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 × 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 (OD(450)) 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.
Lavrikova
Elena Y
EY
Department of Molecular Diagnostics, National Research Center GosNIIgenetika, Moscow, Russia.
Nikitin
Alexey G
AG
Kuraeva
Tamara L
TL
Peterkova
Valentina A
VA
Tsitlidze
Nina M
NM
Chistiakov
Dimitry A
DA
Nosikov
Valery V
VV
D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D001120:Arginine / Q000235:genetics; D001772:Blood Cell Count; D016022:Case-Control Studies; D049109:Cell Proliferation; D002648:Child; D003430:Cross-Sectional Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009000:Monocytes / Q000378:metabolism / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011506:Proteins / Q000235:genetics*; D014364:Tryptophan / Q000235:genetics; D015854:Up-Regulation; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C490778:SH2B3 protein, human; D014364:Tryptophan; D001120:Arginine