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Coupling genetics with circulating blood proteomics at birth can identify stable and infancy-specific protein quantitative trait loci (pQTL). Such early-life biomarkers might help uncover mechanistic insights for certain diseases.
To use this approach to better understand the biology of type 1 diabetes (T1D), a German team constructed a genome-wide pQTL map of 1,985 proteins in 695 newborn babies (median age 2 days) at increased genetic risk of developing the condition.
They identified 535 pQTLs (352 cis-pQTLs, 183 trans-pQTLs), 62 of which were characteristic of newborns. They showed colocalization of pQTLs for CTRB1, APOBR, IL7R, CPA1, and PNLIPRP1 with T1D GWAS signals.
They wrote, “We have established a protocol for quantifying the levels of circulating proteins from dried blood spots in 695 newborn babies (N. females = 346; 49.78%) enrolled in the GPPAD POInT trial to identify post-natal proteomic signatures at birth and investigate their association with T1D. Imputed genotype data were also available for the same newborns.”
The study was published in Nature Communications; the lead author is Mauro Tutino, a staff scientist at the Institute of Translational Genomics, Helmholtz Zentrum München – German Research Center for Environmental Health.
Type 1 diabetes is a chronic, autoimmune disease characterized by the destruction of insulin-producing β-cells in the pancreas. It is often diagnosed during childhood and adolescence. Over one million U.S. adults alone are estimated to have the disease, and its incidence is increasing. Having T1D reduces quality of life, shortens life span, and causes cost-intensive treatment. New therapies and strategies to prevent T1D are needed.
Circulating proteins can provide insights into early disease mechanisms. The researchers wrote, “Advances in genomics and proteomics present new opportunities to better understand disease mechanisms and develop preventive therapies. Both Olink and SomaScan technologies have been employed to measure plasma protein levels in tens of thousands of individuals.”
By integrating genotype data available for the same individuals, hundreds of genetic variants have been linked to both protein levels (protein quantitative trait loci, or pQTL) and complex diseases. These findings provide a genetic anchor to explore potential causal relationships between protein levels and disease risk.
The researchers noted, “A major limitation of proteogenomic studies to date is their focus on adult cohorts. Consequently, the applicability of adult pQTL findings to earlier life stages, such as infancy, remains unproven. Moreover, these population-based studies might have missed disease-specific signals.”
The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) has been established to screen for neonates at increased risk of developing T1D and enroll them in clinical trials for early intervention strategies.
“By generating pQTL profiles and combining these with genetic colocalization and causal inference analyses, we aimed to identify key pathways and proteins involved in T1D. The insights gained from this research could serve as a solid foundation for developing therapeutic targets or repurposing existing drugs to prevent or treat T1D,” the German team wrote.