Alpha thalassemia, but not βS-globin haplotypes, influence sickle cell anemia clinical outcome in a large, single-center Brazilian cohort

Hatzlhofer, Betânia Lucena Domingues; Pereira-Martins, Diego A; Domingos, Igor de Farias; Arcanjo, Gabriela da Silva; Weinhäuser, Isabel; Falcão, Daniela; Farias, Isabela Cristina Cordeiro; Batista, Jéssica Vitória Gadelha de Freitas; Prado, Luana Priscilla Laranjeira; Oliveira, Jéssica Maria; Batista, Thais Helena Chaves; Sobreira, Marcondes José de Vasconcelos Costa; Santana, Rodrigo Marcionilo; Araújo, Amanda Bezerra de Sá; Melo, Márcia Almeida de; Ancântara, Bruna Vasconcelos de; Coelho-Silva, Juan Luiz; Rafael, Ana Beatriz Lucas de Moura; Silva, Danízia Menezes de Lima; Albuquerque, Flávia Peixoto; Santos, Magnun Nueldo Nunes; Anjos, Ana Claudia; Costa, Fernando Ferreira; Araújo, Aderson da Silva; Lucena-Araújo, Antonio R.; Bezerra, Marcos André Cavalcanti

doi:10.1007/s00277-021-04450-x

Cited by 4 publications

(2 citation statements)

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“…In addition, there is an independent haplotype in India and Saudi Arabia [ 211 ]. However, the majority of the available data suggests that the β-haplotypes are not associated with stroke [ 93 , 212 , 213 , 214 , 215 ] and, although there have been few studies in Africa, there is currently no evidence that there are large difference in prevalence of stroke between populations [ 4 , 47 ]. Stroke risk is reduced in the presence of co-inherited alpha-thalassemia [ 85 , 215 , 216 ].…”

Section: Risk Factors For Neurological Cognitive and Neuroradiological Abnormalitiesmentioning

confidence: 99%

“…However, the majority of the available data suggests that the β-haplotypes are not associated with stroke [ 93 , 212 , 213 , 214 , 215 ] and, although there have been few studies in Africa, there is currently no evidence that there are large difference in prevalence of stroke between populations [ 4 , 47 ]. Stroke risk is reduced in the presence of co-inherited alpha-thalassemia [ 85 , 215 , 216 ]. The effect of co-inherited Glucose-6-phosphate dehydrogenase deficiency remains controversial [ 85 , 193 , 217 , 218 , 219 , 220 , 221 ].…”

Section: Risk Factors For Neurological Cognitive and Neuroradiological Abnormalitiesmentioning

confidence: 99%

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Epidemiology of Stroke in Sickle Cell Disease

Kirkham

Lagunju

2021

JCM

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Sickle cell disease is the most common cause of stroke in childhood, both ischaemic and haemorrhagic, and it also affects adults with the condition. Without any screening or preventative treatment, the incidence appears to fall within the range 0.5 to 0.9 per 100 patient years of observation. Newborn screening with Penicillin prophylaxis and vaccination leading to reduced bacterial infection may have reduced the incidence, alongside increasing hydroxyurea prescription. Transcranial Doppler screening and prophylactic chronic transfusion for at least an initial year has reduced the incidence of stroke by up to 10-fold in children with time averaged mean of the maximum velocity >200 cm/s. Hydroxyurea also appears to reduce the incidence of first stroke to a similar extent in the same group but the optimal dose remains controversial. The prevention of haemorrhagic stroke at all ages and ischaemic stroke in adults has not yet received the same degree of attention. Although there are fewer studies, silent cerebral infarction on magnetic resonance imaging (MRI), and other neurological conditions, including headache, epilepsy and cognitive dysfunction, are also more prevalent in sickle cell disease compared with age matched controls. Clinical, neuropsychological and quantitative MRI screening may prove useful for understanding epidemiology and aetiology.

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Section: Risk Factors For Neurological Cognitive and Neuroradiological Abnormalitiesmentioning

confidence: 99%

Section: Risk Factors For Neurological Cognitive and Neuroradiological Abnormalitiesmentioning

confidence: 99%

Epidemiology of Stroke in Sickle Cell Disease

Kirkham

Lagunju

2021

JCM

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Genetic Variation and Sickle Cell Disease Severity

Kirkham,

Estepp,

Weiss

et al. 2023

JAMA Netw Open

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ImportanceSickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD remain poorly understood.ObjectiveTo assess all reported genetic modifiers of SCD, evaluate the design of associated studies, and provide guidelines for future analyses according to modern genetic study recommendations.Data SourcesPubMed, Web of Science, and Scopus were searched through May 16, 2023, identifying 5290 publications.Study SelectionAt least 2 reviewers identified 571 original, peer-reviewed English-language publications reporting genetic modifiers of human SCD phenotypes, wherein the outcome was not treatment response, and the comparison was not between SCD subtypes or including healthy controls.Data Extraction and SynthesisData relevant to all genetic modifiers of SCD were extracted, evaluated, and presented following STREGA and PRISMA guidelines. Weighted z score meta-analyses and pathway analyses were conducted.Main Outcomes and MeasuresOutcomes were aggregated into 25 categories, grouped as acute complications, chronic conditions, hematologic parameters or biomarkers, and general or mixed measures of SCD severity.ResultsThe 571 included studies reported on 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries. Of the 17 757 extracted results (4890 significant) in 1552 genes, 3675 results met the study criteria for meta-analysis: reported phenotype and genotype, association size and direction, variability measure, sample size, and statistical test. Only 173 results for 62 associations could be cross-study combined. The remaining associations could not be aggregated because they were only reported once or methods (eg, study design, reporting practice) and genotype or phenotype definitions were insufficiently harmonized. Gene variants regulating fetal hemoglobin and α-thalassemia (important markers for SCD severity) were frequently identified: 19 single-nucleotide variants in BCL11A, HBS1L-MYB, and HBG2 were significantly associated with fetal hemoglobin (absolute value of Z = 4.00 to 20.66; P = 8.63 × 10−95 to 6.19 × 10−5), and α-thalassemia deletions were significantly associated with increased hemoglobin level and reduced risk of albuminuria, abnormal transcranial Doppler velocity, and stroke (absolute value of Z = 3.43 to 5.16; P = 2.42 × 10−7 to 6.00 × 10−4). However, other associations remain unconfirmed. Pathway analyses of significant genes highlighted the importance of cellular adhesion, inflammation, oxidative and toxic stress, and blood vessel regulation in SCD (23 of the top 25 Gene Ontology pathways involve these processes) and suggested future research areas.Conclusions and RelevanceThe findings of this comprehensive systematic review and meta-analysis of all published genetic modifiers of SCD indicated that implementation of standardized phenotypes, statistical methods, and reporting practices should accelerate discovery and validation of genetic modifiers and development of clinically actionable genetic profiles.

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