TY - JOUR

T1 - Genetic risk factors for type 1 diabetes

AU - Pociot, Flemming

AU - Lernmark, Åke

N1 - Copyright © 2016 Elsevier Ltd. All rights reserved.

PY - 2016/6

Y1 - 2016/6

N2 - Type 1 diabetes is diagnosed at the end of a prodrome of β-cell autoimmunity. The disease is most likely triggered at an early age by autoantibodies primarily directed against insulin or glutamic acid decarboxylase, or both, but rarely against islet antigen-2. After the initial appearance of one of these autoantibody biomarkers, a second, third, or fourth autoantibody against either islet antigen-2 or the ZnT8 transporter might also appear. The larger the number of β-cell autoantibody types, the greater the risk of rapid progression to clinical onset of diabetes. This association does not necessarily mean that the β-cell autoantibodies are pathogenic, but rather that they represent reproducible biomarkers of the pathogenesis. The primary risk factor for β-cell autoimmunity is genetic, mainly occurring in individuals with either HLA-DR3-DQ2 or HLA-DR4-DQ8 haplotypes, or both, but a trigger from the environment is generally needed. The pathogenesis can be divided into three stages: 1, appearance of β-cell autoimmunity, normoglycaemia, and no symptoms; 2, β-cell autoimmunity, dysglycaemia, and no symptoms; and 3, β-cell autoimmunity, dysglycaemia, and symptoms of diabetes. The genetic association with each one of the three stages can differ. Type 1 diabetes could serve as a disease model for organ-specific autoimmune disorders such as coeliac disease, thyroiditis, and Addison's disease, which show similar early markers of a prolonged disease process before clinical diagnosis.

AB - Type 1 diabetes is diagnosed at the end of a prodrome of β-cell autoimmunity. The disease is most likely triggered at an early age by autoantibodies primarily directed against insulin or glutamic acid decarboxylase, or both, but rarely against islet antigen-2. After the initial appearance of one of these autoantibody biomarkers, a second, third, or fourth autoantibody against either islet antigen-2 or the ZnT8 transporter might also appear. The larger the number of β-cell autoantibody types, the greater the risk of rapid progression to clinical onset of diabetes. This association does not necessarily mean that the β-cell autoantibodies are pathogenic, but rather that they represent reproducible biomarkers of the pathogenesis. The primary risk factor for β-cell autoimmunity is genetic, mainly occurring in individuals with either HLA-DR3-DQ2 or HLA-DR4-DQ8 haplotypes, or both, but a trigger from the environment is generally needed. The pathogenesis can be divided into three stages: 1, appearance of β-cell autoimmunity, normoglycaemia, and no symptoms; 2, β-cell autoimmunity, dysglycaemia, and no symptoms; and 3, β-cell autoimmunity, dysglycaemia, and symptoms of diabetes. The genetic association with each one of the three stages can differ. Type 1 diabetes could serve as a disease model for organ-specific autoimmune disorders such as coeliac disease, thyroiditis, and Addison's disease, which show similar early markers of a prolonged disease process before clinical diagnosis.

KW - Adolescent

KW - Adult

KW - Aged

KW - Autoantibodies

KW - Child

KW - Child, Preschool

KW - Diabetes Complications

KW - Diabetes Mellitus, Type 1

KW - Gene-Environment Interaction

KW - Genetic Predisposition to Disease

KW - Genome, Human

KW - HLA Antigens

KW - Haplotypes

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Insulin-Secreting Cells

KW - Middle Aged

KW - RNA

KW - Risk Factors

KW - Young Adult

KW - Journal Article

KW - Review

U2 - 10.1016/S0140-6736(16)30582-7

DO - 10.1016/S0140-6736(16)30582-7

M3 - Review

C2 - 27302272

VL - 387

SP - 2331

EP - 2339

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 10035

ER -