RESUMEN
OBJECTIVE: Children with type 1 diabetes (T1DM) are at increased risk for celiac disease (CD); however, the benefits of screening for IgA tissue transglutaminase autoantibodies (TG), a marker for CD, are unclear. STUDY DESIGN: We compared 71 screening-identified TG+ with 63 matched TG- children with TIDM. Growth, bone density, and diabetes control measures were obtained. RESULTS: The group was 10 +/- 3 years of age, 46% male, with TIDM for 4 +/- 3 years. Z scores for weight (0.3 +/- 1 vs 0.7 +/- 0.8, P = .024), body mass index (BMI) (0.3 +/- 0.9 vs 0.8 +/- -0.8, P = .005), and midarm circumference (0.3 +/- 1.1 vs 0.6 +/- 0.9, P = .031) were lower in the TG+ group. Bone mineral density and diabetes control measures were similar. When limiting the analysis to the 35 TG+ subjects with biopsy changes of CD, the BMI Z score was lower than the control group (0.4 +/- 0.9 vs 0.7 +/- 0.7, P = .05). CONCLUSIONS: In children with TIDM, screening-identified evidence of CD is associated with altered body composition, but not bone mineral density or diabetes control. Further study is needed to determine the benefit of early diagnosis and treatment of CD in TIDM children.
Asunto(s)
Autoanticuerpos/sangre , Enfermedad Celíaca/sangre , Enfermedad Celíaca/inmunología , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/complicaciones , Autoinmunidad , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/diagnóstico , Niño , Femenino , Humanos , Masculino , Transglutaminasas/inmunologíaRESUMEN
OBJECTIVE: Certain human leukocyte antigen (HLA)-DR,DQ genotypes have been associated with type 1 diabetes mellitus (T1DM) risk, although it is unknown whether the association is due to alleles, haplotypes, genotypes, the formation of heterodimers, or all of the above. To characterize the role of the HLA-DR,DQ genotype and ethnicity on the onset age of T1DM, we analyzed these factors in patients with T1DM and the general population. METHODS: One thousand three hundred twenty-two well-characterized patients with T1DM were compared with 3339 children from the general population of Denver, Colorado, USA. Because of the extensive available data across age and ethnic groups, this study population is unique. RESULTS: The HLA-DR3/4,DQB1*0302, DRX/4,DQB1*0302 (where X=1, 4, 8, and 9), and HLA--DR3/3 genotypes were associated with T1DM, supporting previous research. Additionally, the DR3/9 genotype showed a positive association with T1DM, which has not previously been described in Caucasian populations. The HLA-DR3/4*0302 genotype was most strongly associated with T1DM in diabetic individuals with the youngest onset age. Genotype frequencies were similar between Hispanics and non-Hispanic whites, except for the DR3/3 genotype, which was more likely to be found in non-Hispanic whites. CONCLUSIONS: These results indicate that there are multiple alleles and genotypes associated with T1DM and that the risk associated with different genetic markers depends on the age of disease onset, suggesting that some markers may be involved in more rapid disease progression.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Antígenos HLA-DQ , Antígenos HLA-DR , Edad de Inicio , Diabetes Mellitus Tipo 1/etnología , Progresión de la Enfermedad , Femenino , Genotipo , Humanos , Recién Nacido , Masculino , Factores de RiesgoRESUMEN
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.
Asunto(s)
Autoinmunidad/genética , Diabetes Mellitus Tipo 1/inmunología , Islotes Pancreáticos/inmunología , Polimorfismo de Nucleótido Simple/genética , Adolescente , Antígenos CD , Antígenos de Diferenciación/genética , Antígeno CTLA-4 , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Genotipo , Haplotipos , Humanos , Lactante , Insulina/genética , Interleucina-13/genética , Interleucina-4/genética , Masculino , Receptores de Interleucina-4/genéticaRESUMEN
CONTEXT: While gluten ingestion is responsible for the signs and symptoms of celiac disease, it is not known what factors are associated with initial appearance of the disease. OBJECTIVE: To examine whether the timing of gluten exposure in the infant diet was associated with the development of celiac disease autoimmunity (CDA). DESIGN, SETTING, AND PATIENTS: Prospective observational study conducted in Denver, Colo, from 1994-2004 of 1560 children at increased risk for celiac disease or type 1 diabetes, as defined by possession of either HLA-DR3 or DR4 alleles, or having a first-degree relative with type 1 diabetes. The mean follow-up was 4.8 years. MAIN OUTCOME MEASURE: Risk of CDA defined as being positive for tissue transglutaminase (tTG) autoantibody on 2 or more consecutive visits or being positive for tTG once and having a positive small bowel biopsy for celiac disease, by timing of introduction of gluten-containing foods into the diet. RESULTS: Fifty-one children developed CDA. Findings adjusted for HLA-DR3 status indicated that children exposed to foods containing wheat, barley, or rye (gluten-containing foods) in the first 3 months of life (3 [6%] CDA positive vs 40 [3%] CDA negative) had a 5-fold increased risk of CDA compared with children exposed to gluten-containing foods at 4 to 6 months (12 [23%] CDA positive vs 574 [38%] CDA negative) (hazard ratio [HR], 5.17; 95% confidence interval [CI], 1.44-18.57). Children not exposed to gluten until the seventh month or later (36 [71%] CDA positive vs 895 [59%] CDA negative) had a marginally increased risk of CDA compared with those exposed at 4 to 6 months (HR, 1.87; 95% CI, 0.97-3.60). After restricting our case group to only the 25 CDA-positive children who had biopsy-diagnosed celiac disease, initial exposure to wheat, barley, or rye in the first 3 months (3 [12%] CDA positive vs 40 [3%] CDA negative) or in the seventh month or later (19 [76%] CDA positive vs 912 [59%] CDA negative) significantly increased risk of CDA compared with exposure at 4 to 6 months (3 [12%] CDA positive vs 583 [38%] CDA negative) (HR, 22.97; 95% CI, 4.55-115.93; P = .001; and HR, 3.98; 95% CI, 1.18-13.46; P = .04, respectively). CONCLUSION: Timing of introduction of gluten into the infant diet is associated with the appearance of CDA in children at increased risk for the disease.
Asunto(s)
Enfermedad Celíaca/inmunología , Dieta , Grano Comestible , Glútenes/administración & dosificación , Autoanticuerpos , Autoinmunidad , Biopsia , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/epidemiología , Preescolar , Humanos , Lactante , Intestino Delgado/patología , Estudios Prospectivos , Factores de Riesgo , Factores de Tiempo , Transglutaminasas/inmunologíaRESUMEN
OBJECTIVE: Families of children diagnosed with type 1 diabetes require counseling concerning type 1 diabetes risk in nondiabetic siblings and parents. No U.S. population-specific life-table risk estimates are currently available for parents, and those for siblings (2-6% by age 20 years) are based on family studies completed before 1987. RESEARCH DESIGN AND METHODS: We analyzed family histories of 1,586 patients in Colorado with type 1 diabetes (83% non-Hispanic white, 10% Hispanic, and 7% other) diagnosed before 16 years of age and interviewed during 1999-2002. Families of probands with type 2, undetermined, or secondary diabetes (n = 53) or those with incomplete data (n = 137) were excluded. The median age at onset of the proband was 7.1 years and the median diabetes duration 3.5 years. Cumulative risk estimates were calculated using survival analysis for 2,081 full siblings and 3,016 biological parents. RESULTS: In siblings, the overall risk of type 1 diabetes by age 20 years was 4.4%, but it was significantly (P < 0.0001) higher in siblings of probands diagnosed under age 7 years than in those diagnosed later. In parents, the overall risk by age 40 years was 2.6% and higher in fathers (3.6%) than in mothers (1.7%) of probands (P < 0.001). Similar to siblings, the risk was also higher (P = 0.006) in parents of probands diagnosed <7 years of age than in those diagnosed later. CONCLUSIONS: Current risks of type 1 diabetes in Colorado siblings and parents of type 1 diabetic probands are higher than in the 1982 Pittsburgh study but similar to contemporary European rates. Recurrence risk of type 1 diabetes is significantly higher in first-degree relatives of probands diagnosed at a young age.
Asunto(s)
Diabetes Mellitus Tipo 1/epidemiología , Adulto , Edad de Inicio , Autoanticuerpos/sangre , Niño , Preescolar , Colorado/epidemiología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Padre , Femenino , Humanos , Incidencia , Islotes Pancreáticos/inmunología , Masculino , Madres , Análisis Multivariante , Factores de Riesgo , HermanosRESUMEN
OBJECTIVE: At-risk groups commonly undergo screening for autoantibodies associated with celiac disease (CD). However, the clinical significance of a positive test remains uncertain. The objective of this study was to evaluate growth and clinical features of children who test positive for an autoantibody associated with CD. METHODS: A case-control study of Denver area healthy infants and young children with and without CD autoantibodies was conducted. A cohort of HLA-characterized children were followed prospectively since birth for the development of immunoglobulin A antitissue transglutaminase autoantibodies (TG). Clinical evaluation, questionnaire, blood draw, and small bowel biopsy were performed. Growth and nutrition and frequency of positive responses were measured. RESULTS: Compared with 100 age- and gender-matched TG-negative controls, 18 TG-positive children, 5.5 +/- 0.5 years of age, had a greater number of symptoms and lower z scores for weight-for-height and for body mass index. Responses that were independently associated with TG-positive status were irritability/lethargy, abdominal distention/gas, and difficulty with weight gain. CONCLUSIONS: Screening-identified TG-positive children demonstrate mild alterations in growth and nutrition and report more symptoms than control subjects. Additional study is needed on the benefit and risk of identifying CD in at-risk groups.