HLA-DQB1 alleles as genetic modifiers in β-thalassemia major: association with clinical heterogeneity

Abstract

Background: Clinical expression among children with transfusion-dependent β-thalassemia major varies substantially, and this heterogeneity is not fully explained by HBB mutations alone. We evaluated whether HLA-DQB1 alleles were associated with case status in a pediatric case-control cohort and whether selected alleles correlated with hematologic and hemoglobin fraction profiles among affected children.

Methods: This single-center case-control study included 45 children with transfusion-dependent β-thalassemia major and 45 age- and sex-matched healthy controls. HLA-DQB1 genotyping was performed using a sequence-specific primer real-time PCR assay. Allele frequencies were compared between groups, and within-patient analyses examined associations with pre-transfusion hemoglobin, reticulocyte counts, and hemoglobin fractions. Multivariable and internal-validation analyses were treated as exploratory because of the modest sample size.

Results: DQB1 0601 was more frequent in cases than controls (9.7% vs. 2.2%, p = 0.034), whereas the DQB1 03 family (30.1% vs. 45.6%, p = 0.031) and particularly DQB1 0302 (6.5% vs. 26.7%, p < 0.001) were less frequent among cases. After Bonferroni correction for 15 allele comparisons, only DQB1 0302 remained significant. Within the patient group, DQB1 0502/0504 was associated with higher pre-transfusion hemoglobin (p = 0.036), DQB1 0501 with higher reticulocyte counts (p = 0.021), and DQB1 0601 with lower HbA1 and higher HbF (both p ≈ 0.03); these phenotype associations were exploratory and did not survive strict multiplicity correction. In adjusted exploratory models, the direction of association remained similar.

Conclusion: In this Egyptian cohort, HLA-DQB1 alleles were associated with case status and with selected laboratory features among children with transfusion-dependent β-thalassemia major. These findings should be interpreted as association signals rather than evidence of etiologic susceptibility or causation, and they require validation in larger multi-group cohorts that include non-transfusion-dependent thalassemia.

Keywords: Case-control study; Clinical heterogeneity; Genetic modifiers; HLA-DQB1; Hemoglobin F; β-Thalassemia major.