Genetic regulation of the plasma proteome and its link to cardiometabolic disease in Greenlandic Inuit.
Sara E Stinson, Renzo F Balboa, Mette K Andersen, Frederik F Stæger, Shixu He, Anne Cathrine Baun Thuesen, Long Lin, Emil Jørsboe, Peter Bjerregaard, Christina V L Larsen, Niels Grarup, Marit E Jørgensen, Ida Moltke, Anders Albrechtsen, Torben Hansen
Abstract
Open AccessCirculating proteins play essential roles in complex diseases, yet protein quantitative trait locus (pQTL) studies in non-European, isolated populations remain limited. We analyzed genotypes and plasma proteomics data (Olink Target 96 Inflammation and Cardiovascular II panels) from 3,707 Greenlandic individuals (mean age: 47.9 years; 54.5% female), using linear mixed models to account for relatedness and population structure. Among 177 proteins, we identified 251 primary pQTLs-235 additive (84 cis, 8 semi-cis, 12 semi-trans, and 131 trans) and 16 recessive (1 cis, 2 semi-trans, and 13 trans)-48 secondary pQTLs, and 70 (28%) novel associations. Several common pQTLs in Greenlanders explained a substantial proportion of variance in protein levels (>30% for interleukin [IL]-27, IgG Fc receptor II-b, IL-16, and Galectin-9) compared to Europeans. A novel cis pQTL for IL-6 (rs7802307) was associated with increased cardiovascular disease risk based on registry data. Associations between Arctic-enriched variants in CPT1A (rs80356779), HNF1A (rs2135845768), TBC1D4 (rs61736969), LDLR (rs730882082), and PCSK9 (rs4609471) and altered protein abundance provide mechanistic insights into cardiometabolic disease in this population. These findings underscore the importance of pQTL studies in genetically diverse populations.