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Arhire AI, Ioacara S, Papuc T, Chiper MS, Dutescu IM, Moise A, Badea IR, Florea S, Vlad A, Fica S. Association of HLA Haplotypes with Autoimmune Pathogenesis in Newly Diagnosed Type 1 Romanian Diabetic Children: A Pilot, Single-Center Cross-Sectional Study. Life (Basel) 2024; 14:781. [PMID: 38929763 PMCID: PMC11205248 DOI: 10.3390/life14060781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/16/2024] [Accepted: 06/17/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND The increasing incidence of autoimmune diseases in type 1 diabetes mellitus (T1DM) patients highlights the influence of human leukocyte antigen (HLA) haplotypes on their development. This study aims to determine genetic predisposition to autoimmune diseases in T1DM patients, including thyroid disease and celiac diseases, and explore its correlation with vitamin D deficiency. METHODS A cross-sectional study involving thirty-six T1DM children was conducted. Typing was performed for the HLA A, B, C, DP, DR, and DQ loci. Regression analysis linked DR-DQ haplotypes to T1DM and the associated conditions. RESULTS The most frequent predisposing alleles and haplotypes were HLA-DR3 (70.27%), DQ2 (70.27%), DR3-DQ2 (70.27%), DQB1*02:01 (70.27%), A02 (54.05%), whereas the most prevalent protecting allele was DPB1*04:01 (52.63%). Positive correlations were observed between positive anti-thyroid peroxidase antibodies and the absence of protective alleles (DPB1*04:02, p = 0.036; DPB1*04:01, p = 0.002). Associations were found between the absence of DPB1*04:01 and anti-thyroglobulin antibodies (p = 0.03). HLA allele DPB1*03:01 was linked with vitamin D deficiency (p = 0.021). Positive anti-transglutaminase antibodies correlated with C03:03 (p = 0.026) and DRB1*04:01-DQA1*03-DQB1*03:01 (p < 0.0001) and the lack of DQA1*01:03-DQB1*06:03-DRB1*13:01 (p < 0.0001). CONCLUSIONS The predisposing T1DM haplotypes were associated with the presence of anti-transglutaminase and anti-thyroid antibodies, indicating a genetic predisposition to autoimmune diseases.
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Affiliation(s)
- Amalia Ioana Arhire
- General Medicine Faculty, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (A.I.A.); (A.V.); (S.F.)
- Department of Pediatric Endocrinology and Diabetes, Elias Emergency University Hospital, 011461 Bucharest, Romania; (T.P.); (M.S.C.)
| | - Sorin Ioacara
- General Medicine Faculty, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (A.I.A.); (A.V.); (S.F.)
- Department of Pediatric Endocrinology and Diabetes, Elias Emergency University Hospital, 011461 Bucharest, Romania; (T.P.); (M.S.C.)
| | - Teodora Papuc
- Department of Pediatric Endocrinology and Diabetes, Elias Emergency University Hospital, 011461 Bucharest, Romania; (T.P.); (M.S.C.)
| | - Miruna Sânziana Chiper
- Department of Pediatric Endocrinology and Diabetes, Elias Emergency University Hospital, 011461 Bucharest, Romania; (T.P.); (M.S.C.)
| | - Irina Monica Dutescu
- HLA Laboratory, “C.T. Nicolau” National Institute of Blood Transfusion, 011154 Bucharest, Romania; (I.M.D.); (A.M.); (I.R.B.)
| | - Ana Moise
- HLA Laboratory, “C.T. Nicolau” National Institute of Blood Transfusion, 011154 Bucharest, Romania; (I.M.D.); (A.M.); (I.R.B.)
| | - Ioana Roxana Badea
- HLA Laboratory, “C.T. Nicolau” National Institute of Blood Transfusion, 011154 Bucharest, Romania; (I.M.D.); (A.M.); (I.R.B.)
| | - Suzana Florea
- Immunology Laboratory, Elias Emergency University Hospital, 011461 Bucharest, Romania;
| | - Adelina Vlad
- General Medicine Faculty, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (A.I.A.); (A.V.); (S.F.)
| | - Simona Fica
- General Medicine Faculty, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (A.I.A.); (A.V.); (S.F.)
- Department of Pediatric Endocrinology and Diabetes, Elias Emergency University Hospital, 011461 Bucharest, Romania; (T.P.); (M.S.C.)
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Xie Z, Chang C, Huang G, Zhou Z. The Role of Epigenetics in Type 1 Diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1253:223-257. [PMID: 32445098 DOI: 10.1007/978-981-15-3449-2_9] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease caused by the interaction between genetic alterations and environmental factors. More than 60 susceptible genes or loci of T1D have been identified. Among them, HLA regions are reported to contribute about 50% of genetic susceptibility in Caucasians. There are many environmental factors involved in the pathogenesis of T1D. Environmental factors may change the expression of genes through epigenetic mechanisms, thus inducing individuals with susceptible genes to develop T1D; however, the underlying mechanisms remain poorly understood. The major epigenetic modifications include DNA methylation, histone modification, and non-coding RNA. There has been extensive research on the role of epigenetic mechanisms including aberrant DNA methylation, histone modification, and microRNA in the pathogenesis of T1D. DNA methylation and microRNA have been proposed as biomarkers to predict islet β cell death, which needs further confirmation before any clinical application can be developed. Small molecule inhibitors of histone deacetylases, histone methylation, and DNA methylation are potentially important for preventing T1D or in the reprogramming of insulin-producing cells. This chapter mainly focuses on T1D-related DNA methylation, histone modification, and non-coding RNA, as well as their possible translational potential in the early diagnosis and treatment of T1D.
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Affiliation(s)
- Zhiguo Xie
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China
| | - Christopher Chang
- Division of Pediatric Immunology and Allergy, Joe DiMaggio Children's Hospital, Hollywood, FL, 33021, USA.,Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, Davis, CA, 95616, USA
| | - Gan Huang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China. .,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China.
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Beloso C, Souto J, Fabregat M, Romanelli G, Javiel G, Mimbacas A. Association of TCF7L2 mutation and atypical diabetes in a Uruguayan population. World J Diabetes 2018; 9:157-164. [PMID: 30254725 PMCID: PMC6153121 DOI: 10.4239/wjd.v9.i9.157] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 06/29/2018] [Accepted: 07/10/2018] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate if mutations in TCF7L2 are associated with “atypical diabetes” in the Uruguayan population.
METHODS Healthy, nondiabetic controls (n = 133) and patients with type 2 diabetes (n = 177) were selected from among the presenting population at level-3 referral healthcare centers in Uruguay. Patients with type 2 diabetes were subgrouped according to “atypical diabetes” (n = 92) and “classical diabetes” (n = 85). Genotyping for the rs12255372 and rs7903146 single nucleotide polymorphisms (SNPs) in the TCFTL2 gene was carried out with TaqMan® probes. Random samples were sequenced by Macrogen Ltd. (South Korea). Statistical analysis of the SNP data was carried out with the SNPStats online tool (http://bioinfo.iconcologia.net/SNPstats). The best inheritance model was chosen according to the lowest values of Akaike’s information criterion and Bayesian information criterion. Differences between groups were determined by unpaired t-tests after checking the normal distribution or were converted to normalize the data. The association of SNPs was tested for matched case-control samples by using χ2 analysis and calculation of odds ratios (ORs) with 95% confidence intervals (CIs). All statistical tests were performed using SPSS v10.0 and EpiInfo7 statistical packages. Significant statistical differences were assumed in all cases showing adjusted P < 0.05.
RESULTS We genotyped two TCF7L2 SNPs (rs7903146 and rs12255372) in a population-based sample of 310 Uruguayan subjects, including 133 healthy control subjects and 177 clinical diagnosed with type 2 diabetes. For both SNPs analyzed, the best model was the dominant type: rs12255372 = G/G vs G/T+T/T, OR = 0.63, 95%CI: 0.40-0.98, P < 0.05 and rs7903146 = C/C vs C/T+T/T, OR = 0.79, 95%CI: 0.41-1.55, P = 0.3. The rs12255372 SNP showed high association with the type 2 diabetes cases (OR = 1.60, 95%CI: 1.20-2.51, P < 0.05). However, when the type 2 diabetics group was analyzed according to the atypical and classical subgroupings, the association with diabetes existed only for rs12255372 and the classical subgroup (vs controls: OR = 2.1, 95%CI: 1.21-3.75, P < 0.05); no significant differences were found for either SNP or atypical diabetes.
CONCLUSION This is the first time SNPs_TCF7L2 were genotyped in a diabetic population stratified by genotype instead of phenotype. Classical and atypical patients showed statistical differences.
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Affiliation(s)
- Carolina Beloso
- Biodiversity and Genetics Department, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo 11600, Uruguay
| | - Jorge Souto
- Cytogenetics Laboratory, Hematology and Transplant Service of Hematopoietic Progenitors, Maciel Hospital, ASSE, Montevideo 11600, Uruguay
- Department of Genetics, Faculty of Medicine, UDELAR, Montevideo 11800, Uruguay
| | - Matias Fabregat
- Human Molecular Genetics Laboratory, Institut Pasteur de Montevideo 11400, Uruguay
| | - Gerardo Romanelli
- Cell Signaling and Nanobiology Laboratory, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo 11600, Uruguay
| | - Gerardo Javiel
- Unit of Diabetes Hospital Pasteur, ASSE-Ministry of Public Health, Montevideo 11400, Uruguay
- Diabetologyc Service of Private Health Center, Centro de Asistencia del Sindicato Médico del Uruguay, Montevideo 11600, Uruguay
| | - Adriana Mimbacas
- Biodiversity and Genetics Department, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo 11600, Uruguay
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Xie Z, Chang C, Zhou Z. Molecular Mechanisms in Autoimmune Type 1 Diabetes: a Critical Review. Clin Rev Allergy Immunol 2014; 47:174-92. [DOI: 10.1007/s12016-014-8422-2] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Abstract
A general introduction to the origins and history of Latin American populations is followed by a systematic review of the data from molecular autosomal assessments of the ethnic/continental (European, African, Amerindian) ancestries for 24 Latin American countries or territories. The data surveyed are of varying quality but provide a general picture of the present constitution of these populations. A brief discussion about the applications of these results (admixture mapping) is also provided. Latin American populations can be viewed as natural experiments for the investigation of unique anthropological and epidemiological issues.
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Affiliation(s)
- Francisco Mauro Salzano
- Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS,
Brazil
| | - Mónica Sans
- Departamento de Antropología Biológica, Facultad de Humanidades y Ciencias de la Educación, Universidad de la República, Montevideo,
Uruguay
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Guerini FR, Bolognesi E, Manca S, Sotgiu S, Zanzottera M, Agliardi C, Usai S, Clerici M. Family-based transmission analysis of HLA genetic markers in Sardinian children with autistic spectrum disorders. Hum Immunol 2009; 70:184-90. [PMID: 19167444 DOI: 10.1016/j.humimm.2008.12.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2008] [Revised: 12/19/2008] [Accepted: 12/23/2008] [Indexed: 10/21/2022]
Abstract
Analyses of a 6-Mb region spanning the human leukocyte antigen (HLA) region from the HLA-DR to the HFE gene were performed in 37 families of Sardinian ancestry, all of whom had at least one autistic child, to identify genetic markers associated with autism spectrum disorders (ASD) development. In particular, four microsatellites (MIB, D6S265, MOGc, and D6S2239) and three single-nucleotide polymorphisms (SNPs; two in positions -308 and -238 in the promoter of the TNF-alpha and SNP rs2857766 [V142L] in exon 3 of the MOG gene) were analyzed. An intrafamilial case-control method (affected family-based controls) and transmission disequilibrium test analysis were used to evaluate the association of microsatellite and SNP markers with ASD-affected children. Results indicated positive associations with ASD for D6S265*220 (p < 0.01) and MOGc*131 (p < 0.05) and negative associations for MOGc*117 and MIB*346 alleles (p < 0.01) in ASD children. Polymorphism haplotype analysis indicated that D6S265 allele *220 and MOGc allele *131 were significantly more likely to be transmitted together, as a whole haplotype, to ASD children (p < 0.05). Conversely, the D6S265*224-MOGc*117-rs2857766(G) haplotype was significantly less frequently transmitted to ASD children (p < 0.01). The results present novel gene markers, reinforcing the hypothesis that genetic factors play a pivotal role in the pathogenesis of ASD.
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Affiliation(s)
- Franca R Guerini
- Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi Foundation IRCCS, S. Maria Nascente, Milan, Italy.
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Temajo NO, Howard N. The Co-operative Specificity Theory: phenotypic protection from T1D by certain HLA Class II DRB1 and DQ alleles identifies the absence of co-operation between the respective DR and DQ molecules eventuating in no T1D-predisposition. Autoimmun Rev 2008; 8:364-8. [PMID: 19068242 DOI: 10.1016/j.autrev.2008.11.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2008] [Accepted: 11/21/2008] [Indexed: 01/14/2023]
Abstract
It is well established that both DR and DQ genes are involved in type 1 diabetes (T1D) -susceptibility. But how the DR and DQ molecules contrive to effect collectively the same function of T1D predisposition remains unexplained. We advance the Co-operative Specificity Theory which attempts to project the relationship by which this occurs. The Co-operative Specificity Theory says that what is involved and being observed is a phenomenon of specific reciprocal recognition between corresponding DR- and DQ-molecules in a haplotype, resulting in a co-operation that realizes effects: this specificity varies in degrees. It is a situation of co-operative participation restricted to a specific DR- and its corresponding specific DQ-molecules that results in susceptibility. Thus susceptibility may not result when a corresponding specific DR or DQ allele is substituted by a non-specific allele in the haplotype. It thus ensues that phenotypic protection identifies the absence of this specific co-operation between the respective DR and DQ molecules giving rise to no predisposition.
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Affiliation(s)
- Norbert O Temajo
- Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney NSW, Australia.
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