ABSTRACT
Type 1 diabetes (T1D) tends to cluster in families, suggesting there may be a genetic component predisposing to disease. However, a recent large-scale genome-wide association study concluded that identified genetic factors, single nucleotide polymorphisms, do not account for overall familiality. Another class of genetic variation is the amplification or deletion of >1 kilobase segments of the genome, also termed copy number variations (CNVs). We performed genome-wide CNV analysis on a cohort of 20 unrelated adults with T1D and a control (Ctrl) cohort of 20 subjects using the Affymetrix SNP Array 6.0 in combination with the Birdsuite copy number calling software. We identified 39 CNVs as enriched or depleted in T1D versus Ctrl. Additionally, we performed CNV analysis in a group of 10 monozygotic twin pairs discordant for T1D. Eleven of these 39 CNVs were also respectively enriched or depleted in the Twin cohort, suggesting that these variants may be involved in the development of islet autoimmunity, as the presently unaffected twin is at high risk for developing islet autoimmunity and T1D in his or her lifetime. These CNVs include a deletion on chromosome 6p21, near an HLA-DQ allele. CNVs were found that were both enriched or depleted in patients with or at high risk for developing T1D. These regions may represent genetic variants contributing to development of islet autoimmunity in T1D.
Subject(s)
DNA Copy Number Variations , Diabetes Mellitus, Type 1/genetics , Genome-Wide Association Study/methods , Polymorphism, Single Nucleotide , Adult , Chromosome Deletion , Chromosomes, Human, Pair 13/genetics , Chromosomes, Human, Pair 2/genetics , Chromosomes, Human, Pair 6/genetics , Chromosomes, Human, Pair 7/genetics , Chromosomes, Human, Pair 8/genetics , Cohort Studies , Gene Deletion , Gene Frequency , Genetic Predisposition to Disease/genetics , Genetic Variation , Humans , Oligonucleotide Array Sequence Analysis , Risk Factors , Twins, Monozygotic/geneticsSubject(s)
Autoantibodies/immunology , Diabetes Mellitus, Type 1/immunology , Diseases in Twins/immunology , Islets of Langerhans/immunology , Twins, Monozygotic/immunology , Adolescent , Adult , Autoimmunity , Child , Child, Preschool , Humans , Infant , Longitudinal Studies , Middle Aged , Young AdultABSTRACT
We can now predict the development of Type 1A (Immune Mediated) diabetes primarily through the determination of four biochemically characterized islet autoantibodies [insulin, GAD65, IA-2 (ICA512) and (Znt8)]. Prediction is possible because beta-cell destruction is chronically progressive and very slow in most, but not all individuals. We can also prevent type 1A diabetes in animal models and a major goal is the prevention of type 1A diabetes in man with multiple clinical trials underway.
Subject(s)
Diabetes Mellitus, Type 1/immunology , Animals , Autoimmunity/immunology , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/metabolism , Female , Genetic Predisposition to Disease/genetics , HLA-DQ Antigens/genetics , HLA-DR Antigens/genetics , Haplotypes , Humans , Insulin/immunology , Insulin/metabolism , Insulin Antibodies/immunology , Insulin Antibodies/metabolism , Male , Mice , Mice, Inbred NODABSTRACT
We can now predict the development of Type 1A (Immune Mediated) diabetes primarily through the determination of four biochemically characterized islet autoantibodies [insulin, GAD65, IA-2 (ICA512) and (Znt8)]. Prediction is possible because beta-cell destruction is chronically progressive and very slow in most, but not all individuals. We can also prevent type 1A diabetes in animal models and a major goal is the prevention of type 1A diabetes in man with multiple clinical trials underway.
Atualmente o desenvolvimento do diabetes melito tipo 1 A( imune mediado) pode ser predito através da determinação de quatro auto-anticorpos antiilhotas [antiinsulina, anti-GAD65, anti-IA2 (ICA512) e (anti-Znt8)] caracterizados bioquimicamente. A predição dessa doença é possível devido a destruição das células-beta, não em todos os indivíduos mas na sua maioria, ser crônica e lentamente progressiva. Também é possível prevenir o DM1 A em modelos animais e o objetivo maior é a prevenção dessa doença em humanos, para os quais vários protocolos clínicos estão em andamento.
