Table 1.

Genetic modifiers of β-thalassemia.

A. Primary at level of α/non-α-globin chain imbalance	Mechanism of action
β- globin genotype (1 or 2, severity of β-thalassemia alleles)	Directly affects output of β-globin and chain imbalance
α-globin genotype  α-thalassemia  co-inheritance of extra globin genes (ααα/, αααα/, or HBA cluster duplication)	Reduces α-globin excess Adds to redundant α-globin
Innate ability to increase HbF (co-inheritance of HbF QTLs, e.g., HbF-boosting variants in BCL11A, HMIP, Xmn1-HBG2 and KLF1)	Increased γ-chains combine with excess α reducing chain imbalance
Potential modifiers include variants in ubiquitin proteolytic pathway	Promotes proteolysis of excess α-globin
α-hemoglobin stabilizing protein (AHSP)	Chaperones excess α-globin

B. Secondary at level of disease complications
Bilirubin levels and predisposition to gallstones – UGT1A promoter (TA)n polymorphism
Iron loading e.g., HEF variants
Bone disease e.g., QTLs influencing bone mass (VDR, COL1A1, CoL1A2, TGFB1)
Cardiac disease e.g., apolipoprotein (APOE)ε4 alleles
Predisposition to infection e.g., HLA alleles