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Genetic Modifiers of Hemoglobinopathies: Recent Advances and Future Directions

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 June 2024) | Viewed by 12570

Special Issue Editors


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Guest Editor
Centre for Molecular Medicine and Biobanking, L-Università ta' Malta, Msida 2080, Malta
Interests: human hemoglobinopathies and globin gene control; human genomics

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Guest Editor
Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus
Interests: hemoglobinopathies; genetic modifiers; patient registries; biological databases

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Guest Editor
Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus
Interests: advanced therapies; genetic modifiers; regulation of globin expression; rare anemias
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Special Issue Information

Dear Colleagues,

Hemoglobinopathies, including sickle cell disease and thalassemia syndromes, are the most common monogenic diseases worldwide. Although their primary cause is well established through known pathogenic variants in the two globin gene clusters, the diverse clinical manifestations and the varying severity of hemoglobinopathies are largely attributed to the influence of genetic modifiers. Hundreds of genetic modifiers of different hemoglobinopathy phenotypes have already been identified by association studies, and genome-wide association studies (GWAS) in particular have proven to be powerful tools for the evaluation of the effect of genetic loci on specific disease phenotypes. Established modifiers serve as therapeutic targets, and have already greatly contributed to existing insights in the molecular mechanisms of disease pathogenicity. However, it is expected that there are many additional genetic variants that can modify disease severity and response to treatment. Taken together, a comprehensive understanding of modifiers is critical, as they will increasingly inform genetic counselling, diagnosis, prognosis, treatment decisions and therapy development for hemoglobinopathies.

The International Hemoglobinopathy Research Network (INHERENT; https://inherentnetwork.org) was recently established to study the role of genetic modifiers in hemoglobinopathies, through a large-scale, multi-ethnic GWAS. INHERENT brings together nine existing international or regional consortia in the field of hemoglobinopathies, and involves more than 200 experts from over 110 organizations, spanning 44 countries worldwide. With a target sample size of 30,000 patients and by promoting the participation of different populations, INHERENT aims to address challenges of previous studies related to small sample sizes, low statistical power and limited genetic diversity.

For this Special Issue, we aim to compile current knowledge and identify gaps related to the role of genetic modifiers for hemoglobinopathies and to highlight key priority areas for future collaborative research through INHERENT.

We welcome original research articles, reviews, opinion papers, perspectives, and short communications on topics related to the role of genetic modifiers and associated phenotypes in hemoglobinopathies and encourage the inclusion of illustrations of concepts and pathways.

Prof. Dr. Alex Felice
Dr. Petros Kountouris
Dr. Carsten W. Lederer
Guest Editors

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Keywords

  • hemoglobinopathies
  • genetic modifiers
  • thalassemia
  • sickle cell disease
  • association studies
  • biomarkers
  • GWAS

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Published Papers (8 papers)

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Review

27 pages, 1731 KiB  
Review
Genetic Polymorphisms Associated with Fetal Hemoglobin (HbF) Levels and F-Cell Numbers: A Systematic Review of Genome-Wide Association Studies
by Coralea Stephanou, Stephan Menzel, Sjaak Philipsen and Petros Kountouris
Int. J. Mol. Sci. 2024, 25(21), 11408; https://doi.org/10.3390/ijms252111408 - 23 Oct 2024
Viewed by 438
Abstract
Elevated fetal hemoglobin (HbF), which is partly controlled by genetic modifiers, ameliorates disease severity in β hemoglobinopathies. Understanding the genetic basis of this trait holds great promise for personalized therapeutic approaches. PubMed, MedRxiv, and the GWAS Catalog were searched up to May 2024 [...] Read more.
Elevated fetal hemoglobin (HbF), which is partly controlled by genetic modifiers, ameliorates disease severity in β hemoglobinopathies. Understanding the genetic basis of this trait holds great promise for personalized therapeutic approaches. PubMed, MedRxiv, and the GWAS Catalog were searched up to May 2024 to identify eligible GWAS studies following PRISMA guidelines. Four independent reviewers screened, extracted, and synthesized data using narrative and descriptive methods. Study quality was assessed using a modified version of the Q-Genie tool. Pathway enrichment analysis was conducted on gene lists derived from the selected GWAS studies. Out of 113 initially screened studies, 62 underwent full-text review, and 16 met the inclusion criteria for quality assessment and data synthesis. A total of 939 significant SNP-trait associations (p-value < 1 × 10−5) were identified, mapping to 133 genes (23 with overlapping variant positions) and 103 intergenic sequences. Most SNP-trait associations converged around BCL11A (chr.2), HBS1L-MYB, (chr.6), olfactory receptor and beta globin (HBB) gene clusters (chr.11), with less frequent loci including FHIT (chr.3), ALDH8A1, BACH2, RPS6KA2, SGK1 (chr.6), JAZF1 (chr.7), MMP26 (chr.11), COCH (chr.14), ABCC1 (chr.16), CTC1, PFAS (chr.17), GCDH, KLF1, NFIX, and ZBTB7A (chr.19). Pathway analysis highlighted Gene Ontology (GO) terms and pathways related to olfaction, hemoglobin and haptoglobin binding, and oxygen carrier activity. This systematic review confirms established genetic modifiers of HbF level, while highlighting less frequently associated loci as promising areas for further research. Expanding research across ethnic populations is essential for advancing personalized therapies and enhancing outcomes for individuals with sickle cell disease or β-thalassemia. Full article
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10 pages, 1262 KiB  
Review
Loss-of-Function Variants in SUPT5H as Modifying Factors in Beta-Thalassemia
by Cornelis L. Harteveld, Ahlem Achour, Nik Fatma Fairuz Mohd Hasan, Jelmer Legebeke, Sandra J. G. Arkesteijn, Jeanet ter Huurne, Maaike Verschuren, Sharda Bhagwandien-Bisoen, Rianne Schaap, Linda Vijfhuizen, Hakima el Idrissi, Christian Babbs, Douglas R. Higgs, Tamara T. Koopmann, Christina Vrettou, Joanne Traeger-Synodinos and Frank Baas
Int. J. Mol. Sci. 2024, 25(16), 8928; https://doi.org/10.3390/ijms25168928 - 16 Aug 2024
Cited by 1 | Viewed by 676
Abstract
It is well known that modifiers play a role in ameliorating or exacerbating disease phenotypes in patients and carriers of recessively inherited disorders such as sickle cell disease and thalassemia. Here, we give an overview of the literature concerning a recently described association [...] Read more.
It is well known that modifiers play a role in ameliorating or exacerbating disease phenotypes in patients and carriers of recessively inherited disorders such as sickle cell disease and thalassemia. Here, we give an overview of the literature concerning a recently described association in carriers of SUPT5H Loss-of-Function variants with a beta-thalassemia-like phenotype including the characteristic elevated levels of HbA2. That SUPT5H acts as modifier in beta-thalassemia carriers became evident from three reported cases in whom combined heterozygosity of SUPT5H and HBB gene variants was observed to resemble a mild beta-thalassemia intermedia phenotype. The different SUPT5H variants and hematologic parameters reported are collected and reviewed to provide insight into the possible effects on hematologic expression, as well as potential disease mechanisms in carriers and patients. Full article
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17 pages, 1353 KiB  
Review
Genetic Modifiers of Stroke in Patients with Sickle Cell Disease—A Scoping Review
by Morohuntodun O. Oni, Miguel Brito, Chloe Rotman and Natasha M. Archer
Int. J. Mol. Sci. 2024, 25(12), 6317; https://doi.org/10.3390/ijms25126317 - 7 Jun 2024
Viewed by 1053
Abstract
Sickle cell disease (SCD) clinically manifests itself with a myriad of complications. Stroke, both ischemic and hemorrhagic, as well as silent white matter changes, occurs at a relatively high prevalence. Understanding why and in whom stroke is most likely to occur is critical [...] Read more.
Sickle cell disease (SCD) clinically manifests itself with a myriad of complications. Stroke, both ischemic and hemorrhagic, as well as silent white matter changes, occurs at a relatively high prevalence. Understanding why and in whom stroke is most likely to occur is critical to the effective prevention and treatment of individuals with SCD. Genetic studies, including genome- and exome-wide association studies (GWAS and EWAS), have found several key modifiers associated with increased stroke/stroke risk in SCD via mechanisms including Hemoglobin F (HbF) modulation, inflammation, cellular adhesion, endothelial disruption, and hemolysis. We present a review on the modifiers that have most clearly demonstrated an association to date. More studies are needed to validate other potential polymorphisms and identify new ones. Incorporating gene-focused screenings in clinical care could provide avenues for more targeted, more effective, and less toxic prevention of stroke in this population. The data from this review will be used to inform the initial GWAS performed by the International Hemoglobinopathy Research Network (INHERENT) consortium. Full article
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18 pages, 559 KiB  
Review
Systematic Review of Genetic Modifiers Associated with the Development and/or Progression of Nephropathy in Patients with Sickle Cell Disease
by Veerle Labarque and Emmanuel Chide Okocha
Int. J. Mol. Sci. 2024, 25(10), 5427; https://doi.org/10.3390/ijms25105427 - 16 May 2024
Cited by 1 | Viewed by 1185
Abstract
Sickle cell nephropathy (SCN) is a common complication of sickle cell disease (SCD) that significantly contributes to morbidity and mortality. In addition to clinical and life-style factors, genetic variants influence this risk. We performed a systematic review, searching five databases. Studies evaluating the [...] Read more.
Sickle cell nephropathy (SCN) is a common complication of sickle cell disease (SCD) that significantly contributes to morbidity and mortality. In addition to clinical and life-style factors, genetic variants influence this risk. We performed a systematic review, searching five databases. Studies evaluating the effect of genetic modifiers on SCN were eligible. Twenty-eight studies (fair-to-good quality) were included: one genome-wide association study, twenty-six case-control studies, and one article combining both approaches. APOL1 was significantly associated with albuminuria and hyperfiltration in children and with worse glomerular filtration in adults. On the other hand, alpha-thalassemia protected patients against albuminuria and hyperfiltration, while BCL11A variants were protective against albuminuria alone. The HMOX1 long GT-tandem repeat polymorphism led to a lower glomerular filtration rate. No modifiers for the risk of hyposthenuria were identified. A genome-wide association approach identified three new loci for proteinuria (CRYL1, VWF, and ADAMTS7) and nine loci were linked with eGFR (PKD1L2, TOR2A, CUBN, AGGF1, CYP4B1, CD163, LRP1B, linc02288, and FPGT-TNNI3K/TNNI3K). In conclusion, this systematic review supports the role of genetic modifiers in influencing the risk and progression of SCN. Incorporating and expanding this knowledge is crucial to improving the management and clinical outcomes of patients at risk. Full article
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17 pages, 1230 KiB  
Review
Pulmonary Hypertension in Sickle Cell Disease: Novel Findings of Gene Polymorphisms Related to Pathophysiology
by Sevastianos Chatzidavid, Pagona Flevari, Ioanna Tombrou, Georgios Anastasiadis and Maria Dimopoulou
Int. J. Mol. Sci. 2024, 25(9), 4792; https://doi.org/10.3390/ijms25094792 - 27 Apr 2024
Cited by 1 | Viewed by 1337
Abstract
Pulmonary hypertension (PH) is a progressive and potentially fatal complication of sickle cell disease (SCD), affecting 6–10% of adult SCD patients. Various mechanisms and theories have been evaluated to explain the pathophysiology of this disease. However, questions remain, particularly regarding the clinical heterogeneity [...] Read more.
Pulmonary hypertension (PH) is a progressive and potentially fatal complication of sickle cell disease (SCD), affecting 6–10% of adult SCD patients. Various mechanisms and theories have been evaluated to explain the pathophysiology of this disease. However, questions remain, particularly regarding the clinical heterogeneity of the disease in terms of symptoms, complications, and survival. Beyond the classical mechanisms that have been thoroughly investigated and include hemolysis, nitric oxide availability, endothelial disorders, thrombosis, and left heart failure, attention is currently focused on the potential role of genes involved in such processes. Potential candidate genes are investigated through next-generation sequencing, with the transforming growth factor-beta (TGF-β) pathway being the initial target. This field of research may also provide novel targets for pharmacologic agents in the future, as is already the case with idiopathic PH. The collection and processing of data and samples from multiple centers can yield reliable results that will allow a better understanding of SCD-related PH as a part of the disease’s clinical spectrum. This review attempts to capture the most recent findings of studies on gene polymorphisms that have been associated with PH in SCD patients. Full article
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26 pages, 3200 KiB  
Review
Pharmacogenomics of Drugs Used in β-Thalassemia and Sickle-Cell Disease: From Basic Research to Clinical Applications
by Roberto Gambari, Aliyu Dahiru Waziri, Hemali Goonasekera and Emmanuel Peprah
Int. J. Mol. Sci. 2024, 25(8), 4263; https://doi.org/10.3390/ijms25084263 - 12 Apr 2024
Cited by 1 | Viewed by 2272
Abstract
In this short review we have presented and discussed studies on pharmacogenomics (also termed pharmacogenetics) of the drugs employed in the treatment of β-thalassemia or Sickle-cell disease (SCD). This field of investigation is relevant, since it is expected to help clinicians select the [...] Read more.
In this short review we have presented and discussed studies on pharmacogenomics (also termed pharmacogenetics) of the drugs employed in the treatment of β-thalassemia or Sickle-cell disease (SCD). This field of investigation is relevant, since it is expected to help clinicians select the appropriate drug and the correct dosage for each patient. We first discussed the search for DNA polymorphisms associated with a high expression of γ-globin genes and identified this using GWAS studies and CRISPR-based gene editing approaches. We then presented validated DNA polymorphisms associated with a high HbF production (including, but not limited to the HBG2 XmnI polymorphism and those related to the BCL11A, MYB, KLF-1, and LYAR genes). The expression of microRNAs involved in the regulation of γ-globin genes was also presented in the context of pharmacomiRNomics. Then, the pharmacogenomics of validated fetal hemoglobin inducers (hydroxyurea, butyrate and butyrate analogues, thalidomide, and sirolimus), of iron chelators, and of analgesics in the pain management of SCD patients were considered. Finally, we discuss current clinical trials, as well as international research networks focusing on clinical issues related to pharmacogenomics in hematological diseases. Full article
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18 pages, 1399 KiB  
Review
Impact of α-Globin Gene Expression and α-Globin Modifiers on the Phenotype of β-Thalassemia and Other Hemoglobinopathies: Implications for Patient Management
by Joanne Traeger-Synodinos, Christina Vrettou, Christalena Sofocleous, Matteo Zurlo, Alessia Finotti and Roberto Gambari
Int. J. Mol. Sci. 2024, 25(6), 3400; https://doi.org/10.3390/ijms25063400 - 17 Mar 2024
Cited by 2 | Viewed by 1543
Abstract
In this short review, we presented and discussed studies on the expression of globin genes in β-thalassemia, focusing on the impact of α-globin gene expression and α-globin modifiers on the phenotype and clinical severity of β-thalassemia. We first discussed the impact of the [...] Read more.
In this short review, we presented and discussed studies on the expression of globin genes in β-thalassemia, focusing on the impact of α-globin gene expression and α-globin modifiers on the phenotype and clinical severity of β-thalassemia. We first discussed the impact of the excess of free α-globin on the phenotype of β-thalassemia. We then reviewed studies focusing on the expression of α-globin-stabilizing protein (AHSP), as a potential strategy of counteracting the effects of the excess of free α-globin on erythroid cells. Alternative processes controlling α-globin excess were also considered, including the activation of autophagy by β-thalassemia erythroid cells. Altogether, the studies reviewed herein are expected to have a potential impact on the management of patients with β-thalassemia and other hemoglobinopathies for which reduction in α-globin excess is clinically beneficial. Full article
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17 pages, 612 KiB  
Review
Endocrinopathies in Hemoglobinopathies: What Is the Role of Iron?
by Paschalis Evangelidis, Theodora-Maria Venou, Barmpageorgopoulou Fani, Efthymia Vlachaki and Eleni Gavriilaki
Int. J. Mol. Sci. 2023, 24(22), 16263; https://doi.org/10.3390/ijms242216263 - 13 Nov 2023
Cited by 6 | Viewed by 2543
Abstract
Hemoglobinopathies, including β-thalassemia and sickle cell disease (SCD), are common genetic blood disorders. Endocrine disorders are frequent manifestations of organ damage observed mainly in patients with β-thalassemia and rarely in SCD. Iron overload, oxidative stress-induced cellular damage, chronic anemia, and HCV infection contribute [...] Read more.
Hemoglobinopathies, including β-thalassemia and sickle cell disease (SCD), are common genetic blood disorders. Endocrine disorders are frequent manifestations of organ damage observed mainly in patients with β-thalassemia and rarely in SCD. Iron overload, oxidative stress-induced cellular damage, chronic anemia, and HCV infection contribute to the development of endocrinopathies in β-thalassemia. The above factors, combined with vaso-occlusive events and microcirculation defects, are crucial for endocrine dysfunction in SCD patients. These endocrinopathies include diabetes mellitus, hypothyroidism, parathyroid dysfunction, gonadal and growth failure, osteoporosis, and adrenal insufficiency, affecting the quality of life of these patients. Thus, we aim to provide current knowledge and data about the epidemiology, pathogenesis, diagnosis, and management of endocrine disorders in β-thalassemia and SCD. We conducted a comprehensive review of the literature and examined the available data, mostly using the PubMed and Medline search engines for original articles. In the era of precision medicine, more studies investigating the potential role of genetic modifiers in the development of endocrinopathies in hemoglobinopathies are essential. Full article
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