The -1123G>C variant of PTPN22 gene promoter is associated with latent autoimmune diabetes in adult Chinese Hans.
ABSTRACT The protein tyrosine phosphatase non-receptor 22 (PTPN22) gene encodes for lymphoid protein tyrosine phosphatase. Recent studies demonstrated the association between the +1858T, -1123G>C variants of PTPN22 gene and type 1 diabetes mellitus in Caucasian and Japanese populations. This study examined the relationship between the polymorphism of PTPN22 gene and latent autoimmune 1 diabetes in adults (LADA) in Chinese Hans. We studied 229 adult Chinese patients with LADA (LADA group) and 210 healthy volunteers (control group). The -1123G>C and +1858C>T polymorphisms of PTPN22 gene were determined by PCR-restriction fragment length polymorphism method. Further, genotypic/allelic frequencies and clinical characteristics were compared between two groups. There was a significant difference of frequencies of the -1123G>C polymorphism between LADA and control groups (OR = 1.99, 95% CI = 1.24-3.2; P = 0.001). However, no significant differences in the +1858C>T genotypic (CC, CT) and allelic (C, T) frequencies were found. Furthermore, the frequencies of the -1123 GC, CC genotype in male patients with LADA were significantly higher compared with male healthy volunteers (OR = 1.65, 95% CI = 1.21-2.26; P = 0.005). The analysis of covariance demonstrated no difference between glycosylated hemoglobin, body mass index, duration of diabetes, C-peptide, and GAD-Ab titer between the group carrying GC/CC and the group without allele C. In conclusion, the -1123G>C promoter polymorphism of PTPN22 gene, but not the +1858C>T variant, is associated with LADA in adult Chinese Hans.
- SourceAvailable from: Massimo Pietropaolo[Show abstract] [Hide abstract]
ABSTRACT: There is a paucity of literature describing metabolic and histological data in adult-onset autoimmune diabetes. This subgroup of diabetes mellitus affects at least 5% of clinically diagnosed type 2 diabetic patients (T2DM) and it is termed Latent Autoimmune Diabetes in Adults (LADA). We evaluated indexes of insulin secretion, metabolic assessment, and pancreatic pathology in clinically diagnosed T2DM patients with and without the presence of humoral islet autoimmunity (Ab). A total of 18 patients with at least 5-year duration of clinically diagnosed T2DM were evaluated in this study. In those subjects we assessed acute insulin responses to arginine, a glucose clamp study, whole-body fat mass and fat-free mass. We have also analyzed the pancreatic pathology of 15 T2DM and 43 control cadaveric donors, using pancreatic tissue obtained from all the T2DM organ donors available from the nPOD network through December 31, 2013. The presence of islet Ab correlated with severely impaired β-cell function as demonstrated by remarkably low acute insulin response to arginine (AIR) when compared to that of the Ab negative group. Glucose clamp studies indicated that both Ab positive and Ab negative patients exhibited peripheral insulin resistance in a similar fashion. Pathology data from T2DM donors with Ab or the autoimmune diabetes associated DR3/DR4 allelic class II combination showed reduction in beta cell mass as well as presence of autoimmune-associated pattern A pathology in subjects with either islet autoantibodies or the DR3/DR4 genotype. In conclusion, we provide compelling evidence indicating that islet Ab positive long-term T2DM patients exhibit profound impairment of insulin secretion as well as reduced beta cell mass seemingly determined by an immune-mediated injury of pancreatic β-cells. Deciphering the mechanisms underlying beta cell destruction in this subset of diabetic patients may lead to the development of novel immunologic therapies aimed at halting the disease progression in its early stage.PLoS ONE 01/2014; 9(9):e106537. · 3.53 Impact Factor
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ABSTRACT: Although the polymorphisms of PTPN22 and the variants of CTLA-4 have been reported to be the susceptibility genes, which increased risk of latent autoimmune diabetes in adults (LADA), the results remained inconclusive. The aim of this meta-analysis was to evaluate the association between the polymorphisms of two genes and LADA. We performed a systematic review by identifying relevant studies and applied meta-analysis to pool gene effects. Data from ten studies published between 2001 and 2013 were pooled for two polymorphisms: rs2476601 in the PTPN22 gene and rs231775 in the CTLA-4 gene. Data extraction and assessments for risk of bias were independently performed by two reviewers. Fixed-effect model and random-effect model were used to pool the odds ratios; meanwhile, heterogeneity test, publication bias and sensitive analysis were explored. The minor T allele at rs2476601 and the minor G at rs231775 carried estimated relative risks (odds ratio) of 1.52 (95 % CI 1.29-1.79) and 1.39 (95 % CI 1.11-1.74), respectively. These alleles contributed to an absolute lowering of the risk of all LADA by 4.88 and 14.93 % when individuals do not carry these alleles. The estimated lambdas were 0.49 and 0.63, suggesting a codominant model of effects was most likely for two genes. In summary, our systematic review has demonstrated that PTPN22 rs2476601 and CTLA-4 rs231775 are potential risk factors for LADA. An updated meta-analysis is required when more studies are published to increase the power of these polymorphisms and LADA.Acta diabetologica. 07/2014;
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ABSTRACT: Background The major histocompatibility complex (MHC) genes have been implicated as the major genetic component in the predisposition to type 1 diabetes mellitus (T1DM). Other loci outside the MHC had also been reported to contribute in the susceptibility of T1DM. The aim of this study was to examine the role of some variants of polymorphic sites in some genes associated with T1DM in a sample of Egyptian children. Patients and methods 60 patients with T1DM from the diabetes clinic at Alexandria University Children’s Hospital, and 60 healthy individuals were enrolled in this study. Genomic DNA was extracted using isopropanol precipitation method. Interleukin 18 (IL-18), interleukin 10 (IL-10), vitamin D receptor (VDR), protein tyrosine phosphatase non-receptor type 22 (PTPN22) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) were genotyped. Results The findings obtained from logistic regression analysis suggest that the IL-18 single nucleotide polymorphisms SNP-137 G>C (rs#187238), the VDR Fok1 SNP T>A (rs#2228570) and the SNP-1123 C>G (rs#2488457) in PTPN22 gene showed a significant difference between patients and controls (P = 0.026, 0.030, and 0.003, respectively). The genotype distributions of PTPN22 SNP-1858, CTLA-4 SNP 49, IL-10 SNP-819, IL-18 SNP-607, and VDR BsmI SNP G>A did not show any significant difference. Conclusion The IL-18 SNP-137 G>C (rs#187238), VDR SNP-Fok1 T>A (rs#2228570), and the SNP-1123 C>G (rs#2488457) in PTPN22 gene may have an effect on the occurrence of T1DM in Egyptian children. Further large-scale, population-based, case-control studies are needed.Egyptian Journal of Medical Human Genetics 07/2014;