TY - JOUR
T1 - Genome-wide association study of the age of onset of type 1 diabetes reveals HTATIP2 as a novel T cell regulator
AU - Cardinale, Christopher J.
AU - Chang, Xiao
AU - Wei, Zhi
AU - Qu, Hui Qi
AU - Bradfield, Jonathan P.
AU - Polychronakos, Constantin
AU - Hakonarson, Hakon
N1 - Funding Information:
Funding was provided by an Innovation Award (iAward) from Sanofi, S.A. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. Funding was also provided by a donation from the Neff Family Foundation to the Center for Applied Genomics (HH), by an institutional development fund from the Children’s Hospital of Philadelphia to HH, and by the Children’s Hospital of Philadelphia Endowed Chair in Genomic Research to HH. Acknowledgments
Publisher Copyright:
Copyright © 2023 Cardinale, Chang, Wei, Qu, Bradfield, Polychronakos and Hakonarson.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - 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.
AB - 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.
KW - HTATIP2/TIP30
KW - RNA-seq
KW - T cells
KW - gene expression
KW - genome-wide association study (GWAS)
KW - pediatrics
KW - type 1 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85148372362&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85148372362&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2023.1101488
DO - 10.3389/fimmu.2023.1101488
M3 - Article
C2 - 36817429
AN - SCOPUS:85148372362
SN - 1664-3224
VL - 14
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 1101488
ER -