Association of HBB Gene Variants with Laboratory Profiles and Comorbidities in Taiwanese beta thalassemia carriers: A Case–Control Study

Background Heterozygous mutations in the β-globin gene (HBB) underlie beta thalassemia carriers (BTC), traditionally regarded as clinically silent. Emerging data, however, suggest that specific HBB variants may modulate systemic physiology, altering susceptibility to metabolic and renal disorders. Methods We conducted a retrospective case–control study including 478 BTC and 4,780 age- and sex-matched controls from the Taiwan Precision Medicine Initiative (TPMI). Associations between two HBB variants (rs34451549 and rs80356821) and clinical outcomes were examined using univariable and multivariable logistic regression. Multivariable linear regression was applied to evaluate the independent effects of these variants on estimated glomerular filtration rate (eGFR). Results Compared to non-BTC controls, BTC were significantly less likely to have diabetes mellitus (adjusted odds ratio [aOR], 0.39; 95% CI, 0.25–0.60) and hyperlipidemia (aOR, 0.63; 95% CI, 0.42–0.96). The rs80356821 allele was significantly associated with reduced diabetes risk (aOR, 0.48; p = 0.002) and with an increased eGFR of + 6.34 mL/min/1.73 m² per allele (p = 0.001). Conclusions In Taiwanese individuals with BTC, particularly rs80356821 carriers, a distinct genotype–phenotype relationship characterized by reduced diabetes risk and elevated eGFR suggests compensatory iron-metabolic and hemodynamic adaptations, warranting further longitudinal and mechanistic investigations.