KLF10 Gene Expression is Associated with High Fetal Hemoglobin Levels and with Response to Hydroxyurea Treatment in β-Hemoglobinopathy Patients

Abstract

Aim: In humans, fetal hemoglobin (HbF) production is controlled by many intricate mechanisms that, to date, remain only partly understood. Patients & methods: Pharmacogenomic analysis of the effects of hydroxyurea (HU) on HbF production was undertaken in a collection of Hellenic βthalassemia and sickle cell disease (SCD) compound heterozygotes and a collection of healthy and KLF1-haploinsufficient Maltese adults, to identify genomic signatures that follow high HbF patterns. Results:KLF10 emerged as a top candidate. Moreover, genotype analysis of βthalassemia major and intermedia patients and an independent cohort of βthalassemia/SCD compound heterozygous patients that do or do not respond to HU treatment showed that the homozygous mutant state of a tagSNP in the KLF10 3‘UTR is not present in βthalassemia intermedia patients and is underrepresented in βthalassemia/SCD compound heterozygous patients that respond well to HU treatment. Conclusion: These data suggest that KLF10 may constitute a pharmacogenomic marker to discriminate between response and nonresponse to HU treatment.

Original submitted: 2 May 2012; Revision submitted: 17 July 2012

KEYWORDS::

• β-thalassemia
• hydroxyurea
• KLF10
• pharmacogenomics
• sickle cell disease
• transcription profiling

Acknowledgements

The authors are indebted to A Athanassiadou and L Psiouri for their expertise and assistance with the samples of the hemoglobinopathies patients, respectively.

Financial & competing interests disclosure

This work was funded by a long-term EMBO fellowship (ALTF 71-2011) to J Borg, a Research Promotion Foundation of Cyprus grant (RPFPΔE046_02) to GP Patrinos and M Kleanthous, Landsteiner Foundation for Blood Transfusion Research (1040) to FG Grosveld and S Philipsen, and the Netherlands Genomics Initiative to J Hou, FG Grosveld and S Philipsen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was funded by a long-term EMBO fellowship (ALTF 71-2011) to J Borg, a Research Promotion Foundation of Cyprus grant (RPFPΔE046_02) to GP Patrinos and M Kleanthous, Landsteiner Foundation for Blood Transfusion Research (1040) to FG Grosveld and S Philipsen, and the Netherlands Genomics Initiative to J Hou, FG Grosveld and S Philipsen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.