Effect of T330G variant of IL2 gene on some biomarkers in patients with type 1 diabetes mellitus

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by a high risk of vascular complications causing disability and mortality. Immune system dysfunction, especially, imbalance of regulatory T cells (Tregs), plays a central role in pathogenesis of T1DM. Interleukin-2 (IL-2) is a key cytokine for maintaining the Treg function. The T330G (rs2069762) polymorphism in promoter region of IL2 gene may affect its production, but its association with pathological biomarkers of diabetes is not well understood. Our aim was to investigate the possible association between T330G polymorphism of IL2 gene and the levels of laboratory markers reflecting systemic inflammation, endothelial dysfunction, fibrogenesis, and intestinal barrier permeability in T1DM patients. This cross-sectional study included 90 patients with T1DM. Genotyping for the IL-2 T330G polymorphism was performed using PCR method. Plasma concentrations of angiotensin-2, transforming growth factor-b (TGF-b), endothelin-1, C-reactive protein (CRP), markers of intestinal permeability (zonulin, LBP, BPI, sCD14), and other protein factors were determined by ELISA technique. Statistical analysis was performed using non-parametric methods. It was found that the carriers of TT genotype associated with lower IL-2 production, had statistically significantly higher levels of angiotensin-2 compared to the subjects with GG genotype (median 192.4 pg/mL vs. 88.0 pg/mL; p = 0.021). Patients with the TT genotype also showed higher concentrations of TGF-b compared to the heterozygous TG group (median 2.7 ng/mL vs. 1.8 ng/mL; p = 0.015). No significant associations of T330G polymorphism were found with levels of CRP, markers of intestinal permeability, or clinical parameters, including HbA1c and the frequency of The T330G polymorphism of IL2 gene in patients with T1DM is associated with activity of renin-angiotensin system and the levels of TGF-b, the main profibrotic cytokine. The genetically determined decrease in IL-2 production (TT variant of T330G polymorphism) may contribute to hyperactivation of these systems, thus playing a key role in development of vascular complications. This gene variant could be considered a potential genetic marker for risk stratification and personalized therapy in T1DM.

1. Atkinson M.A., Eisenbarth G.S., Michels A.W. Type 1 diabetes. Lancet, 2014, Vol. 383, no. 9911, pp. 69-82.

2. Bluestone J.A., Herold K.C., Eisenbarth G.S. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature, 2010, Vol. 464, no. 7293, pp. 1293-1300.

3. Bottinger E.P. TGF-beta in renal injury and disease. Semin. Nephrol., 2007, Vol. 27, no. 3, pp. 309-320.

4. Chen W., Jin W., Hardegen N., Lei K.-J., Li L., Marinos N., McGrady G., Wahl S.M. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor FoxP3. J. Exp. Med., 2003, Vol. 198, no. 12, pp. 1875-1886.

5. Cole J.B., Florez J.C. Genetics of diabetes mellitus and diabetes complications. Nat. Rev. Nephrol., 2020, Vol. 16, no. 7, pp. 377-390.

6. Forbes J.M., Cooper M.E. Mechanisms of diabetic complications. Physiol. Rev., 2013, Vol. 93, no. 1, pp. 137-188.

7. Harsini S., Ziaee V., Tahghighi S.F., Mahmoudi M., Rezaei A., Soltani S., Moradinejad M., Aghighi Y., Rezaei N. Association of interleukin-2 and interferon-γ single nucleotide polymorphisms with Juvenile systemic lupus erythematosus. Allergol. Immunopathol., 2016, Vol. 44, no. 5, pp. 391-486.

8. Hoffmann S.C., Stanley E.M., Darrin Cox E., Craighead N., DiMercurio B., Koziol D.E., Harlan D.M., Kirk A.D., Blair P.J. Association of cytokine polymorphic inheritance and in vitro cytokine production in anti-CD3/ CD28-stimulated peripheral blood lymphocytes. Transplantation, 2001, Vol. 72, no. 8, pp. 1444-1450.

9. Kvakan H., Kleinewietfeld M., Qadri F., Park J.-K., Fischer R., Schwarz I., Rahn H.-P., Plehm R., Wellner M., Elitok S., Gratze P., Dechend R., Luft F.C., Muller D.N. Regulatory T cells ameliorate angiotensin II-induced cardiac damage. Circulation, 2009, Vol. 119, no. 22, pp. 2904-2912.

10. Lavoie J.L., Sigmund C.D. Minireview: Overview of the renin-angiotensin system—an endocrine and paracrine system. Endocrinology, 2003, Vol. 144, no. 6, pp. 2179-2183.

11. Long S.A., Cerosaletti K., Bollyky P.L., Tatum M., Shilling H., Zhang S., Zhang Z.-Y., Pihoker C., Sanda S., Greenbaum C., Buckner J.H. Defects in IL-2R signaling contribute to diminished maintenance of FOXP3+ regulatory T-cells in type 1 diabetes. Diabetes, 2010, Vol. 59, no. 2, pp. 407-415.

12. Malek T.R., Castro I. Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity, 2010, Vol. 33, no. 2, pp. 153-165.

13. Meng X.M., Nikolic-Paterson D.J., Lan H.Y. TGF-β: The master regulator of fibrosis. Nat. Rev. Nephrol., 2016, Vol. 12, no. 6, pp. 325-338.

14. Ruiz-Ortega M., Lorenzo O., Rupérez M., Esteban V., Suzuki Y., Mezzano S., Plaza J.J., Egido J. Role of the renin-angiotensin system in vascular diseases: Expanding the field. Hypertension, 2001, Vol. 38, no. 6, pp. 1382-1387.

15. Sakaguchi S., Miyara M., Costantino C.M., Hafler D.A. FOXP3+ regulatory T cells in the human immune system. Nat. Rev. Immunol., 2010, Vol. 10, no. 7, pp. 490-500.

16. Todd J.A. Etiology of type 1 diabetes. Immunity, 2010, Vol. 32, no. 4, pp. 457-467.

17. Vaarala O. Gut microbiota and type 1 diabetes. Rev. Diabet. Stud., 2012, Vol. 9, no. 4, pp. 251-259.