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Letters to the Editor
tinction between sexes was anticipated, it raised the question whether males and females were affected in dis- tinctive ways by the disease. In order to examine such a possibility, same sex analysis between healthy partici- pants and patients was performed expecting fewer changes due to the lower number of samples used per differential expression analysis (from 49 participants, 23 were males and 26 were females) and similar DEG between males and females, as β-thalassemia presents with similar phenotype in both sexes and has not been linked to sex-defining genes. Interestingly, very different results were obtained for males and females suffering from TI against healthy participants, with 1,559 DEG in males, but only 14 DEG in females (Table 1; Online Supplementary Tables S8-S9). The very low number of DEG in females highlights the increased biological vari- ability seen in females and suggests that other factors might play an important role in determining the disease outcome. When comparing the significantly DEG identi- fied in both male and female TI patients with the genes identified only in male TI patients, a significant overlap was seen in down-regulated genes, not only in terms of specific genes, but also in terms of gene functionality through Gene Ontology (GO) terms (Figure 2B; Online Supplementary Figure S3A-B; Online Supplementary Table S5). In contrast, in up-regulated genes, fewer common genes were identified and fewer similarities in their func- tionality suggesting less conserved changes. Different results were also found for males and females suffering from TM when compared to healthy participants, albeit less prominent, with 441 DEG identified in males and 310 DEG in females (Table 1; Online Supplementary Tables S10-S11). Furthermore, the overwhelming majority of genes identified in either male or female TM patients were also yielded when all TM patients were analysed against healthy subjects irrespective of their sex (Figure 2C; Online Supplementary Figure S3C-D; Online Supplementary Table S5). The limited number of deregu- lated genes in common between female and male TM patients could demonstrate sex-specific differences, fur- ther supported by the association of different terms relat- ed to diseases and body functions in male and female patients when compared to same sex healthy subjects (Online Supplementary Figure S4). Dissection of the molec- ular pathways involved through pathway and GO analy- sis revealed pathways with opposing status between males and females, such as the production of nitric oxide and reactive oxygen species in macrophages, and glioma invasiveness signalling (Figure 2D-F; Online Supplementary Figure S4). Per sex, all the significant DEG identified exhibited a unanimous direction of transcription, but dif- ferent members of the pathway were differentially expressed in males and females. The DEG identified in male or female TI and TM patients could be potentially invaluable for the development of sex-specific treatment options and stratification strategies (Online Supplementary Tables S5, S12-S13; Online Supplementary Figure S5).
To our knowledge no other studies comparing gene expression profiles in males and females suffering from β- thalassemia currently exist, however, there have been reports of correlations of disease symptoms or complica- tions related to sex. For instance, HbF levels have been found significantly higher in the female population of TM patients and this difference became more apparent after the age of 30 years.8 When considering complications of the disease, male TM patients have shown a strong asso- ciation with diabetes9 and although no clear reason cur- rently exists for such an association, it can be partly attributed to increased sensitivity of males to iron over-
load.10 Better survival rate has also been reported in females rather than males with fewer occurrences of car- diac complications and cardiac-based morbidities.11 In terms of development of osteoporosis and osteopenia in TM patients, a sex difference was seen in the prevalence and the severity of the disorder with males being more frequently and severely affected than females.12 In gener- al, various pathways have been found to exhibit sex- related differences, many of which are linked to β-tha- lassemia, such as oxidative stress defense,13 lipid metabo- lism14 and erythropoietin activity.15 The present study, besides the identification of sex-specific transcriptional profiles in β-thalassemia through public availability of our data, represents a novel resource for meta-analyses and follow-up studies. In conclusion, our data highlight the need for considering sex as an important variable of the disease, which should be taken into account when developing differential diagnostic and therapeutic strate- gies.
Aikaterini Nanou,1 Chrisavgi Toumpeki,1 Pavlos Fanis,2 Nicoletta Bianchi,3 Lucia Carmela Cosenza,3
Cristina Zuccato,3 George Sentis,1 Giorgos Giagkas,1
Coralea Stephanou,2 Marios Phylactides,2 Soteroula Christou,4 Michalis Hadjigavriel,5 Maria Sitarou,6 Carsten W. Lederer,2 Roberto Gambari,3 Marina Kleanthous2 and Eleni Katsantoni1
1Basic Research Center, Biomedical Research Foundation, Academy of Athens, Athens, Greece; 2Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; 3Department of Life Sciences and Biotechnology, Ferrara University, Ferrara, Italy; 4Thalassaemia Clinic, Archbishop Makarios III Hospital, Nicosia, Cyprus; 5Limassol General Hospital, Department of Internal Medicine, Limassol, Cyprus and 6Thalassemia Clinic Larnaca, Larnaca General Hospital, Larnaca, Cyprus
Correspondence:
ELENI KATSANTONI - ekatsantoni@bioacademy.gr
doi:10.3324/haematol.2020.248013
Disclosures: no conflicts of interest to disclose.
Contributions: AN performed experiments, analyzed results and wrote the paper; CT, PF, NB, LCC, CZ and CS performed experiments; GS analyzed results and performed experiments;
GG analyzed results; SC, MH and MS provided patient samples and evaluated the clinical picture of the patients; MP, CWL, RG and MK designed the research; EK designed the research, performed experiments, analyzed results and wrote the paper
Acknowledgments: the authors would like to thank Dr. Sjaak Philipsen for critical reading of the manuscript, GeneCore/EMBL for sequencing support and Panayiota Papasavva for helpful discussions.
Funding: this work was supported by the European Union’s FP7 THALAMOSS (Project no. 306201 to E.K., R.G., M.K.), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 813091 (E.K.) and by the Republic of Cyprus through the Research Promotion Foundation under grants agreements YΓΕΙΑ/ΒΙΟΣ0609 (ΒΕ)/01 (EK, M.K.) and ΥΓΕΙΑ/ΒΙΟΣ/0311(ΒΕ)/20 (M.K.).
References
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