Sickle cell allele HBB-rs334(T) is associated with decreased risk of childhood Burkitt lymphoma in East Africa.

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that significantly contributes to childhood cancer burden in sub-Saharan Africa. Plasmodium falciparum, which causes malaria, is geographically associated with BL, but the evidence remains insufficient for causal inference. Inference could be strengthened by demonstrating that mendelian genes known to protect against malaria-such as the sickle cell trait variant, HBB-rs334(T)-also protect against BL. We investigated this hypothesis among 800 BL cases and 3845 controls in four East African countries using genome-scan data to detect polymorphisms in 22 genes known to affect malaria risk. We fit generalized linear mixed models to estimate odds ratios (OR) and 95% confidence intervals (95% CI), controlling for age, sex, country, and ancestry. The ORs of the loci with BL and P. falciparum infection among controls were correlated (Spearman's ρ = 0.37, p = .039). HBB-rs334(T) was associated with lower P. falciparum infection risk among controls (OR = 0.752, 95% CI 0.628-0.9; p = .00189) and BL risk (OR = 0.687, 95% CI 0.533-0.885; p = .0037). ABO-rs8176703(T) was associated with decreased risk of BL (OR = 0.591, 95% CI 0.379-0.992; p = .00271), but not of P. falciparum infection. Our results increase support for the etiological correlation between P. falciparum and BL risk.

SMARCB1 regulates the hypoxic stress response in sickle cell trait.

Renal medullary carcinoma (RMC) is an aggressive kidney cancer that almost exclusively develops in individuals with sickle cell trait (SCT) and is always characterized by loss of the tumor suppressor SMARCB1. Because renal ischemia induced by red blood cell sickling exacerbates chronic renal medullary hypoxia in vivo, we investigated whether the loss of SMARCB1 confers a survival advantage under the setting of SCT. Hypoxic stress, which naturally occurs within the renal medulla, is elevated under the setting of SCT. Our findings showed that hypoxia-induced SMARCB1 degradation protected renal cells from hypoxic stress. SMARCB1 wild-type renal tumors exhibited lower levels of SMARCB1 and more aggressive growth in mice harboring the SCT mutation in human hemoglobin A (HbA) than in control mice harboring wild-type human HbA. Consistent with established clinical observations, SMARCB1-null renal tumors were refractory to hypoxia-inducing therapeutic inhibition of angiogenesis. Further, reconstitution of SMARCB1 restored renal tumor sensitivity to hypoxic stress in vitro and in vivo. Together, our results demonstrate a physiological role for SMARCB1 degradation in response to hypoxic stress, connect the renal medullary hypoxia induced by SCT with an increased risk of SMARCB1-negative RMC, and shed light into the mechanisms mediating the resistance of SMARCB1-null renal tumors against angiogenesis inhibition therapies.

COVID-19 Infection and Outcomes in Newborn Screening Cohorts of Sickle Cell Trait and Sickle Cell Disease in Michigan and Georgia.

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.

Tailored Parenting Plans of Young Adults With Sickle Cell Disease or Sickle Cell Trait.

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.

HIV-1 infection in sickle cell disease and sickle cell trait: role of iron and innate response.

INTRODUCTION: Sickle cell disease (SCD), an inherited hemoglobinopathy, affects primarily African Americans in the U.S.A. In addition, about 15% African Americans carry sickle cell trait (SCT). Despite the risk associated with blood transfusions, SCD patients have lower risk of acquiring HIV-1 infection. SCT individuals might also have some protection from HIV-1 infection. AREAS COVERED: Here, we will review recent and previous studies with the focus on molecular mechanisms that might underlie and contribute to the protection of individuals with SCD and SCT from HIV-1 infection. As both of these conditions predispose to hemolysis, we will focus our discussion on the effects of systemic and intracellular iron on HIV-1 infection and progression. We will also review changes in iron metabolism and activation of innate antiviral responses in SCD and SCT and their effects on HIV-1 infection. EXPERT OPINION: Previous studies, including ours, showed that SCD might protect from HIV-1 infection. This protection is likely due to the upregulation of complex protein network in response to hemolysis, hypoxia and interferon signaling. These findings are important not only for HIV-1 field but also for SCD cure efforts as antiviral state of SCD patients may adversely affect lentivirus-based gene therapy efforts.

Community based screening for sickle haemoglobin among pregnant women in Benue State, Nigeria: I-Care-to-Know, a Healthy Beginning Initiative.

BACKGROUND: Haemoglobin genotype screening at prenatal care offers women an opportunity to be aware of their genotype, receive education on sickle cell disease (SCD) and may increase maternal demand for SCD newborn screening. In developed countries, most pregnant women who access prenatal care and deliver at the hospital receive haemoglobin genotype screening. In settings with low prenatal care attendance and low hospital deliveries, community-based screening may provide similar opportunity for pregnant women. We assessed the feasibility and acceptability of integrating haemoglobin genotype screening into an existing community-based HIV program. METHODS: Onsite community-based integrated testing for HIV, hepatitis B virus and haemoglobin electrophoresis, were conducted for pregnant women and their male partners. Community Health Advisors implementing the NIH and PEPFAR-supported Healthy Beginning Initiative (HBI) program provided education on SCD, collected blood sample for haemoglobin electrophoresis and provided test results to participants enrolled into the HBI program. We concurrently conducted a cross-sectional study using a pretested, semi-structured, interviewer administered questionnaire to collect demographic data and assess awareness of individual haemoglobin "genotype" among HBI pregnant women participants. RESULTS: In this study, 99.9% (10,167/10,168) of pregnant women who received education on SCD accepted and completed the survey, had blood drawn for haemoglobin electrophoresis and received their results. A majority of participating pregnant women (97.0%) were not aware of their haemoglobin "genotype". Among the participants who were incorrect about their haemoglobin "genotype", 41.1% (23/56) of women who reported their haemoglobin "genotype" as AA were actually AS. The odds of haemoglobin "genotype" awareness was higher among participants who were in younger age group, completed tertiary education, had less number of pregnancies, and attended antenatal care. Overall prevalence of sickle cell trait (AS) was 18.7%. CONCLUSIONS: It is feasible to integrate haemoglobin "genotype" testing into an existing community-based maternal-child program. Most pregnant women who were unaware of their haemoglobin "genotype" accepted and had haemoglobin genotype testing, and received their test results. Increasing parental awareness of their own haemoglobin "genotype" could increase their likelihood of accepting newborn screening for SCD.

Perspectivas recientes del análisis morfológico automatizado en eritrocitos / Recent perspectives of the automated morphological analysis of erythrocytes

Introducción: La anemia drepanocítica es una anomalía genética hereditaria de la hemoglobina, que se caracteriza por la presencia de glóbulos rojos que pierden su forma redonda característica y adquieren forma de hoz. Aunque aún no tiene cura definitiva, se desarrollan varias acciones con el propósito de mejorar la calidad de vida y la atención médica a los pacientes. Objetivos: Conocer los aspectos referidos al análisis automatizado de formas en eritrocitos en los últimos años y proporcionar una visión en el caso de la drepanocitosis, que permita determinar las limitaciones actuales, principalmente para el empleo de herramientas automatizadas en el seguimiento clínico de pacientes con esta enfermedad. Método: Se realizó la revisión sistemática de la literatura de los años 2018, 2019 y dos aportes del 2020, en tres bases de datos electrónicas de amplio alcance: IEEEXplore, Google Scholar y SCOPUS. Los documentos se analizaron teniendo en cuenta preguntas específicas para obtener criterios generales sobre la situación de interés. Conclusiones: Los análisis realizados revelan un volumen creciente de investigaciones en este campo, con resultados de varios países. El examen detallado de las investigaciones permitió identificar problemas referidos a las métricas de evaluación empleadas, a los algoritmos para el análisis y procesamiento de imágenes, empleo del criterio médico, bases de datos empleadas y, herramientas para el análisis automático de formas de eritrocitos(AU)

Introduction: Sickle-cell anemia is a genetic hereditary anomaly of hemoglobin characterized by red blood cells that lose their normal round morphology and acquire a sickle shape. Although no cure is so far available, several actions are in progress to improve the quality of life and medical care of patients. Objective: Become acquainted with aspects related to the automated morphological analysis of erythrocytes in recent years, particularly in the context of sickle-cell anemia, allowing to determine the current limitations, mainly in the use of automated tools for the clinical follow-up of sickle-cell anemia patients. Methods: A systematic review was conducted of the literature published in the years 2018, 2019, and two contributions from 2020, in three broad scope electronic databases: IEEEXplore, Google Scholar and SCOPUS. The documents were analyzed on the basis of specific questions to obtain general criteria about the situation of interest. Conclusions: The analysis conducted revealed a growing volume of research in this field, with results in several countries. Detailed examination of the studies led to identification of problems related to the evaluation metrics used, the algorithms for the analysis and processing of images, the use of medical criteria, the databases used and tools for the automated morphological analysis of erythrocytes(AU)

Identifying Genetic and Biological Determinants of Race-Ethnic Disparities in Stroke in the United States.

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.

Sickle Cell Trait and Risk of Ischemic Stroke in Young Adults.

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, χ2 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.

Thirty-year risk of ischemic stroke in individuals with sickle cell trait and modification by chronic kidney disease: The atherosclerosis risk in communities (ARIC) study.

Sickle cell trait (SCT) has been associated with hypercoagulability, chronic kidney disease (CKD), and ischemic stroke. Whether concomitant CKD modifies long-term ischemic stroke risk in individuals with SCT is uncertain. We analyzed data from 3602 genotyped black adults (female = 62%, mean baseline age = 54 years) who were followed for a median 26 years by the Atherosclerosis Risk in Communities Study. Ischemic stroke was verified by physician review. Associations between SCT and ischemic stroke were analyzed using repeat-events Cox regression, adjusted for potential confounders. SCT was identified in 236 (7%) participants, who more often had CKD at baseline than noncarriers (18% vs 13%, P = .02). Among those with CKD, elevated factor VII activity was more prevalent with SCT genotype (36% vs 22%; P = .05). From 1987-2017, 555 ischemic strokes occurred in 436 individuals. The overall hazard ratio of ischemic stroke associated with SCT was 1.31 (95% CI: 0.95-1.80) and was stronger in participants with concomitant CKD (HR = 2.18; 95% CI: 1.16-4.12) than those without CKD (HR = 1.09; 95% CI: 0.74-1.61); P for interaction = .04. The hazard ratio of composite ischemic stroke and/or death associated with SCT was 1.20 (95% CI: 1.01-1.42) overall, 1.44 (95% CI: 1.002-2.07) among those with CKD, and 1.15 (95% CI: 0.94-1.39) among those without CKD; P for interaction = .18. The long-term risk of ischemic stroke associated with SCT relative to noncarrier genotype appears to be modified by concomitant CKD.

'It means everyone should know their status': exploring lay conceptions of sickle cell trait and sickle cell trait screening among African Americans within middle reproductive age.

OBJECTIVE: This study examined the meaning of sickle cell trait and sickle cell trait screening from the lay perspective of African Americans. DESIGN AND METHODS: African Americans (N = 300), ages 18-35 and unaware of their sickle cell trait status, completed two open-ended questions from a larger survey. One question asked for their understanding of sickle cell trait; the other asked for their understanding of sickle cell trait screening. Content analysis occurred in two phases: (1) In vivo and holistic coding; and (2) focused coding. RESULTS: Four categories emerged illustrating lay conceptions of sickle cell trait; (1) Perceived as an illness; (2) Perceived recognition of the inheritance pattern of sickle cell trait; (3) Perceived lack of knowledge of sickle cell trait; and (4) Perceived importance of sickle cell trait. Five categories emerged illustrating lay conceptions for sickle cell trait screening: (1) Perceived recognition that screening means getting tested for sickle cell trait; (2) Perceived lack of knowledge of sickle cell trait screening; (3) Perceived health benefit of sickle cell trait screening; (4) Perceived importance of sickle cell trait screening; and (5) Perceived barriers to sickle cell trait screening. CONCLUSIONS: Sickle cell trait and sickle cell trait screening are concepts that are both regarded as important among this high-risk population. However, there is still misunderstanding concerning the hereditary nature and reproductive implications of sickle cell trait. Interventions seeking to improve communication on the need for sickle cell trait screening should begin by identifying what the population at large understands, knows and/or believes to improve their ability to make informed health decisions.

[Prevalence of hemoglobin variants in quilombola communities in the state of Piauí, Brazil]. / Prevalência de hemoglobinas variantes em comunidades quilombolas no estado do Piauí, Brasil.

Hemoglobin variants (Hb) result from mutations in globin genes, with amino acid substitution in the polypeptide chain. Among the most common structural variants are HbS, HbC, HbD and HbE. The S hemoglobin gene is a high frequency gene across America and Brazil, where it is more frequent in the Southeast and Northeast. The scope of this article is to investigate the presence of hemoglobin variants in 15 quilombos (fugitive slave communities) of Piaui. The sample was of 1,239 people and hemoglobin was screened by high-performance liquid chromatography (HPLC). A questionnaire was applied related to gender, ethnicity and consanguinity. Of the samples analyzed, 5.4% had AS sickle cell trait, while SS and SC sickle cell anemia showed a rate of 0.8%, with AC, AD and DD hemoglobin. Of the 1,069 Afro-descendants, 84 revealed hemoglobin abnormalities, 34 being male 53 being female. There were 13 consanguineous marriages among the 84 hemoglobin alterations. The study of hemoglobin variants in 15 former quilombo communities in the state of Piaui contributes to their education in health in the aspects of genetic inheritance of hemoglobin, a relevant public health issue, providing input for the implementation of the State Program of Sickle Cell Disease of Piaui.

As hemoglobinas variantes (Hb) decorrem de mutações nos genes da globina. As variantes estruturais mais frequentes são HbS, HbC, HbD e HbE. O gene da hemoglobina S tem frequência elevada na América, enquanto que no Brasil é maior no Sudeste e Nordeste. O presente artigo tem por objetivo investigar a presença de hemoglobinas variantes em 15 comunidades quilombolas do estado do Piauí. Foram analisadas 1.239 amostras, nas quais as hemoglobinas foram triadas pela cromatografia líquida de alta eficiência (HPLC). Aplicou-se questionário referente a gênero, etnia e consanguinidade das populações. Das 1.239 amostras, 5,4% apresentaram o traço falciforme AS, as doenças falciformes SS e SC apareceram em 0,8% do total, nas hemoglobinas AC, AD e DD. Das 1.069 pessoas negras, 84 apresentaram alteração das hemoglobinas; destas, 34 eram do sexo masculino e 53 do feminino. Ocorreu a presença de 13 casamentos consanguíneos dentre as 84 alterações das hemoglobinas. O estudo das hemoglobinas variantes em 15 comunidades remanescentes de quilombos do Piauí contribui para sua educação em saúde frente aos aspectos da herança genética destas proteínas, relevante questão de saúde pública, proporcionando subsídios para a implantação do Programa Estadual da Doença Falciforme do Piauí.

Prevalência de hemoglobinas variantes em comunidades quilombolas no estado do Piauí, Brasil / Prevalence of hemoglobin variants in quilombola communities in the state of Piauí, Brazil

Resumo As hemoglobinas variantes (Hb) decorrem de mutações nos genes da globina. As variantes estruturais mais frequentes são HbS, HbC, HbD e HbE. O gene da hemoglobina S tem frequência elevada na América, enquanto que no Brasil é maior no Sudeste e Nordeste. O presente artigo tem por objetivo investigar a presença de hemoglobinas variantes em 15 comunidades quilombolas do estado do Piauí. Foram analisadas 1.239 amostras, nas quais as hemoglobinas foram triadas pela cromatografia líquida de alta eficiência (HPLC). Aplicou-se questionário referente a gênero, etnia e consanguinidade das populações. Das 1.239 amostras, 5,4% apresentaram o traço falciforme AS, as doenças falciformes SS e SC apareceram em 0,8% do total, nas hemoglobinas AC, AD e DD. Das 1.069 pessoas negras, 84 apresentaram alteração das hemoglobinas; destas, 34 eram do sexo masculino e 53 do feminino. Ocorreu a presença de 13 casamentos consanguíneos dentre as 84 alterações das hemoglobinas. O estudo das hemoglobinas variantes em 15 comunidades remanescentes de quilombos do Piauí contribui para sua educação em saúde frente aos aspectos da herança genética destas proteínas, relevante questão de saúde pública, proporcionando subsídios para a implantação do Programa Estadual da Doença Falciforme do Piauí.

Abstract Hemoglobin variants (Hb) result from mutations in globin genes, with amino acid substitution in the polypeptide chain. Among the most common structural variants are HbS, HbC, HbD and HbE. The S hemoglobin gene is a high frequency gene across America and Brazil, where it is more frequent in the Southeast and Northeast. The scope of this article is to investigate the presence of hemoglobin variants in 15 quilombos (fugitive slave communities) of Piaui. The sample was of 1,239 people and hemoglobin was screened by high-performance liquid chromatography (HPLC). A questionnaire was applied related to gender, ethnicity and consanguinity. Of the samples analyzed, 5.4% had AS sickle cell trait, while SS and SC sickle cell anemia showed a rate of 0.8%, with AC, AD and DD hemoglobin. Of the 1,069 Afro-descendants, 84 revealed hemoglobin abnormalities, 34 being male 53 being female. There were 13 consanguineous marriages among the 84 hemoglobin alterations. The study of hemoglobin variants in 15 former quilombo communities in the state of Piaui contributes to their education in health in the aspects of genetic inheritance of hemoglobin, a relevant public health issue, providing input for the implementation of the State Program of Sickle Cell Disease of Piaui.

Cellular function reinstitution of offspring red blood cells cloned from the sickle cell disease patient blood post CRISPR genome editing.

BACKGROUND: Sickle cell disease (SCD) is a disorder of red blood cells (RBCs) expressing abnormal hemoglobin-S (HbS) due to genetic inheritance of homologous HbS gene. However, people with the sickle cell trait (SCT) carry a single allele of HbS and do not usually suffer from SCD symptoms, thus providing a rationale to treat SCD. METHODS: To validate gene therapy potential, hematopoietic stem cells were isolated from the SCD patient blood and treated with CRISPR/Cas9 approach. To precisely dissect genome-editing effects, erythroid progenitor cells were cloned from single colonies of CRISPR-treated cells and then expanded for simultaneous gene, protein, and cellular function studies. RESULTS: Genotyping and sequencing analysis revealed that the genome-edited erythroid progenitor colonies were converted to SCT genotype from SCD genotype. HPLC protein assays confirmed reinstallation of normal hemoglobin at a similar level with HbS in the cloned genome-edited erythroid progenitor cells. For cell function evaluation, in vitro RBC differentiation of the cloned erythroid progenitor cells was induced. As expected, cell sickling assays indicated function reinstitution of the genome-edited offspring SCD RBCs, which became more resistant to sickling under hypoxia condition. CONCLUSIONS: This study is an exploration of genome editing of SCD HSPCs.

Anemia Offers Stronger Protection Than Sickle Cell Trait Against the Erythrocytic Stage of Falciparum Malaria and This Protection Is Reversed by Iron Supplementation.

BACKGROUND: Iron deficiency causes long-term adverse consequences for children and is the most common nutritional deficiency worldwide. Observational studies suggest that iron deficiency anemia protects against Plasmodium falciparum malaria and several intervention trials have indicated that iron supplementation increases malaria risk through unknown mechanism(s). This poses a major challenge for health policy. We investigated how anemia inhibits blood stage malaria infection and how iron supplementation abrogates this protection. METHODS: This observational cohort study occurred in a malaria-endemic region where sickle-cell trait is also common. We studied fresh RBCs from anemic children (135 children; age 6-24months; hemoglobin <11g/dl) participating in an iron supplementation trial (ISRCTN registry, number ISRCTN07210906) in which they received iron (12mg/day) as part of a micronutrient powder for 84days. Children donated RBCs at baseline, Day 49, and Day 84 for use in flow cytometry-based in vitro growth and invasion assays with P. falciparum laboratory and field strains. In vitro parasite growth in subject RBCs was the primary endpoint. FINDINGS: Anemia substantially reduced the invasion and growth of both laboratory and field strains of P. falciparum in vitro (~10% growth reduction per standard deviation shift in hemoglobin). The population level impact against erythrocytic stage malaria was 15.9% from anemia compared to 3.5% for sickle-cell trait. Parasite growth was 2.4 fold higher after 49days of iron supplementation relative to baseline (p<0.001), paralleling increases in erythropoiesis. INTERPRETATION: These results confirm and quantify a plausible mechanism by which anemia protects African children against falciparum malaria, an effect that is substantially greater than the protection offered by sickle-cell trait. Iron supplementation completely reversed the observed protection and hence should be accompanied by malaria prophylaxis. Lower hemoglobin levels typically seen in populations of African descent may reflect past genetic selection by malaria. FUNDING: National Institute of Child Health and Development, Bill and Melinda Gates Foundation, UK Medical Research Council (MRC) and Department for International Development (DFID) under the MRC/DFID Concordat.

Sickle cell trait diagnosis: clinical and social implications.

The sickle hemoglobin (HbS) point mutation has independently undergone evolutionary selection at least five times in the world because of its overwhelming malarial protective effects in the heterozygous state. In 1949, homozygous Hb S or sickle cell disease (SCD) became the first inherited condition identified at the molecular level; however, since then, both SCD and heterozygous Hb S, sickle cell trait (SCT), have endured a long and complicated history. Hasty adoption of early mass screening programs for SCD, recent implementation of targeted screening mandates for SCT in athletics, and concerns about stigmatization have evoked considerable controversy regarding research and policy decisions for SCT. Although SCT is a largely protective condition in the context of malaria, clinical sequelae, such as exercise-related injury, renal complications, and venous thromboembolism can occur in affected carriers. The historical background of SCD and SCT has provided lessons about how research should be conducted in the modern era to minimize stigmatization, optimize study conclusions, and inform genetic counseling and policy decisions for SCT.

Renal medullary carcinoma and sickle cell trait: A systematic review.

Sickle cell trait (SCT) carries a small risk of renal medullary carcinoma (RMC). We conducted a systematic literature review and reported new four RMC cases (total N = 217). Eighty eight percent had SCT and 8% had sickle cell disease; 50% were children. Males had 2.4× risk than females. Isolated hematuria or in combination with abdominal or flank pain was the presenting sign in 66% cases. Tumor-related mortality was 95%. Four non-metastatic patients were long-term disease-free survivors. Although risk appears to be very low, individuals with SCT should be informed about the low risk of RMC with the hope of early diagnosis. Hematuria should prompt immediate investigation.