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

posted on 10.11.2021, 17:24 by Nahid Yazdanpanah, Mojgan Yazdanpanah, Ye Wang, Vincenzo Forgetta, Michael Pollak, Constantin Polychronakos, Brent Richards, Despoina Manousaki

To identify circulating proteins influencing type 1 diabetes susceptibility using Mendelian randomization (MR).


We employed a large-scale two-sample MR study, using cis genetic determinants (protein quantative trait loci or pQTL) of up to 1,611 circulating proteins from five large genome-wide association studies, to screen for causal associations of these proteins with type 1 diabetes risk in 9,684 cases with type 1 diabetes and 15,743 controls. Further, pleiotropy-robust MR methods were used in sensitivity analyses using both cis and trans-pQTL.


We found that a genetically predicted a standard deviation increase in Signal Regulatory Protein Gamma (SIRPG) level was associated with increased risk of type 1 diabetes risk (MR OR = 1.66, 95% 1.36- 2.03; P = 7.1 x 10-7). The risk of type 1 diabetes increased almost two-fold per genetically predicted SD increase in interleukin-27 Epstein-Barr Virus Induced 3 (IL27-EBI3) protein levels (MR OR=1.97, 95% CI = 1.48 – 2.62, P= 3.7 x10-6). However, a SD increase in chymotrypsinogen B1 (CTRB1) was associated with decreased risk of type 1 diabetes (MR OR=0.84, 95% CI = 0.77 – 0.90, P= 6.1 x10-6).

Sensitivity analyses using MR methods testing for pleiotropy while including trans-pQTL showed similar results. While the MR-Egger suggested no pleotropic effect (p-value MR-Egger intercept = 0.31) there was evidence of pleiotropy in MR-PRESSO (p-value global test =0.006).


We identified three novel circulating protein biomarkers associated with type 1 diabetes risk using a MR approach. These biomarkers are promising targets for development of drugs and/or of screening tools for early prediction of type 1 diabetes.


DM received a Pediatric Endocrine Society (PES) Clinical Scholar Award for this research. The funding body had no involvement in the study design, data collection, analysis and interpretation of results, or writing of this manuscript.