PD-L1 gene polymorphisms and low serum level of PD-L1 protein are associated to type 1 diabetes in Chile (original) (raw)
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Tissue Antigens, 2003
The immunoreceptor programmed cell death-1 (PD-1) is reported to play an important role in the regulation of peripheral tolerance in rodents, and it was recently shown that a polymorphism in a regulatory site of the PD-1 gene is associated with susceptibility to the autoimmune disease systemic lupus erythematosus (SLE) in humans. We investigated the existence of single-nucleotide polymorphisms (SNPs) in the PD-1 gene in patients with type 1 diabetes in comparison with healthy control subjects, by analyzing 94 children and adolescents with type 1 diabetes diagnosed before their eighteenth birthday (male : female ¼ 52 : 42) and 155 control subjects. Polymorphisms in the complete PD-1 gene (minus the large intron 1) were detected by sequencing. In total, we identified 14 SNPs, of which six have been previously described, including an intronic 7146G/A SNP. We found this polymorphism to be associated with the development of type 1 diabetes [found in 12.2% of diabetic individuals vs 6.8% in controls; odds ratio (OR) ¼ 1.92]. The associated allele is previously shown to alter a transcription factorbinding site (RUNX1/AML1), and the results of this study suggest that this allele could act as an additional susceptibility allele to type 1 diabetes.
No evidence of association of the PDCD1 gene with Type 1 diabetes
Diabetic Medicine, 2007
To test the association between the immunoreceptor PD-1 ( PDCD1 ) gene and Type 1 diabetes mellitus (T1DM). This gene has been reported to be associated with other autoimmune diseases such as systemic lupus erythematosus (SLE) as well as T1DM.
Annals of Tropical Medicine and Public Health, 2020
Type 2 diabetes mellitus (T2DM) is a metabolic disorder of multiple etiologies characterized by chronic hyperglycemia with disturbances of fat and protein metabolism resulting from defects in insulin secretion, insulin action or both, and mediated in large part by the alteration in adaptive immunity. This study aimed to evaluate the role of programmed cell death protein-1 (PD-1) gene polymorphism and serum level of soluble PD-1 in development of T2DM in Iraqi patients. Forty-five T2DM patients were recruited for this study. Other 45 apparently healthy subjects matched for age, gender and ethnic background for patients were also included as control group. Blood samples were collected from each participant, and DNA was extracted from leukocytes. The gene fragment corresponding the PD-1-538 G/A polymorphism was amplified with conventional PCR using specific primers. The genotyping was performed through restriction fragment length gene polymorphism (RFLP). Serum level of soluble PD-1 (sPD-1) was measured by enzyme linked immune sorbent assay (ELISA). There was no significant association between different genotypes of PD-1-538 G/A polymorphism. However, at allelic level, G allele was less frequent among patients than controls (28.89% versus 44.44%) with a significant difference. The median concentration of sPD-1 in patients was 53.12 pg/ml (range 18.24-312.89 pg/ml) compared to 63.83pg//ml (range 16.89-508.65 pg/ml) in controls with no significant difference. Median levels of sPD-1 in patients carrying GG, GA and AA genotypes were 51.67 pg/ml (range 18.24-160.41 pg/mL), 52.77 pg/ml (range 19.32-154.18 pg/mL) and 220.97 pg/ml (range 129.05-312.89 pg/mL) respectively. The GG genotype carriers differed significantly from AA genotype carriers, while there was no significant between AA genotype carriers and AG genotype carriers. These data suggest that A allele of PD-1-538 G/A might be a risk factor for development of T2DM. The GG genotype of this polymorphism associates with higher serum level of sPD-1 than other genotypes.
PD-1/PD-L and autoimmunity: A growing relationship
Cellular Immunology, 2016
Programmed death 1 (PD-1) and its ligands, namely PD-L1 and PD-L2, are one of the key factors responsible for inhibitory T cell signaling, mediating the mechanisms of tolerance and providing immune homeostasis. Mounting evidence demonstrates that impaired PD-1:PD-L function plays an important role in a variety of autoimmune diseases such as Type 1 diabetes (T1D), encephalomyelitis, inflammatory bowel diseases (IBD), Rheumatoid Arthritis (RA), autoimmune hepatitis (AIH), Behcet's disease (BD), myasthenia gravis (MG), autoimmune uveitis (AU), Sjögren's syndrome (SjS), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), myocarditis, and ankylosing spondylitis (AS). By investigating the candidate genes, genome-wide association studies, and identification of single nucleotide polymorphisms (SNPs) in PD-1 gene in humans, it has been shown that there is a higher risk in relevant genetic associations with developing autoimmune diseases in certain ethnic groups. In this review we have tried to present a comprehensive role of PD-1:PD-L in all recently studied autoimmune diseases.
Human Immunology, 2009
The effect of the vitamin D receptor (VDR) gene polymorphisms on susceptibility to type 1 diabetes (T1DM) is heterogeneous. Genetic factors may also influence the residual -cell function. We studied the frequency of VDR FokI (rs10735810) and BsmI (rs154410) polymorphisms in T1DM and their relationship to -cell autoimmunity and residual -cell function. We genotyped 189 T1DM (diabetes duration, 7.1 Ϯ 5.4 years) and 194 controls (C) by restriction length polymorphism-polymerase chain reaction. GAD65Ab, IA2Ab, ionized calcium (iCa), HbA 1c and fasting C-peptide (FCP) were evaluated. FCP values greater than 0.6 ng/ml were considered as residual -cell function. The BsmI was more frequent in the C (bb plus Bb 79.1 C vs. 66.1% T1DM, p ϭ 0.006), and the FokI polymorphism frequencies were similar between T1DM and C. We did not observe differences in pancreatic autoantibody profiles according to VDR genotypes. We observed that T1DM with f allele tended to have lower residual pancreatic -cell function (5.8% ff and Ff vs. 14.3% FF, p ϭ 0.074) with similar age, diabetes duration, AAb positivity, HbA 1c , and iCa. Age at diagnosis of T1DM with BsmI polymorphism tended to be greater (10.7 Ϯ 4.9 bb and Bb vs. 9.3 Ϯ 4.5 years BB, p ϭ 0.06). In conclusion, the results of this study showed no relationship between VDR polymorphisms and -cell autoimmunity; however we observed a relationship with age and remaining -cell function in Brazilian individuals with T1DM. These data may contribute to understanding the heterogeneous relationship between genetic markers and clinical features observed in this disease.
VDR polymorphisms influence the immune response in type 1 diabetic children from Santiago, Chile
Diabetes Research and Clinical Practice, 2007
Objective: To evaluate the influence of ApaI, BsmI and TaqI polymorphisms of the VDR gene and HLA-DQB1* alleles in type 1 diabetic children and to assess their possible relationship with circulating levels of 25-hydroxyvitamin D 3 , auto-antibodies, and INFg/TGFb1 cytokines levels in Chilean cases and controls. Methods: DNA and serum samples from 216 newly diagnosed type 1 diabetic and 203 unrelated control children were evaluated for IA-2 and GAD 65 auto-antibodies, 25-hydroxyvitamin D 3 levels, HLA-DQB1* alleles, and VDR gene polymorphisms. Results: The frequency of the b allele and the bb genotype in type 1 diabetic patients was significantly lower compared with the control group (0.635 versus 0.749, p < 0.01 and 0.370 versus 0.567, p < 0.04). 25-Hydroxyvitamin D 3 levels showed no differences between type 1 diabetic and healthy children. In cases, 25-hydroxyvitamin D 3 levels were not associated with a special autoantibodies profile according to the presence or absence of GAD 65 + or IA-2 + . The haplotype combination BAT was higher in cases (0.062 versus 0.019, p < 0.0022) and bAT was more frequent in controls (0.266 versus 0.180, p < 0.003). In cases, the aaBbTT genotype showed the most significant increase in TGFb1 level across the VDR categories. Finally, when considering the HLA class II risk genotype (DQB1*0302) and the VDR genotypes (AabbTT and aabbTT), higher levels of GAD 65 , IA-2 and TGFb1 were observed among diabetic children. Conclusion: We found an association between a VDR polymorphism (BsmI) and type 1 diabetes. An association was found of AabbTT and aabbTT genotypes and the HLA-DQB1*0302 allele with high levels of GAD 65 , IA-2 and TGFb1.
BMC Medical Genetics, 2006
Background The identification of the HLA class II, insulin (INS), CTLA-4 and PTPN22 genes as determinants of type 1 diabetes (T1D) susceptibility indicates that fine tuning of the immune system is centrally involved in disease development. Some genes have been shown to affect several immune-mediated diseases. Therefore, we tested the hypothesis that alleles of susceptibility genes previously associated with other immune-mediated diseases might perturb immune homeostasis, and hence also associate with predisposition to T1D. Methods We resequenced and genotyped tag single nucleotide polymorphisms (SNPs) from two genes, CRP and FCER1B, and genotyped 27 disease-associated polymorphisms from thirteen gene regions, namely FCRL3, CFH, SLC9A3R1, PADI4, RUNX1, SPINK5, IL1RN, IL1RA, CARD15, IBD5-locus (including SLC22A4), LAG3, ADAM33 and NFKB1. These genes have been associated previously with susceptibility to a range of immune-mediated diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Graves' disease (GD), psoriasis, psoriatic arthritis (PA), atopy, asthma, Crohn disease and multiple sclerosis (MS). Our T1D collections are divided into three sample subsets, consisting of set 1 families (up to 754 families), set 2 families (up to 743 families), and a case-control collection (ranging from 1,500 to 4,400 cases and 1,500 to 4,600 controls). Each SNP was genotyped in one or more of these subsets. Our study typically had approximately 80% statistical power for a minor allele frequency (MAF) >5% and odds ratios (OR) of 1.5 with the type 1 error rate, α = 0.05. Results We found no evidence of association with T1D at most of the loci studied 0.02 <P < 1.0. Only a SNP in ADAM33, rs2787094, was any evidence of association obtained, P = 0.0004 in set 1 families (relative risk (RR) = 0.78), but further support was not observed in the 4,326 cases and 4,610 controls, P = 0.57 (OR = 1.02). Conclusion Polymorphisms in a variety of genes previously associated with immune-mediated disease susceptibility and/or having effects on gene function and the immune system, are unlikely to be affecting T1D susceptibility in a major way, even though some of the genes tested encode proteins of immune pathways that are believed to be central to the development of T1D. We cannot, however, rule out effect sizes smaller than OR 1.5.
2015
Abstract: Type 1 diabetes is caused by autoreactive T cells that destroy pancreatic beta cells. Animal models suggested that a CD4+CD25+ population has a regulatory function capable of preventing activation and effector functions of autoreactive T cells. However, the role of CD4+CD25high T cells in autoimmunity and their molecular mechanisms remain the subject of investigation. We therefore evaluated T regulatory cell frequencies and their PD-1 expression in the peripheral blood of long-standing diabetics under basal conditions and after CD3/CD28 stimulation. Under basal conditions, the percentages of T regulatory cells were significantly higher while that of T effector cells were significantly lower in patients than in controls. The ratio of regulatory to effector T cells was higher in patients than that in controls, suggesting that T regulatory cells were functional in patients. Percentages of total PD-1+, PD-1low and PD-1high expressing T regulatory cells did not change in patien...
Medicina, 2001
The objective was to evaluate the prevalence and association of several markers (islet cell antibodies: ICA, insulin autoantibodies: IAA, glutamic acid decarboxylase antibodies: GADA and ICA512 antibodies: ICA512A) along with HLA DQB1 genotype in type 1 diabetes mellitus of recent onset, including siblings and individuals without any history of this disease, in an Argentine population. A total of 79 children with type 1 diabetes mellitus of recent onset were studied, as well as 79 control children, and 68 healthy siblings of type 1 diabetic cases. IAA, ICA, GADA, ICA512A and HLA DQB1 alleles were determined. Sensitivity was 67.1% for ICA, 36.7% for IAA, 74.6% for GADA and 63.4% for ICA512A. None of the control subjects was positive for the immunological markers. Combined sensitivity of ICA-IAA-GADA was 89.8%, similar to the ICA512A-GADA (87.3%) or ICA512A-GADA-IAA combination (91.1%). GADA correlated positively with ICA, but no such correlation was found between IAA, ICA512A and ICA...
Acta Diabetologica, 2018
Aims To assess the prevalence of autoantibodies (Aab) to insulin (IAA), glutamic acid decarboxylase 65 (GADA) and insulinoma antigen 2 (IA-2A), as well as human leukocyte antigen (HLA) class II alleles, in first degree relatives (FDR) of Mexican patients with type 1 diabetes (T1D), and to explore whether these parameters mirror the low incidence of T1D in the Mexican population. Methods Aab titers were determined by ELISA in 425 FDR, 234 siblings, 40 offspring and 151 parents of 197 patients with T1D. Typing of HLA-DR and-DQ alleles was performed in 41 Aab-positive FDR using polymerase chain reaction with allele-specific oligotyping. Results Seventy FDR (16.47%) tested positive for Aab. The siblings (19.2%) and the offspring (25%) had significantly higher prevalence of Aab than the parents (9.9%). GADA was the most frequent Aab. Almost half of the Aab-positive FDR had two different Aab (45.7%), and none tested positive for three Aab. The highest prevalence of Aab was found among women in the 15-29 years age group. Moreover, the positivity for two Aab was significantly more frequent among females. A considerable number of FDR (48.8%) carried the susceptible HLA-DR3,-DR4,-DQB1*0201 or-DQB1*0302 alleles, but almost none had the high risk genotype HLA-DR3/DR4. Conclusions FDR of Mexican T1D patients have high prevalence of islet Aab, comparable to countries with the highest incidence of T1D. However, Aab positivity does not seem to be associated with HLA risk genotypes, which may have an impact on the low incidence of T1D in Mexico. Keywords Type 1 diabetes • Patient relatives • Autoantibodies • HLA risk genotypes Managed by Massimo Porta.