Abstract
Introduction: GlycA is a novel biomarker of systemic inflammation and cardiovasculardisease (CVD) risk. It is measured by a signal in the proton nuclear magnetic resonance(NMR) spectra (from the N-acetyl methyl groups of N-acetylglucosamine residues).Epidemiological studies have reported associations between GlycA and increased CVD risk.However, there are few investigations examining the link between GlycA levels and lifestylefactors (diet, physical activity (PA), sleep, etc.), gut microbiota, or genetics at the genome-wide level (GWAS); and even fewer studies have analyzed serum GlycA and genome-widemethylation (EWAS) or the effect of lifestyle intervention on the reduction of GlycA.Therefore, our aims were: i) to investigate lifestyle, genetic, and epigenetic factorsassociated with serum GlycA; ii) to examine changes in serum GlycA after 1-y lifestyleintervention in a Mediterranean population. Methods: Cross-sectional and lifestyleintervention analyses were undertaken in a Mediterranean population at highcardiovascular risk (n=426 older subjects with metabolic syndrome in the PREDIMED-Plus-Valencia trial; ISRCTN89898870). Lifestyle variables were assessed by validatedquestionnaire and quantile-g-computation methods were used to analyze their jointcontribution. Serum GlycA was measured by NMR spectroscopy. Genome-wide genotypingand DNA-methylation were determined by Illumina arrays (OmniExpress and EPIC).Exploratory omics-wide and targeted analyses on GlycA (focusing on autophagy genes andmicrobiome-host-related genes) were undertaken. Changes in serum GlycA levels after a 1-y lifestyle intervention (intensive intervention group with Mediterranean diet and PA versusthe control group) were assessed in a subset of participants. Results: GlycA levels atbaseline (Mean: 1.49+/-0.20 mmol/L) were significantly associated with branched-chainamino acids and a highly atherogenic lipid profile. Also, we obtained an association withdietary factors and PA. Omics analysis suggested novel SNPs (in SFMBT2- DAB1 and TEK)and methylation sites (CpG in RAD50, PPP1R9B, ZDHHC4 and LSP1) associated with GlycA. We also obtained associations with host-microbiome related SNPs in FUT2 and withmethylation signals in selected autophagy genes (STX7, TAX1BP1, ATG9B and ATG10).Moreover, in the intervention trial we detected a significant (P<0.05) decrease in the GlycAlevels after 1 y of intensive lifestyle intervention in comparison with the control group. Conclusions: Serum GlycA levels were strongly associated with cardiometabolic risk factorsin this Mediterranean population and linked to lifestyle variables. Additionally, we haveidentified some genetic and epigenetic factors related to GlycA that may modulate theselevels.
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