Genomic polymorphisms in sickle cell disease: implications for clinical diversity and treatment

Abstract

Sickle cell disease (SCD) is one of the best characterized human monogenic disorders. The development of molecular biology allowed the identification of several genomic polymorphisms responsible for its clinical diversity. Research on the first genetic modulators of SCD, such as coinheritance of α-thalassemia and haplotypes in the β-globin gene cluster, have been followed by studies associating single nucleotide polymorphisms (SNPs) with variable risks for stroke, leg ulceration, pulmonary hypertension, priapism and osteonecrosis, with differences in the response to hydroxyurea, and with variability in the management of pain. Furthermore, multigenic analyses based on genome-wide association studies have shed light on the importance of the TGF-β superfamily and oxidative stress to the pathogenesis of complex traits in SCD, and may guide future therapeutic interventions on a genetically oriented basis.

Keywords::

• α-thalassemia
• β-globin gene cluster haplotype
• fetal hemoglobin
• genome-wide association study
• klotho
• nitric oxide
• sickle cell disease
• single nucleotide polymorphism
• TGF-β/BMP pathway

Acknowledgements

We would like to thank Nicola Conran for the English review of this manuscript.

Financial & competing interests disclosure

The authors are supported by FAPESP and CNPq, Brazil. The Hematology and Hemotherapy Center, UNICAMP, forms part of the National Institute of Science and Technology of Blood (INCT do Sangue - CNPq/MCT). 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.

Notes

^†Indicates studies with controversial results.