Significance of genetic modifiers of hemoglobinopathies leading towards precision medicine

Hariharan, Priya; Gorivale, Manju; Sawant, Pratibha; Mehta, Pallavi; Nadkarni, Anita

doi:10.1038/s41598-021-00169-x

Cited by 15 publications

(11 citation statements)

References 42 publications

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“…Hariharan P et al in their study also reported 3 bp deletional allele of rs66650371 to be significantly associated with higher HbF levels in SCA. Similar findings were reported in our study 15 . In the promoter region of G γ globin, the XmnI polymorphism residing in the − 158 (C → T) was detected in our SCD patient group.…”

Section: Discussionsupporting

confidence: 93%

“…The mutant T allele was significantly associated with raised HbF levels in patients. Similar to our findings Hariharan P et al, 2021 also reported 94% homozygosity for mutant T allele in SCD patient group 15 .…”

Section: Discussionsupporting

confidence: 92%

“…We also tried to look at the association of variant in the 3 main HbF promoting loci [BCL11A, MYB and γ globin promoter region] 14 , 15 (Supplementary Table 1 ). The BCL11A rs11886868 (C → T) and rs1427407 (G → T) polymorphisms were screened in all SCD patients and control group.…”

Section: Resultsmentioning

confidence: 99%

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Role of microRNA in hydroxyurea mediated HbF induction in sickle cell anaemia patients

Kargutkar

Sawant-Mulay

Hariharan

et al. 2023

Sci Rep

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Hydroxyurea (HU) is found to be beneficial in sickle cell anaemia (SCA) patients, due to its ability to increase foetal haemoglobin (HbF), however, patients show a variable response. Differences in HbF levels are attributed to many factors; but, the role of miRNA in HbF regulation is sparsely investigated. In this study, we evaluated the effect of miRNA expression on HbF induction in relation to hydroxyurea therapy in 30 normal controls, 30 SCA patients at baseline, 20 patients after 3 and 6 months of hydroxyurea (HU) therapy. HbF levels were measured by HPLC. Total RNA and miRNA were extracted from CD71+ erythroid cells and the expression was determined using Taqman probes. The mean HbF level increased 7.54 ± 2.44 fold, after 3 months of HU therapy. After the HU therapy 8 miRNAs were significantly up-regulated while 2 were down-regulated. The increase in miR-210, miR16-1, and miR-29a expression and decrease in miR-96 expression were strongly associated with the HU mediated HbF induction. Post HU therapy, decreased miR-96 expression negatively correlate with HbF and γ-globin gene while increased expression of miR-210, miR-16-1 and miR-29a post HU therapy positively corelate with HbF and γ-globin gene. Thus, suggest that miR-210, miR-16-1 and miR-29a are positive regulator of γ-globin gene and miR-96 is negative regulator of γ-globin gene. The study suggests the role of miR-210, miR16-1, miR-29a, and miR-96 in γ-globin gene regulation leading to HbF induction. Identification of the relevant protein targets might be useful for understanding the HU mediated HbF induction.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

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Role of microRNA in hydroxyurea mediated HbF induction in sickle cell anaemia patients

Kargutkar

Sawant-Mulay

Hariharan

et al. 2023

Sci Rep

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show abstract

“…Similar ndings were reported in our study [31]. In the promoter region of G γ globin, the XmnI polymorphism residing in the − 158 (C → T) was detected in our SCD patient group.…”

Section: Discussionsupporting

confidence: 92%

“…The mutant T allele was signi cantly associated with raised HbF levels in patients. Similar to our ndings Hariharan P et al, 2021 also reported 94% homozygosity for mutant T allele in SCD patient group [31].…”

Section: Discussionsupporting

confidence: 92%

Role of MicroRNA in Hydroxyurea mediated HbF induction in Sickle cell anaemia patients

Kargutkar

Sawant-Mulay

Hariharan

et al. 2022

Preprint

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Background:Hydroxyurea (HU) is found to be beneficial in Sickle cell Anaemia (SCA) patients, due to its ability to increase foetal haemoglobin (HbF), however, patients show a variable response. Differences in HbF levels are attributed to many factors; but, the role of miRNA in HbF regulation is sparsely investigated.Materials and Methods:In this study, we evaluated the effect of miRNA expression on HbF induction in relation to hydroxyurea therapy in 30 normal controls, 30 SCA patients at baseline, 20 patients after 3 and 6 months of hydroxyurea (HU) therapy. HbF levels were measured by HPLC. Total RNA and miRNA were extracted from CD71+ erythroid cells and the expression was determined using Taqman probes. Results:The mean HbF level increased 7.54 ±2.44 fold, after 3 months of HU therapy. After the HU therapy 8 miRNAs were significantly up-regulated while 2 were down-regulated. The increase in miR-210, miR16-1, and miR-29a expression and decrease in miR-96 expression were strongly associated with the HU mediated HbF induction. Post HU therapy, decreased miR-96 expression was observed; which might be due to interference of miR-96 binding to g-globin mRNA by HU, facilitating HbF expression. The miR-210 expression was enhanced in association with erythroid differentiation and induction to HbF production. Conclusions:The study suggests the role of miR-210, miR16-1, miR-29a, and miR-96 in g-globin gene regulation leading to HbF induction. Identification of the relevant protein targets might be useful for understanding the HU mediated HbF induction.

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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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Significance of genetic modifiers of hemoglobinopathies leading towards precision medicine

Cited by 15 publications

References 42 publications

Role of microRNA in hydroxyurea mediated HbF induction in sickle cell anaemia patients

Role of microRNA in hydroxyurea mediated HbF induction in sickle cell anaemia patients

Role of MicroRNA in Hydroxyurea mediated HbF induction in Sickle cell anaemia patients

Genetic Variation and Sickle Cell Disease Severity

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