Association of HBA2 Gene rs4021965 (T > C) Polymorphism with Beta-thalassemia Major and Intermedia in Iraqi Patients

BACKGROUND: Beta-thalassemia is a hereditary hematological disorder caused by mutations in the beta-globin (HBB) gene on chromosome 11, leading to reduced or absent β-globin chain synthesis and consequent hemoglobin (Hb) deficiency. The clinical severity of beta-thalassemia is modulated by several genetic modifiers, among which are polymorphisms in the Hb alpha-2 (HBA2) gene. OBJECTIVE: This study aimed to investigate the potential association between the single-nucleotide polymorphism rs4021965 (T > C) in the HBA2 gene and the clinical phenotypes of beta thalassemia major (βTM) and beta-thalassemia intermedia (βTI) in Iraqi patients. MATERIALS AND METHODS: A total of 150 participants were enrolled in this cross-sectional study and divided into three groups: 73 patients with βTM, 27 patients with βTI, and 50 apparently healthy individuals serving as the control group. Participants were recruited from the Hereditary Blood Disorder Center at Al-Karama Teaching Hospital, Baghdad, during the period from June 2023 to April 2024. Genotyping was performed using high-resolution melting (HRM) analysis coupled with quantitative real-time PCR to investigate the association of the rs4021965 T > C polymorphism in the HBA2 gene, as a potential genetic modifier, among the three groups. RESULTS: The genotype distributions in all groups were consistent with Hardy–Weinberg equilibrium. The TC and CC genotypes of the HBA2 gene rs4021965 (T > C) SNP were significantly associated with increased risk for βTM (odds ratio [OR] = 6.1, 95% confidence interval [CI]: 2.02–18.31; and OR = 24.0, 95% CI: 6.14–93.76, respectively) and for βTI (OR = 4.2, 95% CI: 1.09–16.73; and OR = 10.0, 95% CI: 2.05–55.52, respectively), using the TT genotype as the reference. The C allele was significantly more frequent in both patient groups compared with controls. CONCLUSION: The rs4021965 T > C polymorphism in the HBA2 gene was significantly associated with βTM and βTI phenotypes in Iraqi patients. The C allele and the TC and CC genotypes may act as potential genetic modifiers that contribute to disease susceptibility.