Genetic and Environmental Interactions Modify the Risk of Diabetes-Related Autoimmunity by 6 Years of Age: The TEDDY Study

Abstract

OBJECTIVEWe tested the associations between genetic background and selected environmental exposures with respect to islet autoantibodies and type 1 diabetes.RESEARCH DESIGN AND METHODSInfants with HLA-DR high-risk genotypes were prospectively followed for diabetes-related autoantibodies. Single nucleotide polymorphisms (SNPs) came from the Illumina ImmunoChip and environmental exposure data were by parental report. Children were followed to age 6 years.RESULTSInsulin autoantibodies occurred earlier than GAD antibody (GADA) and then declined, while GADA incidence rose and remained constant (significant in HLA-DR4 but not in the DR3/3 children). The presence of SNPs rs2476601 (PTPN22) and rs2292239 (ERBB3) demonstrated increased risk of both autoantibodies to insulin (IAA) only and GADA only. SNP rs689 (INS) was protective of IAA only, but not of GADA only. The rs3757247 (BACH2) SNP demonstrated increased risk of GADA only. Male sex, father or sibling as the diabetic proband, introduction of probiotics under 28 days of age, and weight at age 12 months were associated with IAA only, but only father as the diabetic proband and weight at age 12 months were associated with GADA only. Mother as the diabetic proband was not a significant risk factor.CONCLUSIONSThese results show clear differences in the initiation of autoimmunity according to genetic factors and environmental exposures that give rise to IAA or GADA as the first appearing indication of autoimmunity.

Clinical and genetic correlates of islet-autoimmune signatures in juvenile-onset type 1 diabetes

“…SNP variants that showed the strongest positive change with increased islet autoimmunity in our ranking method were linked to PTPN22, INS, SH2B3, ERBB3, RNLS and IL2RA. Variants in these genes were previously associated with the development of autoantibodies, disease development and progression from presenting with autoantibodies to type 1 diabetes onset in at-risk individuals [12,[22][23][24][25][26]. However, how these SNPs exactly contribute to increased T cell autoimmunity is unclear.…”

Birth and coming of age of islet autoantibodies

“…The typical natural history of type 1 diabetes in children is the appearance of the first high‐affinity autoantibody , which is usually IAA in the youngest children, followed by the appearance of other islet autoantibodies , usually within 3 years , and eventually the development of diabetes. Two islet‐autoimmunity endotypes are distinguished . One is characterized by the first appearance of IAA in children carrying HLA‐DR4, and occurs in the first years of life.…”

Maternal dietary supplement use and development of islet autoimmunity in the offspring: TEDDY study

“…We also examined secondary outcomes of IAA only or GADA only as the first appearing autoantibody (IAA‐first IA and GADA‐first IA, respectively). Previously published studies in TEDDY have showed a relationship between the order of autoantibody appearance and risk of T1D …”

“…Previously published studies in TEDDY have showed a relationship between the order of autoantibody appearance and risk of T1D. [19][20][21][22] The infant screening form completed by the family at birth provided basic demographic information and family history of diabetes. TEDDY has previously reported some concordance between national recommendations and the prevalence of prenatal vitamin D and n-3 FA supplement use among TEDDY mothers.…”