Unique Polymorphisms at BCL11A, HBS1L-MYB and HBB Loci Associated with HbF in Kuwaiti Patients with Sickle Cell Disease

Akbulut-Jeradi, Nagihan; Fernandez, Maria Jinky; Khaldi, Rasha Al; Sukumaran, Jalaja; Adekile, Adekunle

doi:10.3390/jpm11060567

Cited by 4 publications

(5 citation statements)

References 29 publications

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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

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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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Section: Resultsmentioning

confidence: 99%

Section: Methodsunclassified

Genetic Variation and Sickle Cell Disease Severity

Kirkham,

Estepp,

Weiss

et al. 2023

JAMA Netw Open

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show abstract

“…The results showed the presence of two alleles A and C and three genotypes AA, AC, and CC in βthalassemia major, as depicted in Figures 1 and 2. The BCL11A locus is a quantitative trait loci (QTL) that has a high persistence role for the HbF level [15]. Inducing Hb F in β-thalassemia is an extremely promising strategy for reducing disease severity [16].…”

Section: Resultsmentioning

confidence: 99%

Untitled

2023

J. Med. Chem. Sci.

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“…HbF is one important modifier of the SCD phenotype that impedes the polymerization of sickle hemoglobin (HbS), leading to a significant improvement in the clinical course of the disease. The authors investigated the association between single nucleotide polymorphisms and HbF levels through the use of NGS in 237 Kuwaiti SCD patients, divided into three subgroups according to their HbF levels [ 4 ].…”

Section: Genetic and Molecular Basis Of Hematological Diseasesmentioning

confidence: 99%

“…These articles underline the fact that the phenotype has a multi-genic basis and NGS can be deployed to simultaneously screen relevant panels to afford personalized, evidence-based counseling and early intervention [ 3 , 4 ].…”

Section: Genetic and Molecular Basis Of Hematological Diseasesmentioning

confidence: 99%