Can non-HLA Single Nucleotide Polymorphisms Help Stratify Risk in TrialNet Relatives at Risk for Type 1 Diabetes?

Steck, AK; Xu, P; Geyer, S; Redondo, MJ; Antinozzi, P; Wentworth, JM; Sosenko, J; Onengut-Gumuscu, S; Chen, WM; Rich, SS; Pugliese, A; Type 1 Diabetes TrialNet Study Group,

Author(s): Steck, AK; Xu, P; Geyer, S; Redondo, MJ; Antinozzi, P; Wentworth, JM; Sosenko, J; Onengut-Gumuscu, S; Chen, WM; Rich, SS; Pugliese, A; Type 1 Diabetes TrialNet Study Group,;
Details: Publication Year 2017-08-01,Volume 102,Issue #8,Page 2873-2880
Journal Title: Journal of Clinical Endocrinology and Metabolism
Publication Type: Journal Article
Abstract: Context: Genome-wide association studies identified >50 type 1 diabetes (T1D) associated non-HLA loci. Objective: The purpose of this study was to assess the contribution of non-HLA single nucleotide polymorphisms (SNPs) to risk of disease progression. Design and Setting: The TrialNet Pathway to Prevention Study follows relatives of T1D patients for development of autoantibodies (Ab) and T1D. Participants: Using the Immunochip, we analyzed 53 diabetes-associated, non-HLA SNPs in 1,016 Ab positive at risk non-Hispanic White relatives. Main Outcome Measure: Effect of SNPs on the development of multiple Ab and T1D. Results: Cox proportional analyses included all significant non-HLA SNPs, HLA genotypes, relationship to proband, sex, age at initial screening, initial Ab type and number. Factors involved in progression from single to multiple Ab included age at screening, relationship to proband, HLA genotypes and rs3087243 (CTLA4). Significant factors for diabetes progression included age at screening, Ab number, HLA genotypes, rs6476839 (GLIS3) and rs3184504 (SH2B3). When glucose AUC was included, factors involved in disease progression included glucose AUC, age at screening, Ab number, relationship to proband, HLA genotypes, rs6476839 (GLIS3) and rs7221109 (CCR7). In stratified analyses by age, glucose AUC, age at screening, sibling, HLA genotypes, rs6476839 (GLIS3) and rs4900384 (C14orf64) were significantly associated with progression to diabetes in participants <12 years, whereas glucose AUC, sibling, rs3184504 (SH2B3) and rs4900384 (C14orf64) were significant in those >12. Conclusions: In conclusion, we identified five non-HLA SNPs associated with increased risk of progression from Ab positivity to disease that may improve risk stratification for prevention trials.
Publisher: Oxford Academic
Research Division(s): Population Health And Immunity
PubMed ID: 28520980
Publisher's Version: https://doi.org/10.1210/jc.2016-4003
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2017-05-30 09:30:50

Last Modified: 2017-09-12 09:04:43