Genetic Modifiers at the Crossroads of Personalised Medicine for Haemoglobinopathies

Abstract

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.

Effect of HBB genotype on survival in a cohort of transfusion-dependent thalassemia patients in Cyprus

“…We did not have comprehensive data on other genetic modifiers, 33 while some genotype data were missing, particularly α-globin genotype (44/537, 8.2%) and XmnI polymorphism (57/537, 10.6%). However, the prevalence of severity-alleviating factors, such as α 0 deletions and minor allele of the XmnI polymorphism, is low in this population and is unlikely to have affected the overall analysis of survival.…”

The International Hemoglobinopathy Research Network (INHERENT): An international initiative to study the role of genetic modifiers in hemoglobinopathies

“…In addition, data from different studies are not frequently reproducible and their possible effect size remains unknown. 6 Most importantly, with most studies having a sample size of less than 2000 patients, it is not possible to identify genetic modifiers with high confidence. As a result, the translation of these results into clinical practice has been limited.…”

MicroRNA‐2355‐5p regulates γ‐globin expression in human erythroid cells by inhibiting KLF6

“…1,2 Widely accepted genes for modulating c-globin expression include BCL11A, HBS1L-MYB intergenic region and Kruppel-like factor 1 (KLF1). 3 KLFs are a highly conserved family of transcription factors that regulate gene expression through three conserved zinc-finger domains in combination with a CACCC/GC/GT box in DNA sequences. 4 KLF1 is an important transcription factor in erythropoiesis, 5 and regulates haemoglobin switching by inhibiting c-globin expression and activating b-globin expression.…”

“…As elevated HbF (α2γ2) levels ameliorate clinical severity in patients with β‐thalassaemia, genetic modifiers that regulate γ‐globin expression have been investigated extensively 1,2 . Widely accepted genes for modulating γ‐globin expression include BCL11A , HBS1L‐MYB intergenic region and Kruppel‐like factor 1 ( KLF1 ) 3 . KLFs are a highly conserved family of transcription factors that regulate gene expression through three conserved zinc‐finger domains in combination with a CACCC/GC/GT box in DNA sequences 4 .…”