Circulating Proteins May be Early Biomarkers for Type 1 Diabetes Risk

type 1 diabetes
type 1 diabetes
Predicting type 1 diabetes risk has been difficult due to the inability to clearly identify biomarkers and small study sizes. Investigators used Mendelian randomization to identify biomarkers.

A Mendelian randomization (MR) study identified circulating protein biomarkers which may be viable drug targets or early identification markers for individuals at high risk for type 1 diabetes (T1D). These findings were published in Diabetes Care.

Protein data were sourced from 5 proteomic genome wide association studies (GWAS).. The association between protein markers and T1D risk was assessed among 9684 people with T1D and 15,743 controls from 12 European cohorts. Candidate proteins were validated using an enzyme-linked immunosorbent assay (ELISA) assay.

After identifying cis-pQTL as instruments for the MR study, 1558 directly related with T1D and 53 were proxies. Using a Bonferroni correction, 3 risk loci remained significant in association with T1D.

The 3 circulating proteins were signal regulatory protein g (SIRPG), interleukin-27 Epstein-Barr virus–induced 3 (IL27.EBI3), and chymotrypsinogen.. An increase in chymotrypsionogen B1 (CTRB1) was associated with a decreased risk of type 1 diabetes.

Researchers noted increased genetically predicted SIRPG levels were associated with increased risk of type 1 diabetes.

According to previously published data, genetically predicted increases in the standard deviation (SD) of SIRPG levels correlated with risk for T1D (MR odds ratio [OR], 1.66; 95% CI, 1.36-2.03; P =7.1´10-7) and a negative relationship between genetically predicted SD of IL27.EB13 with T1D risk (MR OR, 0.84; 95% CI, 0.77-0.90; P =6.1´10-6).

There was some evidence of a pleiotropic effect between IL27.EBI3 (P =8.71´10-12) and CTRB1 pQTL (P =1.58´10-157) with their specific cis-pQTLs.

Expression of SIRPG cis-pQTL was significant for whole blood and spleen; IL27.EBI3 cis-pQTL for liver; and CTRB1 cis-pQTL for pancreas.

The specific risk variants identified in the analysis included the G allele of CTRB1 cis-pQTL which increased circulating CTRB1 and decreased pancreas-specific expression. The T allele of the IL27.EBI3 cis-pQTL which increased circulating IL27.EBI3. For SIRPG, the G allele in its cis-pQTL increased SIRPG expression in the pancreas.

All 3 proteins were well validated by the ELISA assay.

This study may have been limited as it was designed to detect circulating protein levels and may not have captured the tissue-specific effects accurately, among other limitations.

Researchers concluded the MR study accurately identified 3 circulating proteins which have the potential to be useful in predicting T1D risk and may be candidate drug targets. Additional studies are warranted.

Disclosure: One author declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Yazdanpanah N, Yazdanpanah M, Wang Y, et al. Clinically relevant circulating protein biomarkers for type 1 diabetes: evidence from a two-sample Mendelian randomization study. Diabetes Care. Published November 10, 2021. doi:10.2337/dc21-1049