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 (GWAS) 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 (HLA-DQB1). The second signal identified was in an intron of the NELL1 gene on chromosome 11 and fine-mapped to variant rs10833518 (P < 1.54 × 10-9). Homozygosity for the risk allele leads to average age of onset one year earlier. Knock-down of HIV TAT-interacting protein 2 (HTATIP2), 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.
Keywords: HTATIP2/TIP30; RNA-seq; T cells; gene expression; genome-wide association study (GWAS); pediatrics; type 1 diabetes.
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