Association of HBB gene variants with cardiometabolic and renal phenotypes in a Taiwanese genomic cohort: a cross-sectional study

Abstract

Heterozygous mutations in the β-globin gene (HBB) define beta-thalassemia carriers (BTC), a state traditionally regarded as clinically silent. However, the systemic consequences of HBB variant carriage on metabolic and renal phenotypes remain incompletely characterized, particularly in East Asian populations underrepresented in large-scale genomic studies. We performed a cross-sectional study of 478 BTC and 4,780 age- and sex-matched non-BTC controls from the Taiwan Precision Medicine Initiative (TPMI), a nationwide genomic cohort with linked electronic health records. BTC status was defined by the presence of HBB variants rs34451549 and rs80356821. Associations with metabolic comorbidities were examined using multivariable logistic regression; associations with estimated glomerular filtration rate (eGFR) were assessed using multivariable linear regression. Variant-stratified analyses were performed to evaluate genotype-specific effects. BTC were significantly less likely to have prevalent 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) compared with non-BTC controls. BTC status was independently associated with higher eGFR (β = +4.73 mL/min/1.73 m²; p = 0.003), with a stronger genotype-specific effect observed for rs80356821 (β = +6.34; p = 0.001). After Benjamini-Hochberg false discovery rate correction, associations of BTC with DM, HLD, and eGFR, and of rs80356821 with DM and eGFR remained statistically significant. Variant-stratified analyses revealed directionally consistent associations for both HBB variants across metabolic and renal outcomes. In this Taiwanese population-based genomic cohort, HBB variant carriage was cross-sectionally associated with lower prevalence of diabetes mellitus and hyperlipidemia, and with higher creatinine-based eGFR values, which may partly reflect measurement-related limitations rather than superior renal function. These findings suggest that BTC status may represent a genomic modifier of metabolic phenotypes, with potential implications for precision health stratification in populations with appreciable thalassemia carrier frequencies. Prospective studies incorporating alternative glycemic and renal function assessments are warranted to elucidate the underlying mechanisms and causal directionality.