AIMS/HYPOTHESIS: Monogenic diabetes is estimated to account for 1-6% of paediatric diabetes cases in primarily non-consanguineous populations, while the incidence and genetic spectrum in consanguineous regions are insufficiently defined. In this single-centre study we aimed to evaluate diabetes subtypes, obtain the consanguinity rate and study the genetic background of individuals with syndromic and neonatal diabetes in a population with a high rate of consanguinity. METHODS: Data collection was carried out cross-sectionally in November 2021 at the paediatric diabetic clinic, Dr Jamal Ahmad Rashed Hospital, in Sulaimani, Kurdistan, Iraq. At the time of data collection, 754 individuals with diabetes (381 boys) aged up to 16 years were registered. Relevant participant data was obtained from patient files. Consanguinity status was known in 735 (97.5%) participants. Furthermore, 12 families of children with neonatal diabetes and seven families of children with syndromic diabetes consented to genetic testing by next-generation sequencing. Prioritised variants were evaluated using the American College of Medical Genetics and Genomics guidelines and confirmed by Sanger sequencing. RESULTS: A total of 269 of 735 participants (36.5%) with known consanguinity status were offspring of consanguineous families. An overwhelming majority of participants (714/754, 94.7%) had clinically defined type 1 diabetes (35% of them were born to consanguineous parents), whereas only eight (1.1%) had type 2 diabetes (38% consanguineous). Fourteen (1.9%) had neonatal diabetes (50% consanguineous), seven (0.9%) had syndromic diabetes (100% consanguineous) and 11 (1.5%) had clinically defined MODY (18% consanguineous). We found that consanguinity was significantly associated with syndromic diabetes (p=0.0023) but not with any other diabetes subtype. The genetic cause was elucidated in ten of 12 participants with neonatal diabetes who consented to genetic testing (homozygous variants in GLIS3 [sibling pair], PTF1A and ZNF808 and heterozygous variants in ABCC8 and INS) and four of seven participants with syndromic diabetes (homozygous variants in INSR, SLC29A3 and WFS1 [sibling pair]). In addition, a participant referred as syndromic diabetes was diagnosed with mucolipidosis gamma and probably has type 2 diabetes. CONCLUSIONS/INTERPRETATION: This unique single-centre study confirms that, even in a highly consanguineous population, clinically defined type 1 diabetes is the prevailing paediatric diabetes subtype. Furthermore, a pathogenic cause of monogenic diabetes was identified in 83% of tested participants with neonatal diabetes and 57% of participants with syndromic diabetes, with most variants being homozygous. Causative genes in our consanguineous participants were markedly different from genes reported from non-consanguineous populations and also from those reported in other consanguineous populations. To correctly diagnose syndromic diabetes in consanguineous populations, it may be necessary to re-evaluate diagnostic criteria and include additional phenotypic features such as short stature and hepatosplenomegaly.
- MeSH
- diabetes mellitus 1. typu * epidemiologie genetika MeSH
- diabetes mellitus 2. typu * epidemiologie genetika diagnóza MeSH
- dítě MeSH
- kohortové studie MeSH
- lidé MeSH
- mutace genetika MeSH
- nemoci novorozenců * genetika MeSH
- novorozenec MeSH
- pokrevní příbuzenství MeSH
- proteiny přenášející nukleosidy genetika MeSH
- senioři MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Irák MeSH
Protein tyrosine phosphatase, nonreceptor type 22 (PTPN22), is an archetypal non-HLA autoimmunity gene. It is one of the most prominent genetic contributors to type 1 diabetes mellitus outside the HLA region, and prevalence of its risk variants is subject to enormous geographic variability. Here, we address the genetic background of patients with type 1 diabetes mellitus of Armenian descent. Armenia has a population that has been genetically isolated for 3000 years. We hypothesized that two PTPN22 polymorphisms, rs2476601 and rs1310182, are associated with type 1 diabetes mellitus in persons of Armenian descent. In this association study, we genotyped the allelic frequencies of two risk-associated PTPN22 variants in 96 patients with type 1 diabetes mellitus and 100 controls of Armenian descent. We subsequently examined the associations of PTPN22 variants with the manifestation of type 1 diabetes mellitus and its clinical characteristics. We found that the rs2476601 minor allele (c.1858T) frequency in the control population was very low (q = 0.015), and the trend toward increased frequency of c.1858CT heterozygotes among patients with type 1 diabetes mellitus was not significant (OR 3.34, 95% CI 0.88-12.75; χ2 test p > 0.05). The control population had a high frequency of the minor allele of rs1310182 (q = 0.375). The frequency of c.2054-852TC heterozygotes was significantly higher among the patients with type 1 diabetes mellitus (OR 2.39, 95% CI 1.35-4.24; χ2 test p < 0.001), as was the frequency of the T allele (OR 4.82, 95% CI 2.38-9.76; χ2 test p < 0.001). The rs2476601 c.1858CT genotype and the T allele correlated negatively with the insulin dose needed three to six months after diagnosis. The rs1310182 c.2054-852CC genotype was positively associated with higher HbA1c at diagnosis and 12 months after diagnosis. We have provided the first information on diabetes-associated polymorphisms in PTPN22 in a genetically isolated Armenian population. We found only a limited contribution of the prototypic gain-of-function PTPN22 polymorphism rs2476601. In contrast, we found an unexpectedly close association of type 1 diabetes mellitus with rs1310182.
- MeSH
- diabetes mellitus 1. typu * genetika MeSH
- fosfatasy MeSH
- introny MeSH
- lidé MeSH
- polymorfismus genetický MeSH
- tyrosinfosfatasa nereceptorového typu 22 genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Arménie MeSH
- MeSH
- autoprotilátky * MeSH
- diabetes mellitus 1. typu * genetika MeSH
- lidé MeSH
- mutace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- komentáře MeSH
- práce podpořená grantem MeSH
AIMS: To evaluate access to screening tools for monogenic diabetes in paediatric diabetes centres across the world and its impact on diagnosis and clinical outcomes of children and youth with genetic forms of diabetes. METHODS: 79 centres from the SWEET diabetes registry including 53,207 children with diabetes participated in a survey on accessibility and use of diabetes related antibodies, c-peptide and genetic testing. RESULTS: 73, 63 and 62 participating centres had access to c-peptide, antibody and genetic testing, respectively. Access to antibody testing was associated with higher proportion of patients with rare forms of diabetes identified with monogenic diabetes (54 % versus 17 %, p = 0.01), lower average whole clinic HbA1c (7.7[Q1,Q2: 7.3-8.0]%/61[56-64]mmol/mol versus 9.2[8.6-10.0]%/77[70-86]mmol/mol, p < 0.001) and younger age at onset (8.3 [7.3-8.8] versus 9.7 [8.6-12.7] years p < 0.001). Additional access to c-peptide or genetic testing was not related to differences in age at onset or HbA1c outcome. CONCLUSIONS: Clinical suspicion and antibody testing are related to identification of different types of diabetes. Implementing access to comprehensive antibody screening may provide important information for selecting individuals for further genetic evaluation. In addition, worse overall clinical outcomes in centers with limited diagnostic capabilities indicate they may also need support for individualized diabetes management. TRIAL REGISTRATION: NCT04427189.
- MeSH
- C-peptid MeSH
- diabetes mellitus 1. typu * diagnóza genetika MeSH
- diabetes mellitus * diagnóza MeSH
- dítě MeSH
- glykovaný hemoglobin analýza MeSH
- lidé MeSH
- mladiství MeSH
- plošný screening MeSH
- registrace MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- Publikační typ
- časopisecké články MeSH
- klinická studie MeSH
- multicentrická studie MeSH
Loss of pancreatic beta cells is a central feature of type 1 (T1D) and type 2 (T2D) diabetes, but a therapeutic strategy to preserve beta cell mass remains to be established. Here we show that the death receptor TMEM219 is expressed on pancreatic beta cells and that signaling through its ligand insulin-like growth factor binding protein 3 (IGFBP3) leads to beta cell loss and dysfunction. Increased peripheral IGFBP3 was observed in established and at-risk T1D/T2D patients and was confirmed in T1D/T2D preclinical models, suggesting that dysfunctional IGFBP3/TMEM219 signaling is associated with abnormalities in beta cells homeostasis. In vitro and in vivo short-term IGFBP3/TMEM219 inhibition and TMEM219 genetic ablation preserved beta cells and prevented/delayed diabetes onset, while long-term IGFBP3/TMEM219 blockade allowed for beta cell expansion. Interestingly, in several patients' cohorts restoration of appropriate IGFBP3 levels was associated with improved beta cell function. The IGFBP3/TMEM219 pathway is thus shown to be a physiological regulator of beta cell homeostasis and is also demonstrated to be disrupted in T1D/T2D. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes.
- MeSH
- beta-buňky metabolismus MeSH
- diabetes mellitus 1. typu genetika metabolismus patologie MeSH
- diabetes mellitus 2. typu genetika metabolismus patologie MeSH
- dospělí MeSH
- homeostáza genetika MeSH
- IGFBP-3 genetika metabolismus MeSH
- imunoblotting MeSH
- kultivované buňky MeSH
- lidé středního věku MeSH
- lidé MeSH
- membránové proteiny genetika metabolismus MeSH
- myši inbrední C57BL MeSH
- myši inbrední NOD MeSH
- myši knockoutované MeSH
- myši transgenní MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- regulace genové exprese * MeSH
- signální transdukce genetika MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
A number of human autoinflammatory diseases manifest with severe inflammatory bone destruction. Mouse models of these diseases represent valuable tools that help us to understand molecular mechanisms triggering this bone autoinflammation. The Pstpip2cmo mouse strain is among the best characterized of these; it harbors a mutation resulting in the loss of adaptor protein PSTPIP2 and development of autoinflammatory osteomyelitis. In Pstpip2cmo mice, overproduction of interleukin-1β (IL-1β) and reactive oxygen species by neutrophil granulocytes leads to spontaneous inflammation of the bones and surrounding soft tissues. However, the upstream signaling events leading to this overproduction are poorly characterized. Here, we show that Pstpip2cmo mice deficient in major regulator of Src-family kinases (SFKs) receptor-type protein tyrosine phosphatase CD45 display delayed onset and lower severity of the disease, while the development of autoinflammation is not affected by deficiencies in Toll-like receptor signaling. Our data also show deregulation of pro-IL-1β production by Pstpip2cmo neutrophils that are attenuated by CD45 deficiency. These data suggest a role for SFKs in autoinflammation. Together with previously published work on the involvement of protein tyrosine kinase spleen tyrosine kinase, they point to the role of receptors containing immunoreceptor tyrosine-based activation motifs, which after phosphorylation by SFKs recruit spleen tyrosine kinase for further signal propagation. We propose that this class of receptors triggers the events resulting in increased pro-IL-1β synthesis and disease initiation and/or progression.
- MeSH
- adaptorové proteiny signální transdukční genetika imunologie MeSH
- antigeny CD45 genetika imunologie MeSH
- cytoskeletální proteiny genetika imunologie MeSH
- diabetes mellitus 1. typu genetika imunologie patologie MeSH
- interleukin-1beta genetika imunologie MeSH
- myši knockoutované MeSH
- myši MeSH
- neutrofily imunologie patologie MeSH
- osteomyelitida genetika imunologie patologie MeSH
- signální transdukce genetika imunologie MeSH
- stupeň závažnosti nemoci MeSH
- toll-like receptory genetika imunologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Diabetes mellitus 1. typu (DM1) je multifaktorálne autoimunitné ochorenie, ktoré spočíva v napadnutí inzulín produkujúcich beta buniek v pankrease cytotoxickými CD8 lymfocytmi. No nielen T lymfocyty sa podieľajú na tomto ničení beta buniek. Práve kooperáciou rôznych zložiek vrodenej a získanej imunity dochádza k rozvoji zápalu a následnej autoimunitnej reakcii. Dysregulácia vrodenej imunity je zjavná nielen u dlhodobobých pacientov s DM1 a nie je asociovaná so zmenami v metabolizme, z čoho vyplýva, že ide o potenciálne geneticky podmienené faktory. Pretože presymptomatickí pacienti by mali veľký úžitok z včasnej identifikácie nástupu patologických procesov vedúcich k symptomatickému DM1, je dôležité porozumieť tejto dysregulácii čo najdetailnejšie. V tomto prehľade sa budeme venovať neutrofilom a ich produktom, ktoré sa volajú neutrofilné extracelulárne pasce (NET). Skladajú sa najmä z vlastnej DNA a antimikrobiálnych proteínov a sú význačným mechanizmom antiinfekčnej imunity. Avšak v posledných rokoch si NETy získali nemalú pozornosť v oblasti autoimunitných ochorení, pretože sami o sebe predstavujú potenciálny zdroj autoantigénov, na ktoré by imunitný systém mohol prehnane reagovať. Monocyty a dendritické bunky (DC) od DM1 pacientov prehnane reagujú na prítomnosť DNA, mikrobiálnej aj vlastnej DNA. A preto NETy u DM1 sú schopné indukovať IFNγ-produkujúce T lymfocyty skrz aktiváciu DC a tým prispievať k autoimunitnému procesu.
Type 1 diabetes (T1D) is an autoimmune disease with multifactorial aetiology that involves an attack of self-reactive cytotoxic CD8 lymphocytes on insulin-producing beta cells in the pancreas. However, not only T lymphocytes contribute to the T1D pathophysiology. Both innate and adaptive immunity mechanisms cooperate in the development of inflammation leading to autoimmune destruction. Innate immunity dysregulation is apparent not only in long-term treated T1D patients and is not associated with metabolic changes, suggesting that the changes are intrinsic and potentially determined genetically. Since presymptomatic patients would benefit from early identification of the onset of the pathological processes leading to symptomatic T1D, we believe that thorough understanding the underlying mechanisms is crucial. Here, we focus on neutrophils and their products called neutrophil extracellular traps (NETs). NET structures are predominantly composed of neutrophil DNA and antimicrobial proteins and are an important mechanism of antimicrobial defence; however, in recent years, NETs gained considerable attention in the field of autoimmune diseases as a source of potential autoantigens. They are able to induce IFNγ-producing T cells through activation of dendritic cells (DCs), since we show that T1D monocytes and DCs inappropriately react to the presence of DNA regardless of the origin, including microbial or endogenous sources, suggesting that aberrant recognition of DNA contained in NETs also participates in the inflammation associated.
- MeSH
- autoimunitní nemoci genetika imunologie MeSH
- diabetes mellitus 1. typu * genetika imunologie patofyziologie MeSH
- extracelulární pasti imunologie metabolismus MeSH
- lidé MeSH
- neutrofily imunologie metabolismus MeSH
- pankreas imunologie patofyziologie patologie MeSH
- přirozená imunita genetika imunologie MeSH
- Check Tag
- lidé MeSH
Imprinted genes, giving rise to parent-of-origin effects (POEs), have been hypothesised to affect type 1 diabetes (T1D) and rheumatoid arthritis (RA). However, maternal effects may also play a role. By using a mixed model that is able to simultaneously consider all kinds of POEs, the importance of POEs for the development of T1D and RA was investigated in a variance components analysis. The analysis was based on Swedish population-scale pedigree data. With P = 0.18 (T1D) and P = 0.26 (RA) imprinting variances were not significant. Explaining up to 19.00% (± 2.00%) and 15.00% (± 6.00%) of the phenotypic variance, the maternal environmental variance was significant for T1D (P = 1.60 × 10-24) and for RA (P = 0.02). For the first time, the existence of maternal genetic effects on RA was indicated, contributing up to 16.00% (± 3.00%) of the total variance. Environmental factors such as the social economic index, the number of offspring, birth year as well as their interactions with sex showed large effects.
- MeSH
- biologická variabilita populace genetika MeSH
- diabetes mellitus 1. typu genetika patologie MeSH
- dítě MeSH
- dospělí MeSH
- epigeneze genetická genetika MeSH
- genetická predispozice k nemoci * MeSH
- genomový imprinting genetika MeSH
- genotyp MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- maternální dědičnost genetika MeSH
- mladiství MeSH
- mladý dospělý MeSH
- populační genetika MeSH
- předškolní dítě MeSH
- revmatoidní artritida genetika patologie MeSH
- rodokmen MeSH
- senioři MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- diabetes mellitus 1. typu genetika MeSH
- diabetes mellitus 2. typu genetika MeSH
- diabetes mellitus * genetika MeSH
- genetické testování MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
