Trait May Not Boost Risk of Stroke for African Americans

NEW YORK (GenomeWeb) – A new meta-analysis suggests that African Americans with the sickle cell trait may not necessarily be at enhanced risk of ischemic stroke, despite the increase in stroke risk documented in individuals of African ancestry.

Members of a large team led by investigators from Emory University, Johns Hopkins University, the University of Vermont, and elsewhere brought together data from four prospective population studies, including from more than 1,500 African Americans with the sickle cell trait — a heterozygous single base change in the hemoglobin beta subunit-coding gene HBB — and 17,944 without.

In contrast with the increased stroke risk previously reported for individuals with full-blown sickle cell anemia, the researchers identified 2.9 cases of ischemic stroke for every 1,000 person-years in individuals with the heterozygous sickle cell trait, compared with 3.2 ischemic stroke cases per 1,000 person-years in the sickle cell trait-free individuals. Likewise, they reported, individuals with or without the sickle cell trait appeared to have similar stroke rates after adjusting for other known stroke risk contributors.

"The results of this study suggest performing a more thorough clinical evaluation of a stroke patient with [sickle cell trait] rather than assuming that [sickle cell trait] is the etiologic factor for the stroke," corresponding and first author Hyacinth Hyacinth, a pediatric researcher at Emory University's Aflac Cancer and Blood Disorder Center, and his colleagues wrote in a study published today in JAMA Neurology.

The researchers noted that while age-adjusted stroke rates are on the decline in non-Hispanic white individuals in the US, stroke risk remains relatively high in African American individuals, who are also more prone to stroke at earlier ages. They reasoned that genetic contributors, including sickle cell mutations, may contribute to this discrepancy, prompting the current meta-analysis of ischemic stroke incidence in sickle cell carriers.

Although the sickle cell trait has been implicated in a range of cardiovascular changes, including enhanced pulmonary embolism risk, the authors noted that there has been ongoing debate about whether ischemic stroke risk is itself linked to sickle cell heterozygosity. "The aim of our study was to provide more definitive data on the association between [sickle cell trait] and incident ischemic stroke in African Americans," they wrote.

Using data for 19,464 African American individuals participating in the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, the Reasons for Geographic and Racial Differences in Stroke, or the Women's Health Initiative, the team identified 1,520 sickle cell trait carriers with a well-known single nucleotide change in HBB based on available genotyping, exome sequence, and/or imputed data. Another 17,944 African American individuals appeared to be free from the sickle cell trait.

Folding in information from the participants' hospitalization records or self-reported cardiovascular events, the researchers saw 620 ischemic stroke cases. But neither the crude stroke incidence rates nor the risk-adjusted stroke rates revealed associations between ischemic stroke and the sickle cell trait.

The study authors cautioned that nearly half of the individuals included in the analysis were not genotyped directly. Consequently, they noted that it is possible that sickle cell trait status was incorrect for some of the individuals with imputed data, though they estimated that misclassification rates are relatively low in the imputed data.

"Future studies with large numbers of African Americans, longer follow-up, and carefully subtyped ischemic stroke events are needed to further elucidate the possible association of [sickle cell trait] with incident ischemic stroke overall and by specific ischemic stroke subtypes," Hyacinth and his colleagues concluded.