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The clinical and phenotypic heterogeneity of patients with sickle cell anemia (SCA) is influenced by environmental and genetic factors. Several genetic modifiers, such as the KLOTHO (KL) gene, have been associated with SCA clinical outcomes. The KL gene and its encoded proteins are implicated in important biological pathways, which affect the disease’s pathophysiology, such as expression of adhesion molecules VCAM-1 and ICAM-1, oxidative stress, and nitric oxide biology. Here, we evaluated the clinical relevance of two polymorphisms found on the KL gene (rs685417 and rs211239) in 588 unrelated patients with SCA. Genotyping analyses were performed using the TaqMan system. The KL rs211239 was associated with increased number of vaso-occlusive crisis (VOCs) per year (P = 0.001), while KL rs685417 was associated with increased frequency of stroke (P = 0.034), priapism (P = 0.011), number of complications (P = 0.019), and with a lower incidence of priapism (P = 0.036). Additionally, the associations with VOCs, stroke, and priapism remained consistent in multivariate analyses (P < 0.05). Our data highlight the clinical importance of KL in SCA.

Alpha thalassemia and beta-globin haplotype are considered classical genetic disease modifiers in sickle cell anemia (SCA) causing clinical heterogeneity. Nevertheless, their functional impact on SCA disease emergence and progression remains elusive. To better understand the role of alpha thalassemia and beta-globin haplotype in SCA, we performed a retrospective study evaluating the clinical manifestations of 614 patients. The univariate analysis showed that the presence of alpha-thalassemia -3.7-kb mutation (αα/-α and -α/-α) decreased the risk of stroke development (p = 0.046), priapism (p = 0.033), and cholelithiasis (p = 0.021). Furthermore, the cumulative incidence of stroke (p = 0.023) and cholelithiasis (p = 0.006) was also significantly lower for patients carrying the alpha thalassemia -3.7-kb mutation. No clinical effects were associated with the beta-globin haplotype analysis, which could be explained by the relatively homogeneous haplotype composition in our cohort. Our results reinforce that alpha thalassemia can provide protective functions against hemolysis-related symptoms in SCA. Although, several genetic modifiers can impact the inflammatory state of SCA patients, the alpha thalassemia mutation remains one of the most recurrent genetic aberration and should therefore always be considered first.

Hyperbilirubinemia in patients with sickle cell anemia (SCA) as a result of enhanced erythrocyte destruction, lead to cholelithiasis development in a subset of patients. Evidence suggests that hyperbilirubinemia may be related to genetic variations, such as the UGT1A1 gene promoter polymorphism, which causes Gilbert syndrome (GS). Here, we aimed to determine the frequencies of UGT1A1 promoter alleles, alpha thalassemia, and βS haplotypes and analyze their association with cholelithiasis and bilirubin levels. The UGT1A1 alleles, -3.7 kb alpha thalassemia deletion and βS haplotypes were determined using DNA sequencing and PCR-based assays in 913 patients with SCA. The mean of total and unconjugated bilirubin and the frequency of cholelithiasis in GS patients were higher when compared to those without this condition, regardless of age (P 0.05). However, not cholelithiasis but total and unconjugated bilirubin levels were associated with βS haplotype. These findings confirm in a large cohort that the UGT1A1 polymorphism influences cholelithiasis and hyperbilirubinemia in SCA. HbF and alpha thalassemia also appear as modulators for cholelithiasis risk.

Objective: This study has as objective to verify whether MBL2 gene polymorphisms are related to the occurrence of cerebrovascular disease (CD) in sickle cell anemia (SCA) patients. Methods: Overall, 259 unrelated SCA patients were enrolled. The patients were divided into three groups: control group, stroke group ad range of risk group. Peripheral blood samples were collected and DNA extraction was performed. All patients were genotyped for exon 1, promoter region -221 and promoter region -550 of MBL2 gene, along with β-globin gene haplotypes. Results: Concerning the genotyping of the MBL2, there was no difference in the frequency of allelic and genotypic variants of the exon 1 and the promoter regions -221 and -550 of the MBL2 gene among the studied groups. Conclusion: Despite the small number of patients, and the lack of association between MBL2 polymorphisms and CD, our study represents an effort to understand the impact of MBL2 polymorphisms in the clinical outcome of patients with SCA. Objetivo: Este estudio tiene como objetivo verificar si los polimorfismos del gen MBL2 están relacionados con la aparición de enfermedad cerebrovascular (EC) en pacientes con anemia falciforme (AF). Métodos: en total, se incluyeron 259 pacientes con AF no relacionada. Los pacientes se dividieron en tres grupos: grupo de control, grupo de accidente cerebrovascular y rango de riesgo. Se recogieron muestras de sangre periférica y se realizó extracción de DNA. Todos los pacientes fueron genotipados para el exón 1, la región promotora -221 y la región promotora -550 del gen MBL2, junto con los haplotipos del gen de la β-globina. Resultados: con respecto al genotipo MBL2, no hubo diferencia en la frecuencia de variantes alélicas y genotípicas del exón 1 y en las regiones promotoras -221 y -550 del gen MBL2 entre los grupos estudiados. Conclusión: a pesar del pequeño número de pacientes y la falta de asociación entre los polimorfismos MBL2 y EC, nuestro estudio representa un esfuerzo por comprender el impacto de los polimorfismos MBL2 en el curso clínico de los pacientes com AF. Objetivo: Este estudo tem como objetivo verificar se os polimorfismos do gene MBL2 estão relacionados com a ocorrência de doença cerebrovascular (DC) em pacientes com anemia falciforme (AF). Métodos: No total, 259 pacientes com AF não relacionados foram incluídos. Os pacientes foram divididos em três grupos: grupo controle, grupo acidente vascular cerebral (AVC) e faixa de risco. Amostras de sangue periférico foram coletadas e foi realizada extração de DNA. Todos os pacientes foram genotipados para o éxon 1, região promotora -221 e região promotora -550 do gene MBL2, juntamente com os haplótipos do gene da β-globina. Resultados: Em relação à genotipagem do MBL2, não houve diferença na frequência das variantes alélicas e genotípicas do éxon 1 e nas regiões promotoras -221 e -550 do gene MBL2 entre os grupos estudados. Conclusão: Apesar do pequeno número de pacientes e da falta de associação entre polimorfismos do MBL2 e DC, nosso estudo representa um esforço para entender o impacto dos polimorfismos do MBL2 no curso clínico de pacientes com AF.

Overt stroke in adults with sickle cell anemia (SCA) continues to be a major cause of morbidity and mortality, while no evidence-based strategy for prevention has been reached so far. Although transcranial Doppler ultrasonography represents the most important tool for identifying young patients with SCA at risk of primary stroke, strategies for stroke prediction in adulthood remain challenging. Emerging data suggest that oxidative stress may exert a pivotal role in the pathogenesis of ischemic brain injury. Combining these pieces of evidences with the well-known genetic contribution to the development of stroke in SCA, we hypothesized that genetic variants related to the biology of oxidative stress could be used to identify adult patients at higher risk of stroke. Overall, 499 unrelated patients with SCA aged >18 years were genotyped for SOD2 Val16Ala (rs4880), GPX3 T-568C (rs8177404), GPX3 T-518C (rs8177406), GPX3 T-65C (rs8177412), and CAT01 C-262 T (rs1001179) polymorphisms, along with α-thalassemia status and β-globin gene haplotypes. Of these, only the SOD2 Val16Ala polymorphism was associated with stroke. SOD2 Val16Ala polymorphism was independently associated with risk of stroke (odds ratio: 1.98; 95% confidence interval [CI]: 1.18–3.32; P = .009) and with the long-term cumulative incidence of stroke (hazard ratio: 2.24, 95% CI: 1.3–3.9; P = .004). In summary, we provide evidence that oxidative stress-related genetic variants, in particular, the SOD2 Val16Ala polymorphism, may represent a simple and inexpensive alternative for identifying patients at risk of stroke.

Sickle cell anemia (SCA) presents heterogenous clinical manifestations that cannot be explained solely by alterations to hemoglobin (Hb); other components such as endothelial adhesion, thrombosis and inflammation may be involved. The mannose-binding lectin (MBL) has an important role in innate immunity and inflammatory diseases. In this report, we describe an association between MBL2 polymorphism related to low production of serum MBL and the frequency of vasoocclusive events (FVOE) in children ≤ 5 years old with SCA (p = 0.0229; OR 5.55; CI 1.11-27.66). Further studies are needed to explore the role of low MBL2 in the pathophysiology of vasoocclusive events in SCA.

The SOD2 polymorphism Val16Ala TàC influences the antioxidative response. This study investigated the association of the SOD2 polymorphism and superoxide dismutase (SOD) activity with vaso-occlusive crisis (VOC) and acute splenic sequestration (ASS) in children with sickle cell anemia (SCA). One hundred ninety-five children aged 1-9 years old were analyzed. The TC and CC genotypes were associated with lower SOD activity compared with the TT genotype (p=0.0321; p=0.0253, respectively). Furthermore, TC/CC were more frequent in patients with VOC or ASS (p=0.0285; p=0.0090, respectively). These results suggest that the SOD2 polymorphism associated with low SOD activity could be involved in SCA physiopathology.

BACKGROUND: Sickle cell disease is the most common monogenic hereditary disease in Brazil. Although strokes are one of the main causes of morbidity and mortality in these patients, the use of transcranial Doppler to identify children at risk is not universally used. OBJECTIVE: To develop Brazilian guidelines for the use of transcranial Doppler in sickle cell disease children and adolescents, so that related health policies can be expanded, and thus contribute to reduce morbidity and mortality. METHODS: The guidelines were formulated in a consensus meeting of experts in transcranial Doppler and sickle cell disease. The issues discussed were previously formulated and scientific articles in databases (MEDLINE, SciELO and Cochrane) were carefully analyzed. The consensus for each question was obtained by a vote of experts on the specific theme. RESULTS: Recommendations were made, including indications for the use of transcranial Doppler according to the sickle cell disease genotype and patients age; the necessary conditions to perform the exam and its periodicity depending on exam results; the criteria for the indication of blood transfusions and iron chelation therapy; the indication of hydroxyurea; and the therapeutic approach in cases of conditional transcranial Doppler. CONCLUSION: The Brazilian guidelines on the use of transcranial doppler in sickle cell disease patients may reduce the risk of strokes, and thus reduce the morbidity and mortality and improve the quality of life of sickle cell disease patients. Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti Faculdade de Ciências Médicas da Santa Casa de São Paulo Fundação de Hematologia e Hemoterapia de Pernambuco Universidade de São Paulo Faculdade de Medicina de Ribeirão Preto Hospital das Clínicas Fundação Hemocentro Fundação Centro de Hematologia e Hemoterapia de Minas Gerais UFRGS Hospital de Clínicas de Porto Alegre Serviço de Hematologia e Transplante de Medula Óssea Universidade Federal de São Paulo (UNIFESP) Universidade Federal do Paraná Hospital de Clínicas Serviço de Neurologia Ecodopler Laboratório Universidade Federal do Rio de Janeiro Instituto de Puericultura e Pediatria Martagão Gesteira Medical University of South Carolina Universidade de São Paulo Faculdade de Medicina Universidade Federal de São Paulo, EPM, São Paulo, Brazil SciELO

Introduction Patients with sickle cell anemia (SCA) may present chronic hemolytic anemia, vaso-occlusion and respiratory tract infection (RTI) episodes. Galectin-3 (GAL-3) is a multifunctional protein involved in inflammation, apoptosis, adhesion and resistance to reactive oxygen species. Studies point to a dual role for GAL-3 as both a circulation damage-associated molecular pattern and a cell membrane associated pattern recognition receptor. Objective To investigate associations between the SNPs of GAL-3 gene (LGALS3) and serum levels with RTI and vaso-occlusive crisis (VOC) in children with SCA. Materials and Methods SNPs +191 and +292 in LGALS3 were studied using the TaqMan real-time PCR system; GAL-3 serum levels were measured by ELISA. The study included 79 children with SCA ranging from 2 to 12 years old. Results GAL-3 serum levels were associated with LGALS3 +191 and +292 genotypes (p