ESPE Yearbook of Paediatric Endocrinology

Nat Commun. 2025;16(1):3750. PMID: 40263317

Brief summary: This study generated a genome-wide protein quantitative trait loci (pQTL) map from 1,985 proteins in 695 newborns at high genetic risk of developing Type 1 diabetes (T1D). A total of 535 pQTLs were identified, of which 62 were characteristic of newborns. Colocalization analysis revealed 5 pQTLs that overlapped with T1D GWAS signals. Mendelian randomization provided causal evidence implicating each of these 5 proteins in T1D aetiology.

Progress in genomics and proteomics holds promise for further uncovering disease mechanisms and guiding the development of preventive therapies in T1D (1). This study explored whether combining genetic data with circulating blood proteomics at birth can identify stable and infancy-specific pQTLs, which could be used as early-life biomarkers and provide mechanistic insights into T1D.

Circulating protein levels were measured by the Olink Explore panel in dried blood spots collected from 695 newborns enrolled in the GPPAD POInT trial (2). These newborns were at genetically increased risk of developing T1D. Imputed genotype data were also available for the same newborns, enabling the integration of genetic and proteomic information.

After quality control, 1,985 proteins were retained for analyses. A GWAS analysis identified 535 pQTL, including 352 cis-pQTLs (variants near the encoding gene) and 183 trans-pQTLs (variants distant from the gene). These findings showed good concordance with pQTLs in adults. Of note, 62 novel, newborn specific pQTLs enriched for the insulin signalling pathway were identified.

Colocalization analyses revealed that pQTLs for 5 proteins aligned with T1D GWAS risk loci: CTRB1, APOBR, IL7R, CPA1, and PNLIPRP1. Importantly, Mendelian randomization analysis suggested that these 5 proteins may each play a causal role in the development of T1D.

Although these findings need to be replicated and validated in larger, more diverse cohorts, they suggest that newborn blood protein profiles may aid in identifying potential drug targets and support the development of early-life diagnostics.

References: 1. Joglekar MV, Kaur S, Pociot F, Hardikar AA. Prediction of progression to type 1 diabetes with dynamic biomarkers and risk scores. Lancet Diabetes Endocrinol. 2024;12(7):483-92.2. Ziegler AG, Achenbach P, Berner R, et al. Oral insulin therapy for primary prevention of type 1 diabetes in infants with high genetic risk: the GPPAD-POInT (global platform for the prevention of autoimmune diabetes primary oral insulin trial) study protocol. BMJ Open 2019;9(6):e028578.