The Effect of Single Nucleotide Polymorphisms on Clinical Phenotypes of Sabahan Transfusion-Dependent β-Thalassemia Patients with Homozygous Filipino β0-Deletion.

Abstract

Sabah has the highest prevalence of β-thalassemia in Malaysia, with the Filipino β⁰-deletion as the predominant mutation. Patients with the homozygous Filipino β⁰-deletion exhibit phenotypic heterogeneity due to various genetic modifiers, yet the effects of these modifiers on the clinical phenotype remain poorly understood. This study investigated the effects of the coinheritance of α-thalassemia, XmnI-^Gγ rs7482144, BCL11A rs766432, and 5'HS4 rs16912979 polymorphisms on the clinical phenotype of homozygous Filipino β⁰-deletion patients in Sabah. Molecular analyses were performed on 124 homozygous Filipino β⁰-deletion patients using gap-PCR, PCR-RFLP, multiplex PCR, ARMS-PCR, gel electrophoresis, and DNA sequencing. Data showed that the coinheritance of the -α^3.7 deletion significantly affected the clinical phenotypes of homozygous Filipino β⁰-deletion patients (p < 0.05). Patients with the -α^3.7/-α^3.7 genotype (5.6%) had a less severe clinical phenotype compared to those with the αα/αα (71.8%) and -α^3.7/αα (22.6%) genotypes. Our data further revealed that the MAFs of the XmnI-^Gγ rs7482144 and BCL11A rs766432 polymorphisms in these patients were 0.032 and 0.194, respectively. Interestingly, none of these single nucleotide polymorphisms significantly influenced the clinical phenotype of the patients. The effect of the 5'HS4 rs16912979 polymorphism on the clinical phenotype could not be assessed due to its rarity (1.6%). However, a novel 5'HS4 c.733+G mutation was identified, warranting further investigation of its potential impact on β-thalassemia pathogenesis. Our findings indicate that the clinical phenotype of patients with the homozygous Filipino β⁰-deletion is strongly influenced by the coinheritance of the -α^3.7 deletion, but not by the XmnI-^Gγ rs7482144 and BCL11A rs766432 polymorphisms.