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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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.

RESULTS

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).

CONCLUSIONS

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.