Abstract
BackgroundCardiometabolic (CM) risk factors are heritable and cluster in individuals. We hypothesized that CM risk factors are associated with multiple shared and unique mRNA and microRNA (miRNA) signatures. We examined associations of mRNA and miRNA levels with 6 CM traits: body mass index, HDL-cholesterol and triglycerides, fasting glucose, and systolic and diastolic blood pressures through cross-sectional analysis of 2812 Framingham Heart Study who had whole blood collection for RNA isolation for mRNA and miRNA expression studies and who consented to genetic research. We excluded participants taking medication for hypertension, dyslipidemia, or diabetes. We measured mRNA (n = 17,318; using the Affymetrix GeneChip Human Exon 1.0 ST Array) and miRNA (n = 315; using qRT-PCR) expression in whole blood. We used linear regression for mRNA analyses and a combination of linear and logistic regression for miRNA analyses. We conducted miRNA-mRNA coexpression and gene ontology enrichment analyses to explore relations between pleiotropic miRNAs, mRNA expression, and CM trait clustering.ResultsWe identified hundreds of significant associations between mRNAs, miRNAs, and individual CM traits. Four mRNAs (FAM13A, CSF2RB, HIST1H2AC, WNK1) were associated with all 6 CM traits (FDR < 0.001) and four miRNAs (miR-197-3p, miR-328, miR-505-5p, miR-145-5p) were associated with four CM traits (FDR < 0.05). Twelve mRNAs, including WNK1, that were coexpressed with the four most pleiotropic miRNAs, were also miRNA targets. mRNAs coexpressed with pleiotropic miRNAs were enriched for RNA metabolism (miR-505-5p), ubiquitin-dependent protein catabolism (miR-197-3p, miR-328) and chromatin assembly (miR-328).ConclusionsWe identified mRNA and miRNA signatures of individual CM traits and their clustering. Implicated transcripts may play causal roles in CM risk or be downstream consequences of CM risk factors on the transcriptome. Studies are needed to establish whether or not pleiotropic circulating transcripts illuminate causal pathways for CM risk.
Highlights
Cardiometabolic (CM) risk factors are heritable and cluster in individuals
TG was associated with the greatest number of circulating messenger RNA (mRNA) (N = 5049), followed by body mass index (BMI) (N = 4826), HDL-C (N = 1768), diastolic blood pressure (DBP) (N = 1499), SBP (N = 1019), and glucose (N = 1014)
Genes associated with BMI shared associations with other CM traits, most notably DBP, TG, and HDL-C. Genes associated with both BMI and TG and those associated with BMI and DBP were positively correlated, whereas genes associated with both BMI and HDL-C were, in general, inversely correlated
Summary
Cardiometabolic (CM) risk factors are heritable and cluster in individuals. We examined associations of mRNA and miRNA levels with 6 CM traits: body mass index, HDL-cholesterol and triglycerides, fasting glucose, and systolic and diastolic blood pressures through cross-sectional analysis of 2812 Framingham Heart Study who had whole blood collection for RNA isolation for mRNA and miRNA expression studies and who consented to genetic research. Metabolic risk factors cluster in individuals and their presence is associated with increased risk for type II diabetes mellitus (T2DM) and cardiovascular disease (CVD) [1, 2]. Genome-wide association studies (GWAS) have identified hundreds of loci associated with cardiometabolic (CM) risk factors including body mass index (BMI), lipid levels, glucose levels, T2DM, and blood pressure [1,2,3,4,5]. Integrative analyses that incorporate multidimensional genomic data are necessary to investigate and characterize complex changes in the regulatory machinery and their effects on biological functions and complex CM phenotypes [6, 7]
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