Type 2 Diabetes (T2D) is characterized by alteration in the circulatory levels of key inflammatory proteins, where our body strives to eliminate the perturbing factor through inflammation as a final resort to restore homeostasis. Plasma proteins play a crucial role to orchestrate this immune response. Over the past two decades, rigorous genetic efforts taken to comprehend T2D physiology have been partially successful and have left behind a dearth of knowledge of its causality. Here, we have investigated how the reported genetic variants of T2D are associated with circulatory levels of key plasma proteins. We identified 99 T2D genetic variants that serve as strong pQTL (protein Quantitative Trait Loci) for 72 plasma proteins, of which 4 proteins namely Small nuclear ribonucleoprotein F [SNRPF] (p = 2.99 × 10-14), Platelet endothelial cell adhesion molecule [PECAM1] (p = 1.9 × 10-45), Trypsin-2 [PRSS2] (p = 7.6 × 10-43) and Trypsin-3 [PRSS3] (p = 5.7 × 10-8) were previously not reported for association to T2D. The genes that encode these 72 proteins were observed to be highly expressed in at least one of the four T2D relevant tissues - liver, pancreas, adipose and whole blood. Comparative analysis of interactions of the studied proteins amongst these four tissues revealed distinct molecular connectivity. Assessment of biological function by gene-set enrichment highlighted innate immune system as the lead process enacted by the identified proteins (FDR q = 3.7 × 10-16). To validate the findings, we analyzed Coronary Artery Disease (CAD) and Rheumatoid Arthritis (RA) individually and as expected, we observed innate immune system as a top enriched pathway for RA but not for CAD. Our study illuminates strong regulation of plasma proteome by the established genetic variants of T2D.
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