Coincidence of PTPN22 c.1858CC and FCRL3 -169CC genotypes as a biomarker of preserved residual β-cell function in children with type 1 diabetes.
BACKGROUND
Genotype-phenotype studies in type 1 diabetes (T1DM) patients are needed for further development of therapy strategies.


OBJECTIVE
Our aims were to investigate the distribution of selected PTPN22 and FCRL3 gene polymorphisms and their associations with clinical course of disease in children with newly diagnosed T1DM from the Pomeranian region of Poland.


METHODS
The prospective, longitudinal study of 147 children with newly diagnosed T1DM-autoimmune subtype was conducted. The PTPN22 c.1858T>C (rs2476601) and FCRL3 -169C>T (rs7528684) polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP) and DNA sequencing. The frequencies of genotypes were compared between the study and population-matched control group (327 random anonymous samples from the Pomeranian region). Selected patients underwent a 24-monthly follow up [periodic re-evaluation of fasting C-peptide concentration (FCP) and hemoglobin A1c (HbA1c ) level].


RESULTS
A significantly lower coincidence of the PTPN22 c.1858CC and FCRL3 -169CC genotypes was found in the study group compared with controls (P = 0.04). The PTPN22 c.1858CC and FCRL3 -169CC genotype combination, restricted to female patients only, was associated with well-preserved residual β-cell function throughout the entire follow up (prolonged FCP level increase up to the sixth month of disease, with further very stable dynamics-FCP median level ≥0.67 ng/mL without significant decrease up to the 24th month). HbA1c levels in this subgroup also remained the lowest during the observation period.


CONCLUSIONS
Ascertained phenomenon could be explained by an interacting mechanism of the two polymorphisms through estrogen-regulated nuclear factor kappa B signaling in regulatory T (Treg) lymphocytes. This hypothesis, if confirmed, may lead to further development of Tregadministration-based therapies.
Department of Paediatrics, Haematology, Oncology and Endocrinology, Medical University of Gdańsk, Gdańsk, Poland.|Department of Developmental Neurology, Medical University of Gdańsk, Gdańsk, Poland.
Małgorzata
M
Pawłowicz
Institute of Mathematics, Faculty of Mathematics, Physics and Informatics, University of Gdańsk, Gdańsk, Poland.
Rafał
R
Filipów
Institute of Informatics, Faculty of Mathematics, Physics and Informatics, University of Gdańsk, Gdańsk, Poland.
Grzegorz
G
Krzykowski
Department of Biology and Genetics, Medical University of Gdańsk, Gdańsk, Poland.
Anna
A
Stanisławska-Sachadyn
Department of Biology and Genetics, Medical University of Gdańsk, Gdańsk, Poland.
Lucyna
L
Morzuch
Laboratory of Immunology and Clinic Transplantology, University Clinical Centre of Gdańsk, Gdańsk, Poland.
Julia
J
Kulczycka
Department of Paediatrics, Haematology, Oncology and Endocrinology, Medical University of Gdańsk, Gdańsk, Poland.
Anna
A
Balcerska
Department of Biology and Genetics, Medical University of Gdańsk, Gdańsk, Poland.
Janusz
J
Limon
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics*; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007223:Infant; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008137:Longitudinal Studies; D008297:Male; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics*
D006442:Glycated Hemoglobin; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D011971:Receptors, Immunologic; C457775:FCRL3 protein, human; C517652:hemoglobin A1c protein, human; C516765:PTPN22 protein, human
FCRL3 protein, human; biomarkers; protein tyrosine phosphatase, non-receptor type 22; sex distribution; type 1 diabetes mellitus