Abnormal lymphocyte-specific protein tyrosine kinase (LCK)-related T cell hyporesponsiveness was discovered in type 1 diabetes (T1D). This study aims to investigate the potential associations between LCK single-nucleotide polymorphisms (SNPs) and the susceptibility of T1D.
DNAs were extracted from blood samples of 589 T1D patients and 596 healthy controls to genotype seven SNPs of the LCK gene using PCR and Sanger sequencing. Associations of these SNPs with the susceptibility of T1D were determined by χ2 test. LCKs were knocked out in peripheral blood mononuclear cells (PBMCs) using CRISPR–Cas9 to investigate the role of LCK SNP in T-lymphocyte activation in T1D.
SNP rs10914542 but not the other six SNPs of the LCK gene was significantly associated with (C vs. G, odds ratio (OR) = 0.581, 95% confidence interval (CI) = 0.470–0.718, P value = 4.13E − 7) the susceptibility of T1D. Peripheral T-lymphocyte activation in response to T cell receptor (TCR)/CD3 stimulation is significantly lower in the rs10914542-G-allele group than in the C-allele group. In vitro experiments revealed that rs10914542 G allele impaired the TCR/CD3-mediated T-cell activation in PBMCs.
This study reveals that the G allele of SNP rs10914542 of LCK impairs the TCR/CD3-mediated T-cell activation and increases the risk of T1D.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $64.85 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Kalyva, E., Malakonaki, E., Eiser, C. & Mamoulakis, D. Health-related quality of life (HRQoL) of children with type 1 diabetes mellitus (T1DM): self and parental perceptions. Pediatr. Diabetes 12, 34–40 (2011).
Oser, T. K., Oser, S. M., McGinley, E. L. & Stuckey, H. L. A novel approach to identifying barriers and facilitators in raising a child with type 1 diabetes: qualitative analysis of caregiver blogs. JMIR Diabetes 2, e27 (2017).
He, B. et al. Combination therapeutics in complex diseases. J. Cell Mol. Med. 20, 2231–2240 (2016).
Welter, M. et al. Polymorphism rs2476601 in the PTPN22 gene is associated with type 1 diabetes in children from the South Region of Brazil. Gene 650, 15–18 (2018).
Peng, H. et al. Genetic variants of PTPN2 gene in chinese children with type 1 diabetes mellitus. Med. Sci. Monit. 21, 2653–2658 (2015).
Roep, B. O. The role of T-cells in the pathogenesis of type 1 diabetes: from cause to cure. Diabetologia 46, 305–321 (2003).
Nervi, S. et al. Specific deficiency of p56lck expression in T lymphocytes from type 1 diabetic patients. J. Immunol. 165, 5874–5883 (2000).
Nervi, S. et al. No association between lck gene polymorphisms and protein level in type 1 diabetes. Diabetes 51, 3326–3330 (2002).
Hulme, J. S. et al. Association analysis of the lymphocyte-specific protein tyrosine kinase (LCK) gene in type 1 diabetes. Diabetes 53, 2479–2482 (2004).
Ran, F. A. et al. In vivo genome editing using Staphylococcus aureus Cas9. Nature 520, 186–191 (2015).
Straus, D. B. & Weiss, A. Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Cell 70, 585–593 (1992).
Mastrangelo, M., Tromba, V., Silvestri, F. & Costantino F. Epilepsy in children with type 1 diabetes mellitus: pathophysiological basis and clinical hallmarks. Eur. J. Paediatr. Neurol. 23, 240–247 (2019).
Zhang, S. M. et al. Prognostic value of EGFR and KRAS in resected non-small cell lung cancer: a systematic review and meta-analysis. Cancer Manag Res. 10, 3393–3404 (2018).
Li, W. et al. Identification of susceptible genes for complex chronic diseases based on disease risk functional SNPs and interaction networks. J. Biomed. Inf. 74, 137–144 (2017).
He, B. et al. Drug discovery in traditional Chinese medicine: from herbal fufang to combinatory drugs. Science 350, S74–S76 (2015).
Griffin, K. J., Thompson, P. A., Gottschalk, M., Kyllo, J. H. & Rabinovitch, A. Combination therapy with sitagliptin and lansoprazole in patients with recent-onset type 1 diabetes (REPAIR-T1D): 12-month results of a multicentre, randomised, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol. 2, 710–718 (2014).
Ju, Z. et al. Role of an SNP in alternative splicing of bovine NCF4 and mastitis susceptibility. PLoS ONE 10, e0143705 (2015).
Kawase, T. et al. Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen. Blood 110, 1055–1063 (2007).
He, B. et al. Bioinformatics and microarray analysis of miRNAs in aged female mice model implied new molecular mechanisms for impaired fracture healing. Int. J. Mol. Sci. 17, E1260 (2016).
This study was supported by the Nantong Science and Technology Project (Grant No. MS12017013-8).