Abstract
To understand how miRNAs contribute to the molecular phenotype of adipose tissues and related traits, we performed global miRNA expression profiling in subcutaneous abdominal and gluteal adipose tissue of 70 human subjects and characterised which miRNAs were differentially expressed between these tissues. We found that 12% of the miRNAs were significantly differentially expressed between abdominal and gluteal adipose tissue (FDR adjusted p<0.05) in the primary study, of which 59 replicated in a follow-up study of 40 additional subjects. Further, 14 miRNAs were found to be associated with metabolic syndrome case-control status in abdominal tissue and three of these replicated (primary study: FDR adjusted p<0.05, replication: p<0.05 and directionally consistent effect). Genome-wide genotyping was performed in the 70 subjects to enable miRNA expression quantitative trait loci (eQTL) analysis. Candidate miRNA eQTLs were followed-up in the additional 40 subjects and six significant, independent cis-located miRNA eQTLs (primary study: p<0.001; replication: p<0.05 and directionally consistent effect) were identified. Finally, global mRNA expression profiling was performed in both tissues to enable association analysis between miRNA and target mRNA expression levels. We find 22% miRNAs in abdominal and 9% miRNAs in gluteal adipose tissue with expression levels significantly associated with the expression of corresponding target mRNAs (FDR adjusted p<0.05). Taken together, our results indicate a clear difference in the miRNA molecular phenotypic profile of abdominal and gluteal adipose tissue, that the expressions of some miRNAs are influenced by cis-located genetic variants and that miRNAs are associated with expression levels of their predicted mRNA targets.
Highlights
Different adipose depots have distinct endocrine and physiological properties [1,2,3]; increased amounts of abdominal adipose tissue are associated with an adverse metabolic risk while gluteal adipose tissue appears to have a relatively protective role with respect to type 2 diabetes (T2D), hypertension and dyslipidaemia [4,5]
To investigate whether any of the five miRNA expression quantitative trait loci (eQTL) Single Nucleotide Polymorphism (SNP) were directly associated with obesity phenotypes, we looked up association pvalues in a genome-wide association study with 113,636 subjects from the GIANT consortium) [33,34]
To determine the general functional characteristics of the miRNA-related activity in each adipose tissue type, we looked at miRNAs that were significantly associated with their mRNA targets, and tested whether or not there was an enrichment of specific KEGG [39] terms in each tissue
Summary
Different adipose depots have distinct endocrine and physiological properties [1,2,3]; increased amounts of abdominal adipose tissue are associated with an adverse metabolic risk while gluteal adipose tissue appears to have a relatively protective role with respect to type 2 diabetes (T2D), hypertension and dyslipidaemia [4,5]. Formation of the miRNA:mRNA complex results in either increased degradation of the target mRNA molecule [6], or alternatively, inhibition of target mRNA translation [7,8,9] Through these mechanisms, miRNAs have been predicted to affect the regulation of up to 30% of protein coding genes in mammals [8] and are involved in regulating a broad set of cellular processes [10,11]. We studied global miRNA expression in gluteal and abdominal adipose tissues in 70 human subjects in the MolOBB study (41 healthy controls and 29 metabolic syndrome cases, see Materials and Methods), with the objective of characterising the global miRNA molecular phenotypic profile in these two adipose depots. All subject in the study were SNP genotyped and miRNA eQTL analysis was carried out, in order to assess whether miRNA expression levels are genetically driven
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