Steck Andrea K, Xu Ping, Geyer Susan, Redondo Maria J, Antinozzi Peter, Wentworth John M, Sosenko Jay, Onengut-Gumuscu Suna, Chen Wei-Min, Rich Stephen S, Pugliese Alberto
Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
Health Informatics Institute, University of South Florida, Tampa, Florida 33612.
J Clin Endocrinol Metab. 2017 Aug 1;102(8):2873-2880. doi: 10.1210/jc.2016-4003.
Genome-wide association studies identified >50 type 1 diabetes (T1D) associated non-human leukocyte antigens (non-HLA) loci.
The purpose of this study was to assess the contribution of non-HLA single nucleotide polymorphisms (SNPs) to risk of disease progression.
The TrialNet Pathway to Prevention Study follows relatives of T1D patients for development of autoantibodies (Abs) and T1D.
Using the Immunochip, we analyzed 53 diabetes-associated, non-HLA SNPs in 1016 Ab-positive, at-risk non-Hispanic white relatives.
Effect of SNPs on the development of multiple Abs and T1D.
Cox proportional analyses included all substantial 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 Abs included age at screening, relationship to proband, HLA genotypes, and rs3087243 (cytotoxic T lymphocyte antigen-4). Significant factors for diabetes progression included age at screening, Ab number, HLA genotypes, rs6476839 [GLIS family zinc finger 3 (GLIS3)], and rs3184504 [SH2B adaptor protein 3 (SH2B3)]. When glucose area under the curve (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 old, whereas glucose AUC, sibling, rs3184504 (SH2B3), and rs4900384 (C14orf64) were significant in those ≥12.
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.
全基因组关联研究确定了50多个与1型糖尿病（T1D）相关的非人类白细胞抗原（非HLA）基因座。
本研究的目的是评估非HLA单核苷酸多态性（SNP）对疾病进展风险的影响。
预防试验网络途径研究对T1D患者的亲属进行自身抗体（Abs）和T1D发展情况的随访。
我们使用免疫芯片分析了1016名抗体阳性、有患病风险的非西班牙裔白人亲属中的53个与糖尿病相关的非HLA SNP。
SNP对多种抗体和T1D发展的影响。
Cox比例分析纳入了所有重要的非HLA SNP、HLA基因型、与先证者的关系、性别、初次筛查时的年龄、初次抗体类型和数量。从单一抗体发展为多种抗体的相关因素包括筛查时的年龄、与先证者的关系、HLA基因型和rs3087243（细胞毒性T淋巴细胞抗原4）。糖尿病进展的显著因素包括筛查时的年龄、抗体数量、HLA基因型、rs6476839[GLIS家族锌指蛋白3（GLIS3）]和rs3184504[SH2B衔接蛋白3（SH2B3）]。当纳入葡萄糖曲线下面积（AUC）时，疾病进展的相关因素包括葡萄糖AUC、筛查时的年龄、抗体数量、与先证者的关系、HLA基因型、rs6476839（GLIS3）和rs722110（CCR7）。在按年龄分层的分析中，葡萄糖AUC、筛查时的年龄、同胞关系、HLA基因型、rs6476839（GLIS3）和rs4900384（C14orf64）与12岁以下参与者的糖尿病进展显著相关，而葡萄糖AUC、同胞关系、rs3184504（SH2B3）和rs4900384（C14orf64）在12岁及以上参与者中具有显著性。
总之，我们确定了五个与抗体阳性发展为疾病风险增加相关的非HLA SNP，这可能会改善预防试验的风险分层。
