Inheritance of the Bantu/Benin haplotype causes less severe hemolytic and oxidative stress in sickle cell anemia patients treated with hydroxycarbamide

Okumura, Jéssika Viviani; Silva, Danilo G. H.; Torres, Lidiane de Souza; Junior, Edis Belini; Barberino, Willian Marcel; Oliveira, Renan Garcia de; Carrocini, Gisele C S; Gelaleti, Gabriela Bottaro; Lobo, Clarisse; Bonini-Domingos, Cláudia Regina

doi:10.1038/jhg.2016.16

Cited by 4 publications

(2 citation statements)

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“… 29 Rs770702363, found in the ACY1, is associated with aminoacylase 1 deficiency. 30 In addition, several genes, previously linked to hematological disorders, are also associated with HBB, 31 G6BD 32 - 34 and ABCG5, 35 were identified in several populations, including Saudi, with a higher MAF compared to the other variants ( Table 1 ).…”

Section: Discussionmentioning

confidence: 99%

Common disease-associated gene variants in a Saudi Arabian population

et al. 2022

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BACKGROUND: Screening programs for the most prevalent conditions occurring in a country is an evidence-based prevention strategy. The burden of autosomal recessive disease variations in Saudi Arabia is high because of the highly consanguineous population. The optimal solution for estimating the carrier frequency of the most prevalent diseases is carrier screening. OBJECTIVES: Identify the most influential recessive alleles associated with disease in the Saudi population. DESIGN: We used clinical whole-exome sequencing data from an in-house familial database to evaluate the most prevalent genetic variations associated with disease in a Saudi population. SETTINGS: King Abdullah International Medical Research Center (KAIMRC) and King Abdulaziz Medical City. METHODS: Whole exome sequencing data obtained from clinical studies of family members, a cohort of 1314 affected and unaffected individuals, were filtered using the in-house pipeline to extract the most prevalent variant in the dataset. MAIN OUTCOME MEASURES: Most prevalent genetic variations associated with disease in the Saudi population. SAMPLE SIZE: 1314 affected and unaffected individuals. RESULTS: We identified 37 autosomal recessive variants and two heterozygous X-linked variants in 35 genes associated with the most prevalent disorders, which included hematologic (32%), endocrine (21%), metabolic (11%) and immunological (10%) diseases. CONCLUSION: This study provides an update of the most frequently occurring alleles, which support future carrier screening programs. LIMITATIONS: Single center that might represent the different regions but may be biased. In addition, most of the families included in the database are part of the proband's genetic identification for specific phenotypes. CONFLICT OF INTEREST: None.

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Section: Discussionmentioning

confidence: 99%

Common disease-associated gene variants in a Saudi Arabian population

et al. 2022

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“…The former group includes the five types mentioned above, while the latter rarely occurs and may originate from a Benin or Bantu chromosome by only one mutation at the 5′ end [ 14 ]. All these forms are responsible for SCA with varying degrees of clinical symptom [ 14 – 18 ]. Thus, the objective of the current research is to ascertain the prevalence of the S gene by analysis of the Xmn1 ′5 to G γ haplotype in a Saudi population from the Jazan area.…”

Section: Introductionmentioning

confidence: 99%

Molecular Analysis of Xmn1-Polymorphic Site ´5 to Gγ of the β-Globin Gene Cluster in a Saudi Population of Jazan Region in Correlation with Hb F Expression

Elderdery

Alsrhani

Alzahrani

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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The southern part of Saudi Arabia has an ethnically diverse population where sickle-cell anemia (sickle cell disease) is common, but little is known about its βs haplotypes. The goal of the current study is to ascertain the prevalence of the Hb S gene with analysis of Xmn1 ′5 to Gγ haplotype among the Saudi population in the Jazan area. Initially recorded findings of (1) Hb S gene and (2) hematological parameters with Hb F levels were collected from 5990 participants. Then, the second series of 70 different patients with established sickling disease and 30 healthy individuals as a control group was recruited, in which the genotype of Xmn1 ′5 to Gγ-SNP was performed by PCR-RFLP. In the first series, the prevalence of Hb types was AA at 86.8% (N = 5198), AS at 12.4% (N = 745), and SS at 0.8% (N = 47). Of the second series, three patients (4.3%) were (±) Xmn1 ′5 to Gγ and 67 (95.7%) were (−/−) in Xmn1 ′5 to Gγ. In the controls, the (±) Xmn1 ′5 to Gγ was observed in only one individual (3.3%), aged 30. These findings possibly represent a new Saudi haplotype, [±] Xmn1 ′5 to Gγ. Our results demonstrate that most patients with SCD in Jazan have [−/−] Xmn1 with higher levels of Hb F and positive Xmn1 ′5 to Gγ normally associated with a low level of Hb F.

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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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Inheritance of the Bantu/Benin haplotype causes less severe hemolytic and oxidative stress in sickle cell anemia patients treated with hydroxycarbamide

Cited by 4 publications

References 59 publications

Common disease-associated gene variants in a Saudi Arabian population

Common disease-associated gene variants in a Saudi Arabian population

Molecular Analysis of Xmn1-Polymorphic Site ´5 to Gγ of the β-Globin Gene Cluster in a Saudi Population of Jazan Region in Correlation with Hb F Expression

Genetic Variation and Sickle Cell Disease Severity

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