Genetic regulation of the plasma proteome and its link to cardiometabolic disease in Greenlandic Inuit

Background Circulating proteins play essential roles in numerous complex diseases, yet our understanding of the genetic influences on inflammation and cardiovascular-related proteins in non-European isolated populations remains sparse. Here, we aimed to characterise the genetic architecture of plasma protein biomarkers in the Greenlandic population. Methods Using combined data from Greenlandic population cohorts (n=3,707 individuals), including genotypes and plasma proteomics (177 proteins) from Olink Target 96 Inflammation and Cardiovascular II panels, we performed a protein quantitative trait loci (pQTL) study using a linear mixed model, accounting for relatedness and population structure. Findings Mapping of 177 plasma proteins in 3,707 adult Greenlandic individuals (mean age 47.9; 54.5% female) reveal 251 primary pQTLs, 235 additive (92 cis and 143 trans) and 16 recessive (1 cis and 15 trans), 48 secondary pQTLs, and 70 novel pQTLs (28%). We demonstrate a higher proportion of variance in protein levels explained in Greenlanders compared to Europeans from the UK Biobank (e.g. IL-27, IgGFcRII-b, IL-16, and Gal-9). We describe changes in expression of inflammation and cardiovascular-related proteins associated with known high impact Arctic-specific variants, including in CPT1A, TBC1D4, HNF1A, LDLR, and PCSK9. Interpretation These findings highlight the importance of genome-wide plasma proteomic analyses in Greenlanders, and diverse populations in general, with implications for biomarker and therapeutic target development. Funding Novo Nordisk Foundation, The Independent Research Fund Denmark, and Karen Elise Jensen Foundation.