ABSTRACT
BACKGROUND: Protein tyrosine phosphatase, non-receptor type 22 (lymphoid) (PTPN22), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and interferon induced with helicase C domain 1 (IFIH1) are among the confirmed type 1 diabetes (T1D) susceptibility genes in several populations. The aim of this study was to evaluate the role of PTPN22, CTLA4, and IFIH1 gene variants in the development of T1D in a Colombian population. METHODS: Associations of PTPN22, CTLA4, and IFIH1 variants with T1D were investigated in a sample of 197 nuclear families, including 205 affected children, in the Colombian population. Three to four single nucleotide polymorphisms (SNPs) were analyzed per gene: rs2476600, rs2476601, rs1217418, and rs2488457 for PTPN22; rs1990760, rs3747517, and rs10930046 for IFIH1; and rs231775, rs3087243, and rs231779 for CTLA4. A transmission disequilibrium test was performed for the global sample, in addition to stratified analysis considering autoimmunity, age at onset, and parent of origin. Haplotypes per gene were also analyzed. RESULTS: There was no significant transmission distortion for CTLA4. Conversely, SNPsâ rs10930046 (IFIH1) and rs2476601 (PTPN222) exhibited significant transmission distortion of the C and T alleles, respectively, from parents to affected children (odds ratio [OR] 0.57 and 1.83, respectively). In addition, decreased transmission of the C allele for rs10930046 occurred preferentially from mothers. Stratification analysis revealed that this association was maintained in individuals who were positive for autoantibodies and in those with an age of diagnosis <5 years. CONCLUSION: The results show that IFIH1 and PTPN22 are associated with T1D in Colombian families.
Subject(s)
CTLA-4 Antigen/genetics , DEAD-box RNA Helicases/genetics , Diabetes Mellitus, Type 1/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics , Age of Onset , Alleles , Child , Colombia/epidemiology , Diabetes Mellitus, Type 1/epidemiology , Female , Genotype , Haplotypes , Humans , Interferon-Induced Helicase, IFIH1 , Male , Retrospective StudiesSubject(s)
Chromosomes, Human, Pair 2 , Diabetes Mellitus, Type 1/genetics , Genetic Linkage , Physical Chromosome Mapping , Age of Onset , Alleles , Autoantigens/genetics , Colombia , Female , Gene Frequency , Genes, Dominant , Genetic Loci , Genetic Markers , Genetic Predisposition to Disease , Haplotypes , Humans , Iodide Peroxidase/genetics , Iron-Binding Proteins/genetics , Lod Score , Male , Nuclear Family , Pedigree , PenetranceABSTRACT
Las enfermedades complejas se caracterizan porque presentan varios genes además de factores ambientales implicados en su etiología. Las bases genéticas de la diabetes mellitus tipo 1 (T1D) supone un efecto mayor del complejo HLA que interactúa con otros genes y con el ambiente. Mucho se ha descrito acerca de la posible participación de las infecciones virales como desencadenadores de T1D. En esta revisión exploramos los posibles mecanismos por los cuales el gen RNASEH1 podría estar participando en la etiología de T1D, a partir de una infección viral. El gen RNASEH1 se localiza en la región cromosómica 2p25, la cual ha sido recientemente implicada por nosotros en la susceptibilidad a T1D. Este gen ha sido implicado en la enfermedad mediante análisis genético. Acá pretendemos dar sentido biológico a los datos genéticos. Considerando que la enfermedad es multifactorial, este planteamiento no excluye la participación de otros genes u otros factores ambientales.
Complex disorders are characterized by presenting many genes and other environmental factors implicated in their etiology. The genetic bases of type 1 diabetes mellitus (T1D) suppose a major effect of the HLA complex which interacts with other genes and the environment. Much has been written about the possible implication of viral infections as triggers of T1D. This review explores the mechanisms by which the RNASEH1 gene could be involved in the etiology of T1D, due to a viral infection. The RNASEH1 gene is located in chromosome 2p25, which has been recently implicated in the susceptibility to T1D by the authors, through genetic analysis.This text hopes to establish a biological context for the genetic data. Taking into account that this is a multifactorial disease, this approach does not exclude the eventual participation of other genes or environmental factors.
Subject(s)
Diabetes Mellitus, Type 1 , Genetic Predisposition to DiseaseABSTRACT
El síndrome de Allgrove fue descrito en 1978 por Allgrove et al. como una entidad familiar de origen desconocido caracterizada por deficiencia aislada de glucorticoides, acalasia esofágica y producción defectuosa de lágrimas, por lo que ha sido denominado síndrome triple AAA (adrenal insufficiency, achalasia, alacrima); por lo general aparece durante la primera década de la vida con disfagia o con crisis suprarrenal severa; son pocos los casos diagnosticados de novo en los adultos en quienes predominan síntomas autonómicos y manifestaciones neurológicas como retardo mental, hiperreflexia, voz nasal, anisocoria, ataxia, hipotensión postural y disfunción sexual. En la consulta de Endocrinología Pediátrica del Hospital Universitario San Vicente de Paúl de Medellín se han identificado 5 pacientes con las características clínicas propias del síndrome. Todos mostraron alacrimia e insuficiencia suprarrenal y sólo en uno de los pacientes la acalasia aún no se ha diagnosticado pero la sintomatología que presenta es muy sugestiva de la misma; la alteración neurológica más común en esta serie es el retraso mental. La edad media de aparición de la alacrimia es 3.8 años, de la insuficiencia suprarrena 4.7 años y de la acalasia 7.2 años. Un hallazgo interesante y poco informado es el hipotiroidismo, que es subclínico en tres pacientes, permanente en uno y transitorio en otro.
The Allgrove syndrome (also known as Triple A syndromes), was described by Allgrove et al. in 1978 as a familiar clinical entity of unknown etiology whose characteristic features are adrenal insufficiency, achalasia and alacrima. The usual presentation is during the first 10 years of life with dysphagia or severe adrenal insufficiency, few new cases have been discovered in adults, whose autonomic symptoms and neurological manifestations such as mental retardation, hyperreflexia, nasal speech, anisocoria, ataxia, postural hypotension and sexual dysfunction are predominant. At the Pediatric Endocrinology Service of Hospital Universitario San Vicente de Paúl, Medellín, Colombia, 5 patients have been identified with the clinical features of Allgrove syndrome. All patients have showed both alacrima and adrenal insufficiency. Achalasia has not been diagnosed in one patient, whose symptomatology is highly suggestive to the syndrome. Mental retardation is the most frequent neurological alteration seen. The mean age of presentation for alacrima was 3.8 years, for adrenal insufficiency was 4.7 years and for achalasia was 7.2 years. An interesting finding and occasionally reported is the presence of hypothyroidism, which is subclinic in three patients, transient hypothyroidism in one patient and clinical hypothyroidism in the other one.
