Exome sequencing in high and low fetal haemoglobin Arab–Indian haplotype sickle cell disease

Al-Nafie, Awatif; Al-Ateeq, Suad; Al-Muhanna, Fahad; Al-Sulaiman, Abdulsalam A.; Alfarhan, Mohammed; Buali, Waleed; Vatte, Chittibabu; Cyrus, Cyril; Keating, Brendan J.; Al-Ali, Amein K.; Steinberg, Martin H.

doi:10.1111/bjh.17542

Cited by 3 publications

(4 citation statements)

References 15 publications

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“…The AI haplotype is the most prevalent in the area and characterised by some children having high HbF. 3 , 26 Given this observation and the possible correlation between dental caries and SCA, we assessed the microbiota abundance based on high DMFT index vs low DMFT index and high HbF vs low HbF. 7 , 8 , 9 , 10 , 11 , 12 Our results provide a valuable addition to the global microbiome reference data set in an underexamined community.…”

Section: Discussionmentioning

confidence: 99%

Oral microbiota analyses of Saudi sickle cell anemics with dental caries

Alyousef¹,

Alonaizan²,

Al-Sulaiman³

et al. 2023

International Dental Journal

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Section: Discussionmentioning

confidence: 99%

Oral microbiota analyses of Saudi sickle cell anemics with dental caries

Alyousef¹,

Alonaizan²,

Al-Sulaiman³

et al. 2023

International Dental Journal

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“…We identified 571 manuscripts published before May 16, 2023, reporting genotype-phenotype associations across 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries (eMethods, eFigures 1 and 2, and eTable 5 in Supplement 1 ; eTable 1 in Supplement 2 ). 8 , 11 , 12 , 13 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ,…”

Section: Resultsmentioning

confidence: 99%

“…A total of 571 publications passed this screening (eFigure 1 in Supplement 1 , eTable 1 in Supplement 2 ). 8 , 11 , 12 , 13 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ...…”

Section: Methodsunclassified

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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“…HbF levels vary 2 to 4-fold among the five common HBB haplotypes associated with the HbS gene. The Arab-Indian (AI) haplotype is associated with HbF that averages ~17% in adults compared with 5 to 7% in the Bantu, Benin and Cameroon haplotypes and 10% in the Senegal haplotype [ 2 , 13 , 14 , 15 ]. Even within the AI haplotype there is variation of HbF levels.…”

Section: Introductionmentioning

confidence: 99%

miRNA Expression Associated with HbF in Saudi Sickle Cell Anemia

et al. 2022

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Background and Objectives: Sickle cell anemia (SCA) is a hereditary monogenic disease due to a single β-globin gene mutation that codes for the production of sickle hemoglobin. Its phenotype is modulated by fetal hemoglobin (HbF), a product of γ-globin genes. Exploring the molecules that regulate γ-globin genes at both transcriptional and translational levels, including microRNA (miRNA), might help identify alternative therapeutic targets. Materials and Methods: Using next-generation sequencing we identified pre-miRNAs and mature miRNA expression signatures associated with different HbF levels in patients homozygous for the sickle hemoglobin gene. The involvement of identified miRNAs in potential SCD-related pathways was investigated with the DIANA TOOL and miRWalk 2.0 database. Results: miR-184 were most highly upregulated in reticulocytes. miR-3609 and miR-483-5p were most highly downregulated in sickle cell anemia with high HbF. miR-370-3p that regulates LIN28A, and miR-451a which is effective in modulating α- and β- globin levels were also significantly upregulated. miRNA targeted gene pathway interaction identified BCL7A, BCL2L1, LIN28A, KLF6, GATA6, solute carrier family genes and ZNF genes associated with erythropoiesis, cell cycle regulation, glycosphingolipid biosynthesis, cAMP, cGMP-PKG, mTOR, MAPK and PI3K-AKT signaling pathways and cancer pathways. Conclusions: miRNA signatures and their target genes identified novel miRNAs that could regulate fetal hemoglobin production and might be exploited therapeutically.

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Exome sequencing in high and low fetal haemoglobin Arab–Indian haplotype sickle cell disease

Abstract: Data sharing statementThe genetic data used in this paper will be made freely available to interested investigators through BK.

Cited by 3 publications

References 15 publications

Oral microbiota analyses of Saudi sickle cell anemics with dental caries

Oral microbiota analyses of Saudi sickle cell anemics with dental caries

Genetic Variation and Sickle Cell Disease Severity

miRNA Expression Associated with HbF in Saudi Sickle Cell Anemia

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