IL1RN VNTR and IL2-330 polymorphic genes are independently associated with chronic immune thrombocytopenia

Chronic Immune Thrombocytopenia (cITP) is an acquired immune-mediated disease associated with a T-helper cell type 1 (Th1) immune polarization, whose genetic risk factors, however, are largely unknown. We investigated polymorphisms in promoter regions of genes that code molecules involved in proinflammatory immune response [IL1B -31T/C, IL1RN variable number tandem repeats (VNTR), IL2 -330T/G, and TNF -307G/A] as well as in genes that code Toll like receptors (TLR) (TLR2 Arg753Gln, TLR4 Asp299Gly and TLR5 Arg(392stop)) in 122 patients with cITP and 541 blood donors. The frequencies of the IL1RN polymorphic allele 2 (P = 0.001) and of the IL2-330 polymorphic allele G (P = 0.004) were significantly higher in cITP patients than in blood donors. In logistic analysis adjusting for age and gender, the polymorphisms remained independently associated with cITP. Enhanced serum concentrations of interleukin (IL)-1 alpha and IL-1 beta were observed in cITP (P < 10(-3)) and blood donor (P = 0.04) carriers of the IL1RN*2. Also, the serum levels of IL-2 and gamma-interferon (IFN-gamma) were increased in cITP patients (P < 10(-3) and P = 0.04 respectively) and blood donors (P < 10(-3) and P = 0.03 respectively) harbouring the IL2 -330G allele. Here we demonstrated that IL2 -330G and IL1RN*2 are independently associated with cITP and are functional in vivo, which strongly suggests that they contribute to the pathogenesis of cITP.