Clinical features, epidemiology, autoantibody status, HLA haplotypes and genetic mechanisms of type 1 diabetes mellitus among children in Qatar

Haris, Basma; Ahmed, Ikhlak; Syed, Najeeb; Almabrazi, Hakeem; Saraswathi, Saras; Al‐Khawaga, Sara; Saeed, Amira; Mundekkadan, Shihab; Mohammed, Idris; Sharari, Sanaa; Hawari, Iman; Hamed, Noor; Afyouni, Houda; Abdel-Karim, Tasneem; Mohammed, Shayma; Khalifa, Amal; Al-Maadheed, Maryam; Zyoud, Mahmoud; Shamekh, Ahmed; Elawwa, Ahmed; Karim, Mohammed Yousuf; Al‐Khalaf, Fawziya; Tatari-Calderone, Zohreh; Petrovski, Goran; Hussain, Khalid

doi:10.1038/s41598-021-98460-4

Cited by 11 publications

(8 citation statements)

References 37 publications

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“…They used the PRG method to identify HLA alleles based on exome sequencing and found that HLA haplotypes DQA1*03:01:01G and DQB1*03:02:01G were common in Qatari children with T1DM. These variants have been previously reported in a study of Europeans, where they were in strong disequilibrium on linkage with HLA-DRB1*4 and were significant risk factors for T1DM development [30].…”

Section: Major Histocompatibility Complex (Hla) Locus: Population Asp...supporting

confidence: 60%

Genetic and Epigenetic Aspects of Type 1 Diabetes Mellitus: Modern View on the Problem

Minniakhmetov,

Yalaev,

Khusainova

et al. 2024

Biomedicines

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Omics technologies accumulated an enormous amount of data that advanced knowledge about the molecular pathogenesis of type 1 diabetes mellitus and identified a number of fundamental problems focused on the transition to personalized diabetology in the future. Among them, the most significant are the following: (1) clinical and genetic heterogeneity of type 1 diabetes mellitus; (2) the prognostic significance of DNA markers beyond the HLA genes; (3) assessment of the contribution of a large number of DNA markers to the polygenic risk of disease progress; (4) the existence of ethnic population differences in the distribution of frequencies of risk alleles and genotypes; (5) the infancy of epigenetic research into type 1 diabetes mellitus. Disclosure of these issues is one of the priorities of fundamental diabetology and practical healthcare. The purpose of this review is the systemization of the results of modern molecular genetic, transcriptomic, and epigenetic investigations of type 1 diabetes mellitus in general, as well as its individual forms. The paper summarizes data on the role of risk HLA haplotypes and a number of other candidate genes and loci, identified through genome-wide association studies, in the development of this disease and in alterations in T cell signaling. In addition, this review assesses the contribution of differential DNA methylation and the role of microRNAs in the formation of the molecular pathogenesis of type 1 diabetes mellitus, as well as discusses the most currently central trends in the context of early diagnosis of type 1 diabetes mellitus.

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Section: Major Histocompatibility Complex (Hla) Locus: Population Asp...supporting

confidence: 60%

Genetic and Epigenetic Aspects of Type 1 Diabetes Mellitus: Modern View on the Problem

Minniakhmetov,

Yalaev,

Khusainova

et al. 2024

Biomedicines

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“…We could not follow up and confirm whether the HC who showed GADA positive status went on to develop T1D. The median disease duration of T1D patients in this study is 6 years, which is quite long and because GADA in sera is known to decrease with time, this could explain the lower prevalence of GADA in T1D patients in our population compared to other populations that have reported higher GADA prevalence 18,36–38 . It has been reported that GADA positivity is associated with an older age at T1D diagnosis and further GADA‐initiated autoimmunity was associated with longer disease duration 39,40 .…”

Section: Discussionmentioning

confidence: 59%

“…The median disease duration of T1D patients in this study is 6 years, which is quite long and because GADA in sera is known to decrease with time, this could explain the lower prevalence of GADA in T1D patients in our population compared to other populations that have reported higher GADA prevalence. 18,[36][37][38] It has been reported that GADA positivity is associated with an older age at T1D diagnosis and further GADA-initiated autoimmunity was associated with longer disease duration. 39,40 When we grouped our patients on the basis of age at T1D onset and disease duration, we found that prevalence of GADA was comparable in RD (disease duration <2 years) vs LS (≥2 years) T1D patients as well as in patients with age at onset <18 years vs ≥18 years.…”

Section: Discussionmentioning

confidence: 99%

HLA‐DR3 mediated CD4 T cell response against GAD65 in type 1 diabetes patients

Chuzho

Tandon

Kanga

et al. 2023

Journal of Diabetes

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Aim We planned this study to identify diabetogenic glutamic acid decarboxylase (GAD65) peptides possibly responsible for human leucocyte antigen (HLA)‐DR3/DQ2‐mediated activation of GAD65‐specific CD4 T cells in type 1 diabetes (T1D). Methods Top 30 GAD65 peptides, found to strongly bind in silico with HLA‐DR3/DQ2 molecules, were selected and grouped into four pools. The peptides were used to stimulate CD4 T cells of study subjects in 16‐h peripheral blood mononuclear cell culture. CD4 T cells' stimulation in terms of interferon‐gamma (IFN‐γ), interleukin (IL)‐17, tumor necrosis factor‐alpha (TNF‐α), and IL‐10 expression was analyzed using flow cytometry. Results Although all four GAD65 peptide pools (PP1‐4) resulted in significantly higher expression of IFN‐γ by CD4 T cells (p = .003, p < .0001, p = .026, and p = .002, respectively), only pool 2 showed significant increase in IL‐17 expression (p < .0001) in T1D patients vs healthy controls. Interpeptide group comparison for immunogenicity revealed significantly higher IFN‐γ and IL‐17 expressions and significantly lower IL‐10 expression for PP2 compared to other groups (p < .0001, p = .02, and p = .04, respectively) in patients but not in controls. Further, group 2 peptides resulted in significant increase in CD4 T cells' expression of IFN‐γ and IL‐17 (p = .002 for both) and significant decrease in IL‐10 (p = .04) in HLA‐DRB1*03‐DQA1*05‐DQB1*02+ patients vs HLA‐DRB1*03‐DQA1*05‐DQB1*02+ controls. The CD4 T cells' expression of IL‐17 was significantly higher (p = .03) in recently diagnosed vs long‐standing HLA‐DRB1*03‐DQA1*05‐DQB1*02+ T1D patients. Conclusion GAD65 peptides, particularly those belonging to PP2, induced CD4 T cells to express IFN‐γ and IL‐17 cytokines in T1D patients, suggesting that group 2 peptides possibly presented by HLA‐DR3 molecule to CD4 T cells shift immune balance toward inflammatory phenotype in patients.

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“…This underscores an essential insight: existing whole genome and exome datasets, even if initially curated for different clinical or research purposes, can be adaptively repurposed. Such datasets then become invaluable secondary resources for endeavours in population genetics ( Gourraud et al, 2014 ), pharmacogenetics ( Dashti et al, 2022 ), and disease association studies ( Haris et al, 2021 ; Afyouni et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of HLA typing content of next-generation sequencing datasets from family trios and individuals of arab ethnicity

Dashti,

Malik,

Nizam

et al. 2024

Front. Genet.

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Introduction: HLA typing is a critical tool in both clinical and research applications at the individual and population levels. Benchmarking studies have indicated HLA-HD as the preferred tool for accurate and comprehensive HLA allele calling. The advent of next-generation sequencing (NGS) has revolutionized genetic analysis by providing high-throughput sequencing data. This study aims to evaluate, using the HLA-HD tool, the HLA typing content of whole exome, whole genome, and HLA-targeted panel sequence data from the consanguineous population of Arab ethnicity, which has been underrepresented in prior benchmarking studies.Methods: We utilized sequence data from family trios and individuals, sequenced on one or more of the whole exome, whole genome, and HLA-targeted panel sequencing technologies. The performance and resolution across various HLA genes were evaluated. We incorporated a comparative quality control analysis, assessing the results obtained from HLA-HD by comparing them with those from the HLA-Twin tool to authenticate the accuracy of the findings.Results: Our analysis found that alleles across 29 HLA loci can be successfully and consistently typed from NGS datasets. Clinical-grade whole exome sequencing datasets achieved the highest consistency rate at three-field resolution, followed by targeted HLA panel, research-grade whole exome, and whole genome datasets.Discussion: The study catalogues HLA typing consistency across NGS datasets for a large array of HLA genes and highlights assessments regarding the feasibility of utilizing available NGS datasets in HLA allele studies. These findings underscore the reliability of HLA-HD for HLA typing in underrepresented populations and demonstrate the utility of various NGS technologies in achieving accurate HLA allele calling.

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Clinical features, epidemiology, autoantibody status, HLA haplotypes and genetic mechanisms of type 1 diabetes mellitus among children in Qatar

Cited by 11 publications

References 37 publications

Genetic and Epigenetic Aspects of Type 1 Diabetes Mellitus: Modern View on the Problem

Genetic and Epigenetic Aspects of Type 1 Diabetes Mellitus: Modern View on the Problem

HLA‐DR3 mediated CD4 T cell response against GAD65 in type 1 diabetes patients

Evaluation of HLA typing content of next-generation sequencing datasets from family trios and individuals of arab ethnicity

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