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Genetic Modifiers at the Crossroads of Personalised Medicine for Haemoglobinopathies

Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus
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Authors to whom correspondence should be addressed.
Equal contribution; Joint last authorship.
J. Clin. Med. 2019, 8(11), 1927; https://doi.org/10.3390/jcm8111927
Received: 20 September 2019 / Revised: 25 October 2019 / Accepted: 5 November 2019 / Published: 9 November 2019
(This article belongs to the Special Issue New Trends in Personalized Therapy of Thalassemia)
Haemoglobinopathies are common monogenic disorders with diverse clinical manifestations, partly attributed to the influence of modifier genes. Recent years have seen enormous growth in the amount of genetic data, instigating the need for ranking methods to identify candidate genes with strong modifying effects. Here, we present the first evidence-based gene ranking metric (IthaScore) for haemoglobinopathy-specific phenotypes by utilising curated data in the IthaGenes database. IthaScore successfully reflects current knowledge for well-established disease modifiers, while it can be dynamically updated with emerging evidence. Protein–protein interaction (PPI) network analysis and functional enrichment analysis were employed to identify new potential disease modifiers and to evaluate the biological profiles of selected phenotypes. The most relevant gene ontology (GO) and pathway gene annotations for (a) haemoglobin (Hb) F levels/Hb F response to hydroxyurea included urea cycle, arginine metabolism and vascular endothelial growth factor receptor (VEGFR) signalling, (b) response to iron chelators included xenobiotic metabolism and glucuronidation, and (c) stroke included cytokine signalling and inflammatory reactions. Our findings demonstrate the capacity of IthaGenes, together with dynamic gene ranking, to expand knowledge on the genetic and molecular basis of phenotypic variation in haemoglobinopathies and to identify additional candidate genes to potentially inform and improve diagnosis, prognosis and therapeutic management. View Full-Text
Keywords: haemoglobinopathies; thalassaemia; sickle cell disease; gene modifiers; biomarkers; gene ranking; protein network haemoglobinopathies; thalassaemia; sickle cell disease; gene modifiers; biomarkers; gene ranking; protein network
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Stephanou, C.; Tamana, S.; Minaidou, A.; Papasavva, P.; Kleanthous, M.; Kountouris, P. Genetic Modifiers at the Crossroads of Personalised Medicine for Haemoglobinopathies. J. Clin. Med. 2019, 8, 1927.

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