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Background: Severe malaria is associated with impaired nitric oxide (NO) synthase (NOS)-dependent vasodilation, and reversal of this deficit improves survival in murine models. Malaria might have selected for genetic polymorphisms that increase endothelial NO signaling and now contribute to heterogeneity in vascular function among humans. One protein potentially selected for is alpha globin, which, in mouse models, interacts with endothelial NOS (eNOS) to negatively regulate NO signaling. We sought to evaluate the impact of alpha globin gene deletions on NO signaling and unexpectedly found human arteries use not only alpha but also beta globin to regulate eNOS., Methods: The eNOS-hemoglobin complex was characterized by multiphoton imaging, gene expression analysis, and coimmunoprecipitation studies of human resistance arteries. Novel contacts between eNOS and hemoglobin were mapped using molecular modeling and simulation. Pharmacological or genetic disruption of the eNOS-hemoglobin complex was evaluated using pressure myography. The association between alpha globin gene deletion and blood pressure was assessed in a population study., Results: Alpha and beta globin transcripts were detected in the endothelial layer of the artery wall. Imaging colocalized alpha and beta globin proteins with eNOS at myoendothelial junctions. Immunoprecipitation demonstrated that alpha globin and beta globin form a complex with eNOS and cytochrome b5 reductase. Modeling predicted negatively charged glutamic acids at positions 6 and 7 of beta globin to interact with positively charged arginines at positions 97 and 98 of eNOS. Arteries from donors with a glutamic acid-to-valine substitution at beta globin position 6 (sickle trait) exhibited increased NOS-dependent vasodilation. Alpha globin gene deletions were associated with decreased arterial alpha globin expression, increased NOS-dependent vasodilation, and lower blood pressure. Mimetic peptides that targeted the interactions between hemoglobin and eNOS recapitulated the effects of these genetic variants on human arterial vasoreactivity., Conclusions: Alpha and beta globin subunits of hemoglobin interact with eNOS to restrict NO signaling in human resistance arteries. Malaria-protective genetic variants that alter the expression of alpha globin or the structure of beta globin are associated with increased NOS-dependent vasodilation. Targeting the hemoglobin-eNOS interface could potentially improve NO signaling in diseases of endothelial dysfunction such as severe malaria or chronic cardiovascular conditions., Competing Interests: H.C.A., S.B., and P.C. are co-inventors on a patent held by the National Institute of Allergy and Infectious Diseases for structures and uses of beta globin mimetic peptides (PCT/US2023/065432). The other authors report no conflicts.

Abstract: Sickle cell trait is typically thought to be an asymptomatic carrier state, but it is rarely associated with exertional rhabdomyolysis in cases termed Exercise Collapse Associated with Sickle Cell Trait (ECAST). In a subset of these cases, underlying disease contributes to the development and/or severity of the ensuing medical complications. We describe the first ever case of ECAST reported in a previously asymptomatic, multiply deployed, highly physically active service member with an underlying heterozygous LAMA2 mutation. Moreover, the mutation identified via whole exome sequencing is a novel, likely pathogenic variant that has yet to be described in the literature., Competing Interests: Conflicts of interest and sources of funding: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The sickle cell mutation increases morbidity in those with sickle cell disease (SCD) and potentially sickle cell trait, impacting pulmonary, coagulation, renal, and other systems that are implicated in COVID-19 severity. There are no population-based registries for hemoglobinopathies, and they are not tracked in COVID-19 testing. We used COVID-19 test data from 2 states linked to newborn screening data to estimate COVID outcomes in people with SCD or trait compared with normal hemoglobin. We linked historical newborn screening data to COVID-19 tests, hospitalization, and mortality data and modeled the odds of hospitalization and mortality. Georgia's cohort aged 0 to 12 years; Michigan's, 0 to 33 years. Over 8% of those in Michigan were linked to positive COVID-19 results, and 4% in Georgia. Those with SCD showed significantly higher rates of COVID-19 hospitalization than the normal hemoglobin Black cohort, and Michigan had higher rates of mortality as well. Outcomes among those with the trait did not differ significantly from the normal hemoglobin Black group. People with SCD are at increased risk of COVID-19-related hospitalization and mortality and are encouraged to be vaccinated and avoid infection. Persons with the trait were not at higher risk of COVID-related severe outcomes., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Our study purpose was to evaluate the variation and accuracy of tailored parenting plans individually generated as a supplement to reproductive health education on the genetic inheritance of sickle cell disease or sickle cell trait. We present a secondary data analysis of experimental group data from a randomized controlled trial. Participants completed the valid and reliable Internet-based Sickle Cell Reproductive Health Knowledge Parenting Intent Questionnaire. We created a computerized algorithm that used participants' responses to generate tailored parenting plans based on their parenting preferences and partner's sickle cell status. Thirty-one different parenting plans were generated to meet the variety in the participants' preferences. The most frequently generated plan was for participants with sickle cell disease who had a partner with hemoglobin AA, who wanted to be a parent, was not likely to be pregnant, and wanted their child to be sickle cell disease free. More than half of the participants required alteration in their reproductive behavior to achieve their parenting goals. Findings provide insight into the variety and accuracy of computer algorithm-generated parenting plans, which could further guide refinement of the algorithm to produce patient-centered, tailored parenting plans supplemental to Internet-based genetic inheritance education., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

In the United States, causes of racial differences in stroke and its risk factors remain only partly understood, and there is a long-standing disparity in stroke incidence and mortality impacting Black Americans. Only half of the excess risk of stroke in the United States Black population is explained by traditional risk factors, suggesting potential effects of other factors including genetic and biological characteristics. Here, we nonsystematically reviewed candidate laboratory biomarkers for stroke and their relationships to racial disparities in stroke. Current evidence indicates that IL-6 (interleukin-6), a proinflammatory cytokine, mediates racial disparities in stroke through its association with traditional risk factors. Only one reviewed biomarker, Lp(a) (lipoprotein[a]), is a race-specific risk factor for stroke. Lp(a) is highly genetically determined and levels are substantially higher in Black than White people; clinical and pharmaceutical ramifications for stroke prevention remain uncertain. Other studied stroke risk biomarkers did not explain racial differences in stroke. More research on Lp(a) and other biological and genetic risk factors is needed to understand and mitigate racial disparities in stroke.

Background and Purpose: Approximately 8% of Blacks have sickle cell trait (SCT), and there are conflicting reports from recent cohort studies on the association of SCT with ischemic stroke (IS). Most prior studies focused on older populations, with few data available in young adults., Methods: A population-based case-control study of early-onset IS was conducted in the Baltimore-Washington region between 1992 and 2007. From this study, 342 Black IS cases, ages 15 to 49, and 333 controls without IS were used to examine the association between SCT and IS. Each participant's SCT status was established by genotyping and imputation. For analysis, χ 2 tests and logistic regression models were performed with adjustment for potential confounding variables., Results: Participants with SCT (n=55) did not differ from those without SCT (n=620) in prevalence of hypertension, previous myocardial infarction, diabetes mellitus, and current smoking status. Stroke cases had increased prevalence in these risk factors compared with controls. We did not find an association between SCT and early-onset IS in our overall population (odds ratio=0.9 [95% CI, 0.5-1.7]) or stratified by sex in males (odds ratio=1.26 [95% CI, 0.56-2.80]) and females (odds ratio=0.67 [95% CI, 0.28-1.69])., Conclusions: Our data did not find evidence of increased risk of early-onset stroke with SCT.

Sickle cell disease and sickle cell trait are identified through universal newborn screening, which has been implemented in all hospitals across the United States since the 1970s. Yet, studies report that only 16% of Americans with sickle cell trait know their status. Despite these striking statistics, there appears to be no standardized methods for reporting positive sickle cell trait results of newborn screening to doctors or families of affected persons. This article will demonstrate how current literature supports the gaps in knowledge of trait status and its implications as well as knowledge deficit of inheritance patterns of prospective parents. The article will also elucidate how knowledge deficit in this subject adversely affects primary prevention strategies including genetic counseling. Primary prevention of sickle cell disease is a public health area that can be championed by registered nurses who have the tools and experiences to effectively handle case management and patient education.

Objective: Plasma levels of the fibrinogen degradation product D-dimer are higher among African Americans (AAs) compared with those of European ancestry and higher among women compared with men. Among AAs, little is known of the genetic architecture of D-dimer or the relationship of D-dimer to incident cardiovascular disease., Approach and Results: We measured baseline D-dimer in 4163 AAs aged 21 to 93 years from the prospective JHS (Jackson Heart Study) cohort and assessed association with incident cardiovascular disease events. In participants with whole genome sequencing data (n=2980), we evaluated common and rare genetic variants for association with D-dimer. Each standard deviation higher baseline D-dimer was associated with a 20% to 30% increased hazard for incident coronary heart disease, stroke, and all-cause mortality. Genetic variation near F3 was associated with higher D-dimer (rs2022030, β=0.284, P =3.24×10 -11 ). The rs2022030 effect size was nearly 3× larger among women (β=0.373, P =9.06×10 -13 ) than among men (β=0.135, P =0.06; P interaction =0.009). The sex by rs2022030 interaction was replicated in an independent sample of 10 808 multiethnic men and women ( P interaction =0.001). Finally, the African ancestral sickle cell variant ( HBB rs334) was significantly associated with higher D-dimer in JHS (β=0.507, P =1.41×10 -14 ), and this association was successfully replicated in 1933 AAs ( P =2.3×10 -5 )., Conclusions: These results highlight D-dimer as an important predictor of cardiovascular disease risk in AAs and suggest that sex-specific and African ancestral genetic effects of the F3 and HBB loci contribute to the higher levels of D-dimer among women and AAs., (© 2017 American Heart Association, Inc.)

Purpose: It remains unclear whether habitual physical activity in sickle cell trait (SCT) carriers modulates the levels of resting and postexercise vascular adhesion and inflammatory molecules., Methods: Plasma levels of pro-inflammatory (interleukin (IL)-4, IL-5, IL-8, sCD40L, and tumor necrosis factor α) and anti-inflammatory (IL-10) cytokines and adhesion molecules (soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), sP-selectin, or sE-selectin) were assessed at rest and in response to an incremental exercise to exhaustion in untrained (UT: no regular physical activity) and trained (T: soccer players, 8 h·wk minimum) SCT and control (CON) subjects (n = 8 per group; age = 23.5 ± 0.35 yr)., Results: sVCAM-1 levels were significantly higher in the UT-SCT group than that in T-SCT group (+43.5%) at rest, at the end, and at 1, 2, and 24 h after the end of the exercise. For the other molecules, no differences emerged among the groups at rest, but in response to exercise plasma, sICAM-1, sVCAM-1, sE-selectin, and sCD40L increased in all groups, and sP-selectin only increased in the UT group. All values that increased with the acute exercise returned to their respective baseline levels 1 h after the end of the exercise., Conclusions: A physically active lifestyle in SCT carriers may decrease endothelial activation and may limit the risk for vascular adhesion events in the microcirculation of SCT subjects.

A Turkish Cypriot family was investigated for suspected heterozygous sickle cell disease, which had been reported in a maternal branch of the family resident in England. Two maternal grandparents were of African Negro origin. Pseudosickling was noted in members of the family who were found to have an abnormal hemoglobin fraction. This abnormal fraction proved to be Hemoglobin Setif (alpha 94 Asp leads to Tyr). Family studies demonstrated the presence of this hemoglobin in varying proportions in the mother and 2 of the 4 children. alpha and beta thalassemia traits are also present in several family members.