Profiling associations between IGHG-FCGR ligand-receptor interactions and disease progression from stage 1 and 2 to stage 3 type 1 diabetes
Year: 2025
Type: other
Abstract: The primary objective is to investigate if ligand-receptor interactions (LRIs) between IGHG and FCGR gene products associate with progression to type 1 diabetes. Utilizing two completed clinical trials (DPT-1 and TN07), we apply next-generation targeted sequencing to genotype IGHG and FCGR genes in a cohort of 1214 individuals and assess LRI associations with disease progression. A Cox regression model is used to quantify LRI associations. Our investigation shows the following results: 1) IGHG or FCGR alone are found to have weak and sporadic associations with progression; 2) Multiple LRIs between IGHG and FCGR gene products are found to associate with progression; especially, LRIs of IGHG2 with multiple FCGR receptors accelerate progression, while those of IGHG4 with multiple FCGR receptors (some are overlapping) delay progression; and 3) as several crystal structures of FcgRs complexed with distinct IgG molecules are known, application of this knowledge here is hampered by the absence of any information on the subclass distribution of each of the several type 1 diabetes-related autoantibodies. It cannot be excluded that their respective state of glycosylation, may influence binding affinity to various FcgRs, and function of thus formed complexes. We found that LRIs of the IGHG and FCGR gene products probably influence progression, likely shedding new insights into some of the immunological mechanisms involved in progression to T1D; our findings potentially facilitate the search for new immunotherapeutic treatment through intervening at key steps in the progression.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4416956214