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

• Published in: Diabetes care Vol. 45; no. 1; pp. 169 - 177
• Main Authors: Yazdanpanah, Nahid, Yazdanpanah, Mojgan, Wang, Ye, Forgetta, Vincenzo, Pollak, Michael, Polychronakos, Constantin, Richards, J. Brent, Manousaki, Despoina
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.01.2022
• Subjects: Biomarkers; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Drug development; Drug screening; Epstein-Barr virus; Epstein-Barr Virus Infections; Gene mapping; Genome-Wide Association Study - methods; Genomes; Health risks; Herpesvirus 4, Human; Humans; Interleukin 27; Interleukins; Mendelian Randomization Analysis - methods; Pleiotropy; Polymorphism, Single Nucleotide; Proteins; Quantitative trait loci; Randomization; Research design; Risk; Robust control; Sensitivity analysis
• ISSN: 0149-5992; 1935-5548; 1935-5548
• DOI: 10.2337/dc21-1049

To identify circulating proteins influencing type 1 diabetes susceptibility using Mendelian randomization (MR). We used a large-scale two-sample MR study, using cis genetic determinants (protein quantitative trait loci [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 case subjects with type 1 diabetes and 15,743 control subjects. Further, pleiotropy-robust MR methods were used in sensitivity analyses using both cis and trans-pQTL. We found that a genetically predicted SD increase in signal regulatory protein gamma (SIRPG) level was associated with increased risk of type 1 diabetes risk (MR odds ratio [OR] 1.66 [95% 1.36-2.03]; P = 7.1 × 10-7). The risk of type 1 diabetes increased almost twofold per genetically predicted standard deviation (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 × 10-6). However, an 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 × 10-6). 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 an MR approach. These biomarkers are promising targets for development of drugs and/or of screening tools for early prediction of type 1 diabetes.