Modifying effect of XmnI, BCL11A, and HBS1L-MYB on clinical appearances: A study on β-thalassemia and hemoglobin E/β-thalassemia patients in Indonesia

Objective/background: Thalassemia is a monogenic hematologic disease that has the highest prevalence globally. In addition, there is complexity of the genetic background associated with a variety of phenotypes presented among patients. Genetic heterogeneity related to fetal hemoglobin (HbF) production has been reported as an influencing phenotypic factor of β-thalassemia (β-thal). Therefore, this study aimed to find the effect of these genetic modifiers, especially in the XmnI locus, rs11886868, rs766432 (BCL11A), and rs9399137 (HBS1L-MYB), among β-thal and HbE/β-thal patients in Indonesia, according to laboratory and clinical outcomes, including HbF levels and clinical scores. This study was also designed to compare these modifying effects among β-thal and HbE/β-thal patients in Indonesia.

Methods: A total of 189 patients with genotyping of β-thal and HbE/β-thal were included in this study. The erythrocytes index and Hb electrophoresis measurements were calculated using appropriate methods. The severity of β-thal and HbE/β-thal was classified based on the Mahidol score. Polymorphism of the XmnI locus, rs11886868, rs766432 (BCL11A), and rs9399137 (HBS1L-MYB) was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and amplification refractory mutation system (ARMS) methods.

Results: The distributions of minor allele in the XmnI locus, rs11886868, rs766432, and rs9399137 were 14%, 22%, 19% and 18% respectively. The variation allele in the XmnI locus, rs11886868, and rs766432 showed a significant value for modifying HbF and clinical score in HbE/β-thal patients, but rs9399137 did not demonstrate such features. In β-thal patients, however, no correlation was found for any single-nucleotide polymorphisms and clinical appearance.

Conclusion: The XmnI locus, rs11886868, and rs766432 have a modifying effect on HbF and clinical score in HbE/β-thal patients in Indonesia, but not in β-thal patients.