Clinically Relevant Circulating Protein Biomarkers for Type 1 Diabetes: Evidence From a Two-Sample Mendelian...

Area of Science:

• Genetics
• Immunology
• Metabolomics

Background:

• Type 1 diabetes (T1D) is an autoimmune disease with complex genetic and environmental factors.
• Identifying circulating proteins that causally influence T1D susceptibility is crucial for understanding disease mechanisms and developing interventions.

Purpose of the Study:

• To employ Mendelian randomization (MR) to identify circulating proteins that causally influence the risk of developing type 1 diabetes.
• To screen a large number of circulating proteins for their potential causal roles in T1D pathogenesis.

Main Methods:

• A two-sample MR study utilizing cis genetic determinants (protein quantitative trait loci [pQTL]) for up to 1,611 circulating proteins.
• Analysis involved large genome-wide association studies datasets with 9,684 T1D cases and 15,743 controls.
• Pleiotropy-robust MR methods and sensitivity analyses using cis and trans-pQTL were performed.

Main Results:

• Genetically predicted increases in signal regulatory protein gamma (SIRPG) and interleukin-27 Epstein-Barr virus-induced 3 (IL27-EBI3) protein levels were associated with significantly increased T1D risk (MR ORs 1.66 and 1.97, respectively).
• Conversely, increased chymotrypsinogen B1 (CTRB1) levels were associated with decreased T1D risk (MR OR 0.84).
• Sensitivity analyses supported these findings, though some evidence of pleiotropy was detected.

Conclusions:

• Three novel circulating protein biomarkers—SIRPG, IL27-EBI3, and CTRB1—were identified as being associated with type 1 diabetes risk through an MR approach.
• These proteins represent promising targets for the development of novel therapeutic drugs and/or screening tools for early T1D prediction.