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作者

Christopher J Cardinale Xiao Chang Zhi Wei Hui-Qi Qu Jonathan P Bradfield Constantin Polychronakos Hakon Hakonarson

作者单位

Affiliations ¹ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States. ² College of Artificial Intelligence and Big Data For Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong, China. ³ Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, United States. ⁴ Quantinuum Research LLC, Wayne, PA, United States. ⁵ Department of Pediatrics, McGill University, Montreal, QC, Canada. ⁶ Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.

刊名

Frontiers in immunology

年份

2023

卷号

Vol.14

页码

1101488

ISSN

1664-3224

关键词

HTATIP2/TIP30 RNA-seq T cells gene expression genome-wide association study (GWAS) pediatrics type 1 diabetes.

摘要

Introduction: Type 1 diabetes, a disorder caused by autoimmune destruction of pancreatic insulin-producing cells, is more difficult to manage when it presents at a younger age. We sought to identify genetic correlates of the age of onset by conducting the first genome-wide association study treating the age of first diagnosis as a quantitative trait. Methods: We performed GWAS with a discovery cohort of 4,014 cases and a replication cohort of 493 independent cases. Genome-wide significant SNPs ...更多

Introduction: Type 1 diabetes, a disorder caused by autoimmune destruction of pancreatic insulin-producing cells, is more difficult to manage when it presents at a younger age. We sought to identify genetic correlates of the age of onset by conducting the first genome-wide association study treating the age of first diagnosis as a quantitative trait. Methods: We performed GWAS with a discovery cohort of 4,014 cases and a replication cohort of 493 independent cases. Genome-wide significant SNPs were mapped to a causal variant by Bayesian conditional analysis and gel shift assay. The causal protein-coding gene was identified and characterized by RNA interference treatment of primary human pan-CD4+ T cells with RNA-seq of the transcriptome. The candidate gene was evaluated functionally in primary cells by CD69 staining and proliferation assays. Results: Our GWAS replicated the known association of the age of diagnosis with the human leukocyte antigen complex . The second signal identified was in an intron of the NELL1 gene on chromosome 11 and fine-mapped to variant rs10833518 . Homozygosity for the risk allele leads to average age of onset one year earlier. Knock-down of HIV TAT-interacting protein 2 , but not other genes in the locus, resulted in alterations to gene expression in signal transduction pathways including MAP kinases and PI3-kinase. Higher levels of HTATIP2 expression are associated with increased viability, proliferation, and activation of T cells in the presence of signals from antigen and cytokine receptors. Discussion: This study implicates HTATIP2 as a new type 1 diabetes gene acting via T cell regulation. Larger population sample sizes are expected to reveal additional loci.收起

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