Circulating pancreatic enzyme levels are a causal biomarker of type 1 diabetes.

Novel biomarkers of type 1 diabetes (T1D) are needed for earlier detection of disease and identifying therapeutic targets. We identified biomarkers of T1D by combining plasma cis and trans protein QTLs (pQTLs) for 2,922 proteins in the UK Biobank with a T1D genome-wide association study (GWAS) in 157k samples. T1D risk variants at over 20% of known loci colocalized with cis or trans pQTLs, and distinct sets of T1D loci colocalized with immune, pancreatic secretion, or gut-related proteins. We identified 23 proteins with evidence for a causal role in using pQTLs as genetic instruments in Mendelian Randomization which included multiple sensitivity analyses. Proteins increasing T1D risk were involved in immune processes (e.g. HLA-DRA) and, more surprisingly, T1D protective proteins were enriched in pancreatic secretions (e.g. CPA1), cholesterol metabolism (e.g. APOA1), and gut homeostasis. Genetic variants associated with plasma levels of T1D-protective pancreatic enzymes such as CPA1 were enriched in cis-regulatory elements in pancreatic exocrine and gut enteroendocrine cells, and the protective effects of CPA1 and other enzymes on T1D were consistent when using instruments specific to acinar cells. Finally, pancreatic enzymes had decreased acinar expression in T1D, including CPA1 which was altered prior to onset. Together, these results reveal causal biomarkers and highlight processes in the exocrine pancreas, immune system, and gut that modulate T1D risk.