Research area: genomics

An interaction map of circulating metabolites, immune gene networks and their genetic regulation

Created on 13th February 2017

Artika P Nath ; Scott Ritchie; Sean G Byars ; Liam Fearnley; Aki Havulinna; Anni Joensuu ; Antti Vähäkangas; Pasi Soininen ; Annika Wennerstrom ; Lili Milani ; Andres Metspalu ; Satu Mannisto ; Peter Wurtz ; Johannes Kettunen ; Emma Raitoharju ; Mika Kahonen ; Markus Juonala ; Aarno Palotie ; Mika Ala-Korpela ; Samuli Ripatti ; Terho Lehtimaki ; Gad Abraham; Olli Raitakari ; Veikko Salomaa; Markus Perola; Michael Inouye

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.

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