RESUMEN
Type 1 diabetes arises from the autoimmune destruction of insulin-producing beta-cells of the pancreas, resulting in dependence on exogenously administered insulin to maintain glucose homeostasis. In this study, our aim was to identify genetic risk factors that contribute to progression from islet autoimmunity to clinical type 1 diabetes. We analyzed 6.8 million variants derived from whole genome sequencing of 160 islet autoantibody positive subjects, including 87 who had progressed to type 1 diabetes. The Cox proportional-hazard model for survival analysis was used to identify genetic variants associated with progression. We identified one novel region, 20p12.1 (TASP1; genome-wide P < 5 × 10-8) and three regions, 1q21.3 (MRPS21-PRPF3), 2p25.2 (NRIR), 3q22.1 (COL6A6), with suggestive evidence of association (P < 8.5 × 10-8) with progression from islet autoimmunity to type 1 diabetes. Once islet autoimmunity is initiated, functional mapping identified two critical pathways, response to viral infections and interferon signaling, as contributing to disease progression. These results provide evidence that genetic pathways involved in progression from islet autoimmunity differ from those pathways identified once disease has been established. These results support the need for further investigation of genetic risk factors that modulate initiation and progression of subclinical disease to inform efforts in development of novel strategies for prediction and intervention of type 1 diabetes.
Asunto(s)
Autoanticuerpos/inmunología , Autoinmunidad/genética , Diabetes Mellitus Tipo 1/genética , Predisposición Genética a la Enfermedad , Genotipo , Islotes Pancreáticos/inmunología , Adolescente , Niño , Preescolar , Diabetes Mellitus Tipo 1/inmunología , Progresión de la Enfermedad , Femenino , Humanos , Lactante , Masculino , Secuenciación Completa del GenomaRESUMEN
OBJECTIVES: To determine the association between childhood growth prior to the development of celiac disease (CD) and CD autoimmunity (CDA) identified by periodic serological screening. STUDY DESIGN: The Diabetes Autoimmunity Study in the Young cohort includes 1979 genetically at-risk children from Denver, Colorado, with annual growth measurements from age nine months until ten years. Between 1993 and February 2019, 120 children developed CDA defined by persistent positive tissue transglutaminase autoantibodies (TGA); among these, 71 met our criteria for CD based on histopathological findings or high TGA levels. Age- and sex-specific z-scores of weight, body mass index (BMI), and height prior to seroconversion were derived using US reference charts as standards. Joint modeling of serial growth measurements was used to estimate adjusted hazard ratios (aHRs) accounting for celiac-associated human leukocyte antigens, early-life feeding practices, and socio-demographics. RESULTS: In the first 10 years of life, there were no significant associations between the child's current weight, BMI and height and the risk of screening-detected CDA or CD, neither was the weight nor BMI velocity associated with CDA or CD as identified by screening (all aHRs approximated 1). Increased height velocity was associated with later CD, but not CDA, development (aHR per 0.01-z score/year, 1.28; 95% confidence interval [CI] 1.18-1.38 and 1.03; 0.97-1.09, respectively). CONCLUSIONS: In the first 10 years of life, from prospectively collected serial growth measurements, we found no evidence of impaired childhood growth before CD and CDA development as identified through early and periodic screening.
Asunto(s)
Enfermedad Celíaca , Autoanticuerpos , Autoinmunidad , Índice de Masa Corporal , Enfermedad Celíaca/diagnóstico , Niño , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Estudios ProspectivosRESUMEN
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.
Asunto(s)
Enfermedad Celíaca/epidemiología , Dieta/estadística & datos numéricos , Proteínas en la Dieta , Glútenes , Adolescente , Enfermedad Celíaca/genética , Enfermedad Celíaca/inmunología , Enfermedad Celíaca/patología , Niño , Femenino , Estudios de Seguimiento , Proteínas de Unión al GTP/inmunología , Predisposición Genética a la Enfermedad , Humanos , Lactante , Masculino , Modelos de Riesgos Proporcionales , Proteína Glutamina Gamma Glutamiltransferasa 2 , Transglutaminasas/inmunologíaRESUMEN
OBJECTIVE: To study the association of gluten intake with development of islet autoimmunity and progression to type 1 diabetes. RESEARCH DESIGN AND METHODS: The Diabetes Autoimmunity Study in the Young (DAISY) follows children with an increased risk of type 1 diabetes. Blood samples were collected at 9, 15, and 24 months of age, and annually thereafter. Islet autoimmunity was defined by the appearance of at least one autoantibody against insulin, IA2, GAD, or ZnT8 (zinc transporter 8) in at least two consecutive blood samples. Using food frequency questionnaires, we estimated the gluten intake (in grams per day) annually from 1 year of age. Cox regression modeling early gluten intake, and joint modeling of the cumulative gluten intake during follow-up, were used to estimate hazard ratios adjusted for confounders (aHR). RESULTS: By August 2017, 1,916 subjects were included (median age at end of follow-up 13.5 years), islet autoimmunity had developed in 178 participants, and 56 of these progressed to type 1 diabetes. We found no association between islet autoimmunity and gluten intake at 1-2 years of age or during follow-up (aHR per 4 g/day increase in gluten intake 1.00, 95% CI 0.85-1.17 and 1.01, 0.99-1.02, respectively). We found similar null results for progression from islet autoimmunity to type 1 diabetes. Introduction of gluten at <4 months of age was associated with an increased risk of progressing from islet autoimmunity to type 1 diabetes compared with introduction at 4-5.9 months (aHR 8.69, 95% CI 1.69-44.8). CONCLUSIONS: Our findings indicate no strong rationale to reduce the amount of gluten in high-risk children to prevent development of type 1 diabetes.
Asunto(s)
Autoinmunidad , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/inmunología , Ingestión de Alimentos/fisiología , Glútenes/administración & dosificación , Islotes Pancreáticos/inmunología , Autoanticuerpos/sangre , Preescolar , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/patología , Encuestas sobre Dietas , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Lactante , Islotes Pancreáticos/patología , Estudios Longitudinales , Masculino , Factores de RiesgoRESUMEN
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.
Asunto(s)
Diabetes Mellitus Tipo 1/diagnóstico , Tamizaje Masivo/psicología , Autoanticuerpos/sangre , Niño , Preescolar , Diabetes Mellitus Tipo 1/inmunología , Estudios de Factibilidad , Femenino , Humanos , Masculino , Tamizaje Masivo/métodos , Pediatría , Transglutaminasas/inmunologíaRESUMEN
Male adult Sprague-Dawley rats were subjected to unilateral crush injury, and expression of LPL protein and mRNA were assessed as a function of time post-crush. LPL activity increased in the distal portion of the injured nerve by Day 4 post-crush, after which LPL activity gradually returned to normal levels. Conversely, quantification of LPL mRNA by reverse transcription-polymerase chain reaction demonstrated unchanged or decreased LPL mRNA in the distal nerve. Immunohistochemical analysis of LPL protein expression using an anti-rat LPL antibody revealed that LPL protein is present throughout the endoneurium of the sciatic nerve and increases in abundance following crush injury. The possibility that infiltrating macrophages are responsible for the increase in LPL protein levels in the crush injured nerve was addressed by immunohistochemical staining for ED-1, a differentiated macrophage marker protein. ED-1 was minimally present in the uninjured nerve and was detected at Day 4 post-crush, suggesting that the increase in LPL protein and activity that occurs following crush injury is at least partly derived from macrophages. These data suggest a role for LPL in the response of peripheral nerves to crush injury, possibly in order to facilitate reutilization of lipids from degenerating myelin.