RESUMO
BACKGROUND & AIMS: Celiac disease (CD) mass screening remains controversial in part because of a paucity of data to support its benefit. The Autoimmunity Screening for Kids study is a mass screening study for pediatric CD and type 1 diabetes in Colorado. METHODS: This study prospectively follows up children ages 1 to 17 years who screened positive for tissue transglutaminase IgA autoantibodies in the Autoimmunity Screening for Kids study subsequently referred for diagnostic evaluation. Children diagnosed with CD by biopsy or serologic criteria were included in this study. Evaluation at baseline and 12 month follow-up evaluation included demographics, laboratory studies, symptoms, health-related quality of life, anxiety/depression, and gluten-free diet adherence. Paired Student t test, chi-square, and Wilcoxon sign rank tests compared baseline and follow-up data. For symptom scores, odds of improvement were assessed. RESULTS: Of the 52 children with CD enrolled, 42 children completed 12-month follow-up evaluation. On the symptom questionnaire completed at diagnostic evaluation, 38 of 42 children reported 1 or more symptoms. CD mean symptom severity and frequency scores improved from baseline to follow-up evaluation (P < .001). Reported health-related quality of life scores improved among caregivers (P = .002). There was no significant change in reported anxiety or depression. Iron deficiency without anemia was common at baseline (21 of 24 children; 87.5%) and normalized at follow-up evaluation (11 of 21 children; 52.3%). Twenty-six of 28 families reported good or excellent gluten-free diet adherence. CONCLUSIONS: This novel study of children with CD identified through a mass screening program demonstrated improvement in symptoms, quality of life, and iron deficiency after 1 year follow-up evaluation. This demonstrates that there may be benefit to CD mass screening.
RESUMO
T cells targeting self-proteins are important mediators in autoimmune diseases. T cells express unique cell-surface receptors (TCRs) that recognize peptides presented by major histocompatibility molecules. TCRs have been identified from blood and pancreatic islets of individuals with type 1 diabetes (T1D). Here, we tracked ~1700 known antigen-specific TCR sequences, islet antigen or viral reactive, in bulk TCRß sequencing from longitudinal blood DNA samples in at-risk cases who progressed to T1D, age/sex/human leukocyte antigen-matched controls, and a new-onset T1D cohort. Shared and frequent antigen-specific TCRß sequences were identified in all three cohorts, and viral sequences were present across all ages. Islet sequences had different patterns of accumulation based upon antigen specificity in the at-risk cases. Furthermore, 73 islet-antigen TCRß sequences were present in higher frequencies and numbers in T1D samples relative to controls. The total number of these disease-associated TCRß sequences inversely correlated with age at clinical diagnosis, indicating the potential to use disease-relevant TCR sequences as biomarkers in autoimmune disorders.
Assuntos
Diabetes Mellitus Tipo 1 , Ilhotas Pancreáticas , Humanos , Diabetes Mellitus Tipo 1/genética , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T , PeptídeosRESUMO
T-cell responses to posttranslationally modified self-antigens are associated with many autoimmune disorders. In type 1 diabetes, hybrid insulin peptides (HIPs) are implicated in the T-cell-mediated destruction of insulin-producing ß-cells within pancreatic islets. The natural history of the disease is such that it allows for the study of T-cell reactivity prior to the onset of clinical symptoms. We hypothesized that CD4 T-cell responses to posttranslationally modified islet peptides precedes diabetes onset. In a cohort of genetically at-risk individuals, we measured longitudinal T-cell responses to native insulin and hybrid insulin peptides. Both proinflammatory (interferon-γ) and antiinflammatory (interluekin-10) cytokine responses to HIPs were more robust than those to native peptides, and the ratio of such responses oscillated between pro- and antiinflammatory over time. However, individuals who developed islet autoantibodies or progressed to clinical type 1 diabetes had predominantly inflammatory T-cell responses to HIPs. Additionally, several HIP T-cell responses correlated to worsening measurements of blood glucose, highlighting the relevance of T-cell responses to posttranslationally modified peptides prior to autoimmune disease development.
Assuntos
Autoantígenos/genética , Diabetes Mellitus Tipo 1/genética , Insulina/imunologia , Interferon gama/genética , Peptídeos/genética , Adolescente , Adulto , Autoanticorpos/genética , Autoanticorpos/imunologia , Autoantígenos/imunologia , Autoimunidade/genética , Autoimunidade/imunologia , Linfócitos T CD4-Positivos/imunologia , Criança , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Progressão da Doença , Feminino , Humanos , Insulina/genética , Células Secretoras de Insulina/imunologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Masculino , Peptídeos/imunologia , Linfócitos T/imunologia , Adulto JovemRESUMO
INTRODUCTION: The Autoimmunity Screening for Kids (ASK) study is a large scale pediatric screening study in Colorado for celiac disease (CD) and type 1 diabetes. This is a report of the CD outcomes for the first 9,973 children screened through ASK. METHODS: ASK screens children aged 1-17 years for CD using 2 highly sensitive assays for tissue transglutaminase autoantibodies (TGA): a radiobinding (RBA) assay for IgA TGA and an electrochemiluminescence (ECL) assay that detects all TGA isotypes. Children who test positive on either assay are asked to return for confirmatory testing. Those with a confirmed RBA TGA level ≥ 0.1 (twice the upper limit of normal) are referred to the Colorado Center for Celiac Disease for further evaluation; all others are referred to primary care. RESULTS: Of the initial 9,973 children screened, 242 children were TGA+ by any assay. Of those initially positive, 185 children (76.4%) have completed a confirmation blood draw with 149 children (80.5%) confirming positive by RBA TGA. Confirmed RBA TGA+ was associated with a family history of CD (odds ratio [OR] = 1.83; 95% confidence interval 1.06-3.16), non-Hispanic white ethnicity (OR = 3.34; 2.32-4.79), and female sex (OR = 1.43; 1.03-1.98). Gastrointestinal symptoms of CD, assessed at the initial screening, were reported equally often among the RBA TGA+ vs TGA- children (32.1% vs 30.5%, P = 0.65). DISCUSSION: The initial results of this ongoing mass-screening program confirm a high prevalence of undiagnosed CD autoimmunity in a screened US population. Symptoms at initial screening were not associated with TGA status (see Visual abstract, Supplementary Digital Content 5, http://links.lww.com/AJG/B587).
Assuntos
Autoanticorpos/imunologia , Doença Celíaca/diagnóstico , Proteínas de Ligação ao GTP/imunologia , Transglutaminases/imunologia , Adolescente , Doenças Assintomáticas , Doença Celíaca/imunologia , Criança , Pré-Escolar , Técnicas de Diagnóstico por Radioisótopos , Técnicas Eletroquímicas , Feminino , Humanos , Imunoglobulina A/imunologia , Imunoglobulina D/imunologia , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Lactente , Masculino , Programas de Rastreamento , Proteína 2 Glutamina gama-Glutamiltransferase , Testes SorológicosRESUMO
OBJECTIVES: To determine the association between the amount of gluten intake in childhood and later celiac disease (CD), for which data are currently scarce. METHODS: The prospective Diabetes Autoimmunity Study in the Young cohort includes 1875 at-risk children with annual estimates of gluten intake (grams/d) from age 1 year. From 1993 through January 2017, 161 children, using repeated tissue transglutaminase (tTGA) screening, were identified with CD autoimmunity (CDA) and persistent tTGA positivity; of these children, 85 fulfilled CD criteria of biopsy-verified histopathology or persistently high tTGA levels. Cox regression, modeling gluten intake between ages 1 and 2 years (i.e., in 1-year-olds), and joint modeling of cumulative gluten intake throughout childhood were used to estimate hazard ratios adjusted for confounders (aHR). RESULTS: Children in the highest third of gluten intake between the ages of 1 and 2 years had a 2-fold greater hazard of CDA (aHR 2.17; 95% confidence interval [CI], 1.22-3.88; P value = 0.01) and CD (aHR 1.96; 95% CI, 0.90-4.24; P value = 0.09) than those in the lowest third. The risk of developing CDA increased by 5% per daily gram increase in gluten intake (aHR 1.05; 95% CI, 1.00-1.09; P value = 0.04) in 1-year-olds. The association between gluten intake in 1-year-olds and later CDA or CD did not differ by the child's human leukocyte antigen genotype. The incidence of CD increased with increased cumulative gluten intake throughout childhood (e.g., aHR 1.15 per SD increase in cumulative gluten intake at age 6; 95% CI, 1.00-1.32; P value = 0.04). DISCUSSION: Gluten intake in 1-year-olds is associated with the future onset of CDA and CD in children at risk for the disease.
Assuntos
Doença Celíaca/epidemiologia , Dieta/estatística & dados numéricos , Proteínas Alimentares , Glutens , Adolescente , Doença Celíaca/genética , Doença Celíaca/imunologia , Doença Celíaca/patologia , Criança , Feminino , Seguimentos , Proteínas de Ligação ao GTP/imunologia , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Modelos de Riscos Proporcionais , Proteína 2 Glutamina gama-Glutamiltransferase , Transglutaminases/imunologiaRESUMO
OBJECTIVE: Our aim was to define the relationships between plasma biomarkers of kidney injury and intrarenal haemodynamic function (glomerular filtration rate [GFR], effective renal plasma flow [ERPF], renal vascular resistance [RVR]) in adults with type 1 diabetes (T1D). METHODS: The study sample comprised patients with longstanding T1D (duration ≥50 years), among whom 44 were diabetic kidney disease (DKD) resistors (eGFR >60 mL/min/1.73 m2 and <30 mg/d urine albumin excretion) and 22 had DKD, in addition to 73 control participants. GFRINULIN and ERPFPAH were measured, RVR was calculated, and afferent (RA )/efferent (RE ) areteriolar resistances were derived from Gomez equations. Plasma neutrophil gelatinase-associated lipocalin (NGAL), ß2 microglobulin (B2M), osteopontin (OPN) and uromodulin (UMOD) were measured using immunoassay kits from Meso Scale Discovery. RESULTS: Plasma NGAL, B2M and OPN were higher and UMOD was lower in DKD patients vs DKD resistors and non-diabetic controls. In participants with T1D, plasma NGAL inversely correlated with GFR (r = -0.33; P = 0.006) and ERPF (r = -0.34; P = 0.006), and correlated positively with RA (r = 0.26; P = 0.03) and RVR (r = 0.31; P = 0.01). In participants without T1D, NGAL and B2M inversely correlated with GFR (NGAL r = -0.18; P = 0.13 and B2M r = -0.49; P < 0.0001) and with ERPF (NGAL r = -0.19; P = 0.1 and B2M r = -0.42; P = 0.0003), and correlated positively with RA (NGAL r = 0.19; P = 0.10 and B2M r = 0.3; P = 0.01) and with RVR (NGAL r = 0.20; P = 0.09 and B2M r = 0.34; P = 0.003). Differences were significant after adjusting for age, sex, HbA1c, SBP and LDL. There were statistical interactions between T1D status, B2M and intrarenal haemodynamic function (P < 0.05). CONCLUSIONS: Elevated NGAL relates to intrarenal haemodynamic dysfunction in T1D, whereas elevated NGAL and B2M relate to intrarenal haemodynamic dysfunction in adults without T1D. These data may define a diabetes-specific interplay between tubular injury and intrarenal haemodynamic dysfunction.
Assuntos
Biomarcadores/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Nefropatias Diabéticas/diagnóstico , Hemodinâmica/fisiologia , Rim/irrigação sanguínea , Rim/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Canadá , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/fisiopatologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/fisiopatologia , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Lipocalina-2/análise , Lipocalina-2/sangue , Longevidade , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Fluxo Sanguíneo Regional/fisiologia , Resistência Vascular/fisiologia , Microglobulina beta-2/análise , Microglobulina beta-2/sangueRESUMO
OBJECTIVE: We tested the associations between genetic background and selected environmental exposures with respect to islet autoantibodies and type 1 diabetes. RESEARCH DESIGN AND METHODS: Infants with HLA-DR high-risk genotypes were prospectively followed for diabetes-related autoantibodies. Single nucleotide polymorphisms (SNPs) came from the Illumina ImmunoChip and environmental exposure data were by parental report. Children were followed to age 6 years. RESULTS: Insulin autoantibodies occurred earlier than GAD antibody (GADA) and then declined, while GADA incidence rose and remained constant (significant in HLA-DR4 but not in the DR3/3 children). The presence of SNPs rs2476601 (PTPN22) and rs2292239 (ERBB3) demonstrated increased risk of both autoantibodies to insulin (IAA) only and GADA only. SNP rs689 (INS) was protective of IAA only, but not of GADA only. The rs3757247 (BACH2) SNP demonstrated increased risk of GADA only. Male sex, father or sibling as the diabetic proband, introduction of probiotics under 28 days of age, and weight at age 12 months were associated with IAA only, but only father as the diabetic proband and weight at age 12 months were associated with GADA only. Mother as the diabetic proband was not a significant risk factor. CONCLUSIONS: These results show clear differences in the initiation of autoimmunity according to genetic factors and environmental exposures that give rise to IAA or GADA as the first appearing indication of autoimmunity.
Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Interação Gene-Ambiente , Criança , Diabetes Mellitus Tipo 1/sangue , Feminino , Seguimentos , Predisposição Genética para Doença , Antígenos HLA/sangue , Antígeno HLA-DR4/sangue , Humanos , Insulina/sangue , Anticorpos Anti-Insulina/sangue , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/metabolismo , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo , Fatores de RiscoRESUMO
OBJECTIVE: N-acetylglucosamine/galactosamine (GlycA) and sialic acid (GlycB) moieties of glycosylated serum proteins are nonspecific measures of inflammation, but conclusive data on their relationship with insulin resistance or insulin secretion are missing. Therefore, we aimed to examine the relation of GlycA, GlycB, and C-reactive protein (CRP) to direct measures of insulin sensitivity (insulin sensitivity index [SI]) and insulin secretion (acute insulin response [AIR]). RESEARCH DESIGN AND METHODS: This study used cross-sectional analyses and included 1,225 participants with and without type 2 diabetes in the Insulin Resistance Atherosclerosis Study (IRAS). SI and AIR were measured using the frequently sampled intravenous glucose tolerance test, and GlycA and GlycB were measured using nuclear magnetic resonance spectroscopy. RESULTS: GlycA and GlycB had a strong correlation with CRP (r = 0.60 [P < 0.001] and r = 0.46 [P < 0.001], respectively). In a linear regression model with both GlycA and CRP as independent variables, GlycA (ß × 1 SD, -0.04 ± 0.02; P < 0.01) and CRP (-0.06 ± 0.02; P < 0.001) were independently associated with SI even after adjusting for demographics, smoking, physical activity, plasma glucose, and BMI. However, neither CRP nor GlycA had an independent relationship with AIR. CONCLUSIONS: GlycA may complement CRP in evaluating the relationship between inflammation, glucose tolerance, and insulin resistance.
Assuntos
Glicemia/metabolismo , Proteína C-Reativa/metabolismo , Inflamação/sangue , Resistência à Insulina , Insulina/metabolismo , Polissacarídeos/sangue , Acetilglucosamina/sangue , Biomarcadores/sangue , Índice de Massa Corporal , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Feminino , Galactosamina/sangue , Teste de Tolerância a Glucose , Humanos , Inflamação/diagnóstico , Insulina/sangue , Secreção de Insulina , Modelos Lineares , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Polissacarídeos/químicaRESUMO
OBJECTIVE: Type 1 diabetes (T1D) or celiac disease (CD) develops in at least 2% of the general population. Early detection of disease-specific autoimmunity and subsequent monitoring would be possible if screening tests were more widely available. Currently, screening for islet autoimmunity is available only in a research setting, and CD-specific autoimmunity screening is limited to those in high-risk groups. This study assessed the feasibility of incorporating T1D and CD autoantibody screening into a pediatric practice. METHODS: Patient engagement strategies, blood collection preference, blood sample volume, rate of autoantibody detection in the general population, and parental satisfaction were assessed. Over 5 weeks, research staff recruited 200 patients, aged 2-6 yr from two pediatric practices in the Denver area to be screened for islet autoantibodies (IAs) and the transglutaminase antibody. RESULTS: Of the 765 parents approached, 200 (26%) completed the same-day screening. Of the 565 subjects who did not complete the screening, 345 expressed interest, but were unable to make a participation decision. A finger stick, compared with a venous draw, was the preferred method of sample collection. Both methods yielded sufficient blood volume for autoantibody determination. IAs or the transglutaminase antibody were detected in 11 subjects. Parents expressed satisfaction with all aspects of participation. CONCLUSIONS: The results of this study suggest that it is feasible to conduct this type of screening in a pediatric clinic. Such screening could lead to increased disease awareness and the possible benefits that can result from early detection.
Assuntos
Diabetes Mellitus Tipo 1/diagnóstico , Programas de Rastreamento/psicologia , Autoanticorpos/sangue , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/imunologia , Estudos de Viabilidade , Feminino , Humanos , Masculino , Programas de Rastreamento/métodos , Pediatria , Transglutaminases/imunologiaRESUMO
BACKGROUND: Children with positive islet autoantibodies monitored prospectively avoid metabolic decompensation at type 1 diabetes (T1D) diagnosis. However, the effects of early diagnosis and treatment on preservation of insulin secretion and long-term metabolic control are unknown. We compared characteristics of children detected through research screening (Diabetes Autoimmunity Study in the Young [DAISY]) versus community controls at baseline and, in a subset, 6- and 12-month metabolic outcomes. MATERIALS AND METHODS: This was a case-control study comparing DAISY children with T1D to children diagnosed in the general community. All participants underwent mixed-meal tolerance testing; a subset wore a continuous glucose monitoring (CGM) device. Fasting and stimulated C-peptide levels, insulin dose-adjusted hemoglobin A1c (IDAA1c), and CGM variables were compared. RESULTS: Children (21 DAISY, 21 community) were enrolled and matched by age, time of diagnosis, and diabetes duration; 18 were enrolled within 2 months and 24 within 2.5 years on average from diagnosis. In the overall group and the subgroup of participants enrolled 2.5 years from diagnosis, there were no IDAA1c or C-peptide differences between DAISY versus community children. The subgroup of DAISY versus community children enrolled near diagnosis, however, had lower baseline hemoglobin A1c (6.5±1.4% vs. 9.2±2.9%; P=0.0007) and IDAA1c (7.4±2.1% vs. 11.2±3.5%; P=0.04) and higher stimulated C-peptide (2.5±0.5 vs. 1.6±0.2 ng/mL; P=0.02). In this subgroup, IDAA1c differences persisted at 6 months but not at 1 year. CGM analyses revealed lower minimum overnight glycemia in community children (72 vs. 119 mg/dL; P=0.01). CONCLUSIONS: Favorable patterns of IDAA1c and C-peptide seen in research-screened versus community-diagnosed children with T1D within 2 months of diagnosis are no longer apparent 1 year from diagnosis.
Assuntos
Glicemia/análise , Peptídeo C/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Hemoglobinas Glicadas/análise , Programas de Rastreamento/métodos , Adolescente , Idade de Início , Autoimunidade , Automonitorização da Glicemia/estatística & dados numéricos , Estudos de Casos e Controles , Criança , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Relação Dose-Resposta a Droga , Diagnóstico Precoce , Jejum/sangue , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Masculino , Estudos ProspectivosRESUMO
BACKGROUND: The presence of HLA haplotype DR3-DQ2 or DR4-DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG). METHODS: We studied 6403 children with HLA haplotype DR3-DQ2 or DR4-DQ8 prospectively from birth in the United States, Finland, Germany, and Sweden. The primary end point was the development of celiac disease autoimmunity, which was defined as the presence of tTG antibodies on two consecutive tests at least 3 months apart. The secondary end point was the development of celiac disease, which was defined for the purpose of this study as either a diagnosis on biopsy or persistently high levels of tTG antibodies. RESULTS: The median follow-up was 60 months (interquartile range, 46 to 77). Celiac disease autoimmunity developed in 786 children (12%). Of the 350 children who underwent biopsy, 291 had confirmed celiac disease; an additional 21 children who did not undergo biopsy had persistently high levels of tTG antibodies. The risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 11% and 3%, respectively, among children with a single DR3-DQ2 haplotype, and 26% and 11%, respectively, among those with two copies (DR3-DQ2 homozygosity). In the adjusted model, the hazard ratios for celiac disease autoimmunity were 2.09 (95% confidence interval [CI], 1.70 to 2.56) among heterozygotes and 5.70 (95% CI, 4.66 to 6.97) among homozygotes, as compared with children who had the lowest-risk genotypes (DR4-DQ8 heterozygotes or homozygotes). Residence in Sweden was also independently associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.90; 95% CI, 1.61 to 2.25). CONCLUSIONS: Children with the HLA haplotype DR3-DQ2, especially homozygotes, were found to be at high risk for celiac disease autoimmunity and celiac disease early in childhood. The higher risk in Sweden than in other countries highlights the importance of studying environmental factors associated with celiac disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).
Assuntos
Doenças Autoimunes/genética , Doença Celíaca/genética , Predisposição Genética para Doença , Antígenos HLA-DQ/genética , Antígeno HLA-DR3/genética , Anticorpos/sangue , Doenças Autoimunes/epidemiologia , Doença Celíaca/epidemiologia , Pré-Escolar , Europa (Continente)/epidemiologia , Feminino , Antígeno HLA-DR4/genética , Homozigoto , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Estudos Prospectivos , Risco , Transglutaminases/imunologia , Estados Unidos/epidemiologiaRESUMO
OBJECTIVE: In 2010, the American Heart Association defined seven metrics (smoking, BMI, physical activity, diet, total cholesterol, blood pressure, and fasting plasma glucose) for ideal cardiovascular health (ICH). Subsequent studies have shown that the prevalence of achieving these metrics is very low in the general population. Adults with type 1 diabetes are at increased risk of cardiovascular disease (CVD), but no studies to date have been published on the prevalence of ICH in this population. RESEARCH DESIGN AND METHODS: Data for this analysis were collected as part of the prospective Coronary Artery Calcification in Type 1 Diabetes study. This analysis involved 546 subjects with type 1 diabetes and 631 subjects without diabetes who had complete information for calculating the ICH metrics. RESULTS: Overall, the prevalence of ICH was low in this population, with none meeting the ideal criteria for all seven metrics. The prevalence of ideal physical activity (10.0%) and diet (1.1%) were particularly low. ICH was significantly associated with both decreased prevalence (odds ratio [OR] 0.70; 95% CI 0.62-0.80) and progression (OR 0.77; 95% CI 0.66-0.90) of coronary artery calcification (CAC). CONCLUSIONS: ICH is significantly associated with decreased prevalence and progression of CAC; however, prevalence of ICH metrics was low in adults both with and without type 1 diabetes. Efforts to increase the prevalence of ICH could have a significant impact on reducing the burden of CVD.
Assuntos
Doença da Artéria Coronariana/epidemiologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/fisiopatologia , Calcificação Vascular/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Doença da Artéria Coronariana/complicações , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estados Unidos/epidemiologia , Calcificação Vascular/complicaçõesRESUMO
INTRODUCTION: Gliadin proteins play a key role in the pathogenesis of celiac disease; however, as a screen for celiac disease, anti-gliadin antibody testing has been replaced by the more sensitive and specific serological assays for transglutaminase autoantibodies (TGAA). A new generation of anti-gliadin antibody assays has been developed to detect synthetic, deamidated homologous gliadin peptides (DGP) with high sensitivity and specificity. METHODS: Sera were collected prospectively from children with an increased risk for celiac disease as part of an ongoing study at Denver, and studied for the development of celiac autoimmunity. We investigated the high-performance DGP antibody assay in 50 TGAA-positive children both before the development of celiac autoimmunity and following the institution of a gluten-free diet to determine the relationship of DGP antibodies to TGAA. TGAA were measured by an in-house radioassay. RESULTS: DGP antibodies and TGAA parallel each other over the period of years children were studied. DGP antibodies resolved sooner than TGAA in subjects on a gluten-free diet. DGP antibodies appeared earlier than TGAA in 9 children. CONCLUSIONS: Measuring DGP antibodies may be more useful than TGAA in monitoring children on a gluten-free diet. DGP antibodies can precede the appearance of TGAA in some at-risk children.
Assuntos
Autoanticorpos , Doença Celíaca/diagnóstico , Gliadina/administração & dosagem , Gliadina/imunologia , Transglutaminases/imunologia , Adolescente , Autoanticorpos/análise , Doença Celíaca/sangue , Doença Celíaca/genética , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Programas de Rastreamento , Fragmentos de Peptídeos , Valor Preditivo dos Testes , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: While adult populations have been well described in terms of nutritional status, such as the concentration of nutrient biomarkers, little work has been done in healthy paediatric populations. OBJECTIVE: The primary objective of this analysis was to explore the determinants of plasma micronutrients in a group of healthy infants and children. DESIGN: The Diabetes Autoimmunity Study in the Young (DAISY) has enrolled 1433 newborns at increased risk for type 1 diabetes in Denver, Colorado. A representative random sample of 257 children from the DAISY cohort between the ages of 9 months and 8 years with a total of 815 clinic visits over time was used in this analysis. Annual dietary intake was assessed over time with Willett food-frequency questionnaires that were validated in this population. Environmental tobacco smoke (ETS) was assessed using a validated survey. Plasma samples were tested for vitamins, carotenoids and total lipids. Predictors of plasma micronutrients were evaluated using mixed models for longitudinal data, while adjusting for age, human leukocyte antigen genotype, type 1 diabetes family history and other potential confounders and covariates. RESULTS: Increased micronutrient intake was associated with increased levels of their respective plasma nutrient, with the exception of gamma-tocopherol. Independent of dietary intake, levels of alpha- and beta-carotene and beta-cryptoxanthin were significantly lower, and gamma-tocopherol was significantly higher, in children who were exposed to ETS. CONCLUSION: Dietary intake predicts plasma micronutrient levels. Exposure to ETS potentially could have negative health effects in this young population.
Assuntos
Dieta , Micronutrientes/administração & dosagem , Micronutrientes/sangue , Estado Nutricional , Poluição por Fumaça de Tabaco/efeitos adversos , Fatores Etários , Biomarcadores/sangue , Carotenoides/sangue , Criança , Fenômenos Fisiológicos da Nutrição Infantil , Pré-Escolar , Inquéritos sobre Dietas , Feminino , Humanos , Lactente , Fenômenos Fisiológicos da Nutrição do Lactente , Lipídeos/sangue , Masculino , Inquéritos e Questionários , Vitaminas/sangueRESUMO
Approximately 50% of the genetic risk for type 1 diabetes is attributable to the HLA region. We evaluated associations between candidate genes outside the HLA region-INS, cytotoxic T-lymphocyte-associated antigen (CTLA)-4, interleukin (IL)-4, IL-4R, and IL-13 and islet autoimmunity among children participating in the Diabetes Autoimmunity Study in the Young (DAISY). Children with persistent islet autoantibody positivity (n = 102, 38 of whom have already developed diabetes) and control subjects (n = 198) were genotyped for single nucleotide polymorphisms (SNPs) in the candidate genes. The INS-23Hph1 polymorphism was significantly associated with both type 1 diabetes (OR = 0.30; 95% CI 0.13-0.69) and persistent islet autoimmunity but in the latter, only in children with the HLA-DR3/4 genotype (0.40; 0.18-0.89). CTLA-4 promoter SNP was significantly associated with type 1 diabetes (3.52; 1.22-10.17) but not with persistent islet autoimmunity. Several SNPs in the IL-4 regulatory pathway appeared to have a predisposing effect for type 1 diabetes. Associations were found between both IL-4R haplotypes and IL-4-IL-13 haplotypes and persistent islet autoimmunity and type 1 diabetes. This study confirms the association between the INS and CTLA-4 loci and type 1 diabetes. Genes involved in the IL-4 regulatory pathway (IL-4, IL-4R, IL-13) may confer susceptibility or protection to type 1 diabetes depending on individual SNPs or specific haplotypes.
Assuntos
Autoimunidade/genética , Diabetes Mellitus Tipo 1/imunologia , Ilhotas Pancreáticas/imunologia , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Antígenos CD , Antígenos de Diferenciação/genética , Antígeno CTLA-4 , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Genótipo , Haplótipos , Humanos , Lactente , Insulina/genética , Interleucina-13/genética , Interleucina-4/genética , Masculino , Receptores de Interleucina-4/genéticaRESUMO
OBJECTIVES: To assess several transglutaminase autoantibody (TGAA) assays in their ability to distinguish celiac disease (CD) in screening-identified children with abnormal intestine biopsy specimens from those with normal biopsy specimens. STUDY DESIGN: Children at risk for CD (n = 54) composed of type 1 diabetics, first-degree relatives of type 1 diabetics or CD, and HLA-DQ2+ individuals followed from birth received intestine biopsy. Sera obtained at the time of biopsy were tested for TGAA, using the radioimmunoassay and 5 other commercially available enzyme-linked immunosorbent assays. RESULTS: False-positive rates ranged from 28% to 80%. The positive predictive value (PPV) of the tests ranged from 63% to 84% (lower than reported for symptomatic children). Setting a higher cutoff for each assay maximized PPV. CONCLUSIONS: There are significant quantitative differences among all TGAA assays that could affect interpretation of a positive test for CD. The overall false-positive rate for all assays was high in this population. Using the assay as a quantitative rather than qualitative tool by increasing the cutoff of positivity to indicate biopsy increases PPV. Multicenter workshops are needed to identify critical differences and to standardize TGAA assays among laboratories.
Assuntos
Autoanticorpos/sangue , Doença Celíaca/sangue , Doença Celíaca/diagnóstico , Transglutaminases/imunologia , Adolescente , Ensaio de Imunoadsorção Enzimática , Humanos , Radioimunoensaio , Sensibilidade e EspecificidadeRESUMO
Oxidative stress has been linked to many diseases, but little information exists on biomarkers of oxidative stress in healthy children. The purpose of this study was to describe factors that correlate with urinary F2-isoprostanes, an indicator of oxidative stress, and to establish normal concentrations of F2-isoprostanes in children at risk to develop type 1 diabetes mellitus. Creatinine-adjusted urinary F2-isoprostanes were assessed in 342 Denver children under the age of 7 years, from whom we had collected data during 769 clinic visits from August 1997 through January 2001 (mean 2.3 visits per child). Children were identified by newborn screening for HLA-markers, of varying degrees of prediction, for the development of type 1 diabetes. Plasma antioxidants and carotenoids, age at clinic visit, vitamin supplement use, exposure to environmental tobacco smoke, gender, and race were evaluated as correlates to the degree of oxidative stress, using mixed models for longitudinal data. F2-isoprostane levels were highest in infancy and decreased nonlinearly until 7 years. Female gender, HLA-DR3/4 genotype, higher plasma gamma-tocopherol:total lipids ratio, and lower alpha-carotene:total lipids ratio correlated with higher F2-isoprostane levels. Normal values in this healthy population can be used as the basis for future studies of disease mechanisms involving oxidative stress.
Assuntos
Diabetes Mellitus Tipo 1 , F2-Isoprostanos/urina , Estresse Oxidativo , Biomarcadores , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Saúde , Humanos , Lactente , Recém-Nascido , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: To investigate differences in LDL oxidizability by glycemic status within the Insulin Resistance Atherosclerosis Study cohort. RESEARCH DESIGN AND METHODS: LDL oxidizability (lag time and oxidation rate) after exposure to copper was compared among 352 subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), newly diagnosed type 2 diabetes, and known type 2 diabetes. RESULTS: After adjustment for age, clinic, ethnicity, sex, and smoking status, LDL oxidation rates differed by glycemic status (P = 0.001), with a strong trend (P = 0.0001) for reduced LDL oxidation rate with increasing extent and duration of glucose intolerance (2,378 +/- 54, 2,208 +/- 65, 2,145 +/- 71, and 2,115 +/- 48 arbitrary units [mean +/- SE] for NGT, IGT, newly diagnosed type 2 diabetes, and known type 2 diabetes, respectively). Differences in LDL oxidation rate among groups were relatively unaltered by adjustment for lipids and lipoproteins, hypertension, BMI, and waist-to-hip ratio (WHR) and remained significant even after further adjustment for dietary antioxidants and fatty acids, as well as medications. LDL lag times differed marginally by glycemic status (P = 0.058), with similar values for NGT, IGT, and newly diagnosed type 2 diabetes (57-60 min) but higher values for known type 2 diabetes (65 +/- 2). These differences were eliminated by further adjustment for lipids and lipoproteins, hypertension, BMI, and WHR. CONCLUSIONS: We found that glycemic status influenced LDL oxidizability, with a paradoxical reduction in LDL oxidizability, as indicated by a lower LDL oxidation rate with increased extent and duration of glucose intolerance. This difference was only slightly attenuated by adjustment for relevant demographic, metabolic, dietary, and pharmacological factors that potentially influence LDL oxidation.
Assuntos
Arteriosclerose/sangue , Glicemia/metabolismo , Diabetes Mellitus/sangue , Lipoproteínas LDL/sangue , Idoso , População Negra , Dieta , Ingestão de Energia , Feminino , Intolerância à Glucose/sangue , Hispânico ou Latino , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Pós-Menopausa , Reprodutibilidade dos Testes , Fumar , Estados Unidos , População BrancaRESUMO
BACKGROUND & AIMS: Asymptomatic children at risk for celiac disease (CD) and seropositive for immunoglobulin A anti-TG autoantibodies (TGAA) may lack small intestinal mucosal changes characteristic of CD. We have followed a group of children with serial testing for TGAA. METHODS: Subjects were a group of at-risk children comprised of infants expressing HLA-DR3 on newborn screening, those with type 1A diabetes, or a first-degree relative of someone with type 1 diabetes. All children participating in the prospective study for development of CD underwent serial testing for TGAA. Data from clinical evaluation and small intestinal biopsy were compared to the TGAA levels followed over time. RESULTS: In 42 children, serial TGAA determinations while on a gluten-containing diet showed levels fluctuating 10-100-fold over 3-12 months. A TGAA index more than 0.5 had a positive predictive value (PPV) for histologic confirmation of CD of 96% (22/23). A TGAA index above the usual cutoff for positivity (0.05) had a PPV of only 76% (28/37). CONCLUSIONS: In children with TGAA seropositivity, the TGAA level varied over time and a higher titer predicted an abnormal biopsy characteristic of CD. A threshold for biopsy for diagnosis of CD could be set higher for screening-identified cases than for clinically identified cases to decrease the frequency of performing "normal" biopsies.