Association of EPHX2 rs751141 and MIF rs755622 gene polymorphisms with cardiac complications in pediatric patients with transfusion-dependent thalassemia

Cardiac complications are a major cause of morbidity and mortality in transfusion-dependent β-thalassemia. Although iron overload is a principal risk factor, genetic variation may contribute to interindividual susceptibility. This study investigated the association of MIF rs755622 and EPHX2 rs751141 polymorphisms with cardiac complications in children with transfusion-dependent β-thalassemia.This case-control study included 150 participants: 50 children with transfusion-dependent β-thalassemia and cardiac complications, 50 without cardiac complications, and 50 healthy controls. Serum ferritin and transfusion-related variables were assessed. Genotyping was performed using TaqMan real-time PCR. Associations between the investigated polymorphisms and cardiac complications were evaluated under different genetic models using logistic regression.Patients with cardiac complications had significantly higher serum ferritin levels, more frequent splenectomy, shorter transfusion intervals, and higher blood transfusion indices than those without complications (all p < 0.05). MIF rs755622 was significantly associated with cardiac complications, with higher frequencies of the C allele and CC genotype among affected patients. After adjustment for transfusion frequency, splenectomy, and serum ferritin, GC+CC carriers had higher odds of cardiac complications than GG homozygotes (adjusted OR = 11.81, 95% CI: 1.46-95.34; p = 0.021). EPHX2 rs751141 showed no significant overall genotype association, although an allele-level difference was observed, with a lower frequency of the A allele among patients with cardiac complications.Transfusion burden, serum ferritin, and splenectomy were significantly associated with cardiac complications in children with transfusion-dependent β-thalassemia. MIF rs755622 was significantly associated with cardiac complications and may contribute to genetic susceptibility, whereas EPHX2 rs751141 finding was limited to a nominal allele-level association and should not be interpreted as definitive evidence of a protective effect. The relatively modest sample size, particularly for less frequent genotype subgroups, limits the precision of some genetic estimates. Larger multicenter studies with appropriate control of multiple testing and functional investigations are required to validate these findings and clarify their biological significance.