LADA and T1D in Estonian population — Two different genetic risk profiles

Kisand, Kalle; Uibo, Raivo

doi:10.1016/j.gene.2012.01.089

Cited by 29 publications

(27 citation statements)

References 43 publications

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“…The SNPs of PTPN22 are among the major causative agents of human autoimmune disorders, including T1DM and LADA [3,4,5,6,7]. The disease risk is transmitted through the altered antigen-presenting function of dendritic cells (that express high levels of LYP), the altered activation of helper T cells and likely also via the decreased function of self-reactive regulatory T cells [48].…”

Section: Discussionmentioning

confidence: 99%

“…Further research should elucidate the mechanisms that lead to the transient exposure of β-cell antigens to the immune system in at least a portion of the MODY patients of Central European origin. Interestingly, it was previously suggested by Kisand and Uibo [6] that the slower forms of LADA are not associated with the classical T1DM risk haplotypes of HLA and non-HLA loci, including PTPN22 c.1858C>T. MODY patients positive for autoantibodies exhibit similar autoantibody onset kinetics and so they may be subject to similar, currently enigmatic, regulation.…”

Section: Discussionmentioning

confidence: 99%

“…The single nucleotide polymorphisms (SNPs) of PTPN22 , predominantly p.Arg620Trp (c.1858C>T), are among the major causative agents of human autoimmune disorders. Associations of PTPN22 SNPs with type 1 diabetes (T1DM) [3,4,5], latent autoimmune diabetes in adults (LADA) [6,7], autoimmune thyroid diseases (including Graves' disease and Hashimoto's thyroiditis) [8,9,10], rheumatoid arthritis (including anticitrullinated peptide antibody-negative subjects) [11], juvenile idiopathic arthritis [12], systemic lupus erythematosus [13,14,15], thymoma-associated myasthenia gravis [16], antineutrophil cytoplasmic autoantibodies (ANCA) disease [17,18], vasculitis (including ANCA-associated vasculitis, Wegener's granulomatosis and Behçet's disease) [19], chronic spontaneous autoreactive urticaria [20], and generalized vitiligo [21,22,23] have repeatedly been reported. PTPN22 polymorphisms also affect the responses of chronic-phase chronic myeloid leukemia patients to treatment with the tyrosine kinase inhibitor imatinib [24].…”

Section: Introductionmentioning

confidence: 99%

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Low Frequencies of Autoimmunity-Associated PTPN22 Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

Heneberg¹,

Malá²,

Yorifuji³

et al. 2015

Int Arch Allergy Immunol

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Background: The protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene encodes lymphoid tyrosine phosphatase (LYP), which is expressed primarily in lymphoid tissues. The functional but geographically highly variable PTPN22 single-nucleotide polymorphisms (SNPs), particularly c.1858C>T, contribute to the onset and progression of autoimmunity-associated diseases and facilitate the expression of disease-associated autoantibodies. In Central Europe, 17-25% of patients with monogenic diabetes (maturity-onset diabetes of the young, MODY) transiently express islet cell autoantibodies. Methods: We addressed the links between the functional and geographically variable PTPN22 SNPs with MODY manifestation and the expression of islet cell autoantibodies in 276 MODY patients who originated from four regions (the Czech Republic, Israel, Japan and Brazil). Results: The frequency of PTPN22 polymorphisms in the MODY patients was similar to those in geographically matched healthy populations, with the exception of c.788G>A, the minor allele frequency of which was significantly elevated in the Czech hepatocyte nuclear factor 1-α (HNF1A) MODY patients [odds ratio (OR) 4.8, 95% confidence interval (CI) 2.2-10.7] and the Brazilian MODY patients (OR 8.4, 95% CI 1.8-39.1). A barely significant increase in the c.788G>A minor allele was also detected in the islet cell autoantibody-positive Czech MODY patients. However, c.788A behaves as a loss-of-function mutant in T cells, and thus protects against autoimmunity. Conclusions: MODY patients (including islet cell autoantibody-positive cases) do not display any increase in autoimmunity-associated PTPN22 alleles. The absence of autoimmunity-associated PTPN22 alleles was also demonstrated in latent autoimmune diabetes in adults, which suggests that the slow kinetics of the onset of autoantibodies is subject to a regulation that is different from that experienced in type 1 diabetes and other autoimmune disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Low Frequencies of Autoimmunity-Associated PTPN22 Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

Heneberg¹,

Malá²,

Yorifuji³

et al. 2015

Int Arch Allergy Immunol

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“…The primers and restriction enzymes used are listed in Table 2. The only polymorphisms previously analyzed in LADA patients were c.1858C>T, which did not show any association with LADA in Estonian patients (OR 0.9 [13]) and c.–1123G>C, which was found to be associated with LADA in Chinese (OR 2.0 [20]) but not Japanese (OR 1.0 [55]) patients.…”

Section: Methodsmentioning

confidence: 99%

“…Table S1; for all online suppl. material, see www.karger.com/doi/10.1159/000489225 [12-13, 15, 20-26]) and increased serum levels of antibodies against glutamic acid decarboxylase (GADA) in LADA patients [16, 17, but see 12 for contradictory results]. The expression of autoantibodies in 1858T carriers increases independently of the disease background as revealed for GADA in individuals without diabetes [18] and for multiple types of autoantibodies in patients with type 1 diabetes mellitus (T1DM) [19].…”

Section: Introductionmentioning

confidence: 99%

Autoimmunity-Associated PTPN22 Polymorphisms in Latent Autoimmune Diabetes of the Adult Differ from Those of Type 1 Diabetes Patients

Heneberg¹,

Kocková²,

Čecháková³

et al. 2018

Int Arch Allergy Immunol

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Background: A portion of adults with humoral immune changes have clinical diabetes that is initially not insulin-requiring (latent autoimmune diabetes of the adult, LADA). One of the genes strongly associated with autoimmune diabetes is PTPN22. We hypothesized that the manifestation and clinical features of LADA are linked to functional variants of PTPN22. Methods: We genotyped allelic frequencies of 1 protective and 3 risk-associated PTPN22 variants in 156 Czech LADA patients, 194 type 2 diabetes mellitus patients with LADA-like progression to insulinotherapy and 324 type 1 diabetes mellitus patients, and subsequently examined the associations of PTPN22 variants with the expression of autoantibodies and other clinical features of LADA. Results: We challenged the paradigm that stated that the PTPN22 c.1858T allele serves as a risk allele for LADA, although we confirmed its risk status in the geographically matched T1DM cohort. In contrast, the frequencies of other PTPN22 alleles (c.–1123C, c.788A and c.1970-852C) differed significantly from the healthy controls. We confirmed gender-related differences in the frequency of some PTPN22 polymorphisms (but not c.1858C>T) in LADA. The particular PTPN22 alleles and genotypes were associated with specific clinical features of the examined patients (autoantibodies, HbA_1c and age at diagnosis of diabetes). Conclusions: The variability in PTPN22 haplotypes suggests that the genetic signature of LADA is independent and should not be considered a hybrid form of T1DM and T2DM. Further studies should elucidate the associations with clinical characteristics of the LADA patients and focus on the newly emerging types of diabetes with the disease onset in early to mid-adulthood.

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Lada

Zampetti¹,

Buzzetti²

2018

Endocrinology

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LADA and T1D in Estonian population — Two different genetic risk profiles

Cited by 29 publications

References 43 publications

Low Frequencies of Autoimmunity-Associated <b><i>PTPN22</i></b> Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

Low Frequencies of Autoimmunity-Associated <b><i>PTPN22</i></b> Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

Autoimmunity-Associated <b><i>PTPN22</i></b> Polymorphisms in Latent Autoimmune Diabetes of the Adult Differ from Those of Type 1 Diabetes Patients

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