RT Journal Article SR Electronic T1 An interaction map of circulating metabolites, immune gene networks and their genetic regulation JF bioRxiv FD Cold Spring Harbor Laboratory SP 089839 DO 10.1101/089839 A1 Artika P. Nath A1 Scott C. Ritchie A1 Sean G. Byars A1 Liam G. Fearnley A1 Aki S. Havulinna A1 Anni Joensuu A1 Antti J. Kangas A1 Pasi Soininen A1 Annika Wennerström A1 Lili Milani A1 Andres Metspalu A1 Satu Männistö A1 Peter Würtz A1 Johannes Kettunen A1 Emma Raitoharju A1 Mika Kähönen A1 Markus Juonala A1 Aarno Palotie A1 Mika Ala-Korpela A1 Samuli Ripatti A1 Terho Lehtimäki A1 Gad Abraham A1 Olli Raitakari A1 Veikko Salomaa A1 Markus Perola A1 Michael Inouye YR 2016 UL http://biorxiv.org/content/early/2016/11/26/089839.abstract AB The interaction between metabolism and the immune system plays a central role in many cardiometabolic diseases. We integrated blood transcriptomic, metabolomic, and genomic profiles from two population-based cohorts, including a subset with 7-year follow-up sampling. We identified topologically robust gene networks enriched for diverse immune functions including cytotoxicity, viral response, B cell, platelet, neutrophil, and mast cell/basophil activity. These immune gene modules showed complex patterns of association with 158 circulating metabolites, including lipoprotein subclasses, lipids, fatty acids, amino acids, and CRP. Genome-wide scans for module expression quantitative trait loci (mQTLs) revealed five modules with mQTLs of both cis and trans effects. The strongest mQTL was in ARHGEF3 (rs1354034) and affected a module enriched for platelet function. Mast cell/basophil and neutrophil function modules maintained their metabolite associations during 7-year follow-up, while our strongest mQTL in ARHGEF3 also displayed clear temporal stability. This study provides a detailed map of natural variation at the blood immuno-metabolic interface and its genetic basis, and facilitates subsequent studies to explain inter-individual variation in cardiometabolic disease.