The carriage of the type 1 diabetes-associated R262W variant of human LNK correlates with increased proliferation of peripheral blood monocytes in diabetic patients

Objective: Lymphocyte adaptor protein (LNK) plays a pivotal role as a suppressor of T-cell receptor-mediated immune signaling and negative regulator of lymphopoiesis and early hematopoiesis. Recently, association between the R262W (c.784T > C) variant of the SH2B3 gene (rs3184504) encoding human LNK and type 1 diabetes (T1D) was found in several populations. In this study, we aimed to check whether this marker is associated with T1D in a Russian population. Methods: Using a Taqman allele discrimination assay, we genotyped 1062 unrelated Russian individuals with diabetes at childhood and adolescence onset and 1020 healthy controls. T-cell proliferation assay based on the measurement of incorporation of bromo-2'-deoxyuridine incorporation into newly synthesized DNA was used to evaluate whether carriage of SH2B3 784T > C correlates with T-cell proliferation in patients' peripheral mononuclear blood cells (PMBCs) stimulated with anti-CD28 and anti-CD3 antibodies. Results: The allele 784C of SH2B3 was related to a higher risk of T1D (odds ratio of 1.52, p = 1.2 x 10-12). A correlation between the carriage of the predisposing C/C variant of LNK and increased proliferation of T lymphocytes was shown in PMBCs of both diabetic [C/C vs. C/T vs.T/T = optical density at 450 nm (OD450) 6.3 +/- 0.8 vs. 4.4 +/- 0.7 vs. 2.7 +/- 0.5, p = 0.0007] and non-diabetic (C/C vs. C/T vs.T/T = OD(450)2.9 +/- 0.6 vs. 2.2 +/- 0.4 vs. 1.7 +/- 0.4, p = 0.022) patients. Conclusions: The SH2B3 784T > C variant could contribute to the pathogenesis of T1D through impaired immune response that promotes activation and expansion of self-reactive lymphocytes in susceptible individuals.