Talk 6
Presenter: Mete Civelek
Wednesday, 1:00pm

Genetic regulation of human adipose microRNA expression and its consequences for metabolic traits

Mete Civelek¹, Raffi Hagopian¹, Calvin Pan¹, Nam Che¹, Wen-pin Yang², Paul Kayne², Niyas K. Saleem³, Henna Cederberg³, Johanna Kuusisto³, Peter Gargalovic⁴, Todd Kirchgessner⁴, Markku Laakso³, Aldons J. Lusis^1,5,6
Departments of ¹Medicine, ⁵Human Genetics, ⁶Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA 90095, USA Departments of ²Applied Genomics, ⁴Cardiovascular Drug Discovery, Bristol-Myers Squibb, Pennington, NJ 08534, USA ³Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland

The genetics of messenger RNA expression has been extensively studied in humans and other organisms, but little is known about genetic factors contributing to microRNA (miRNA) expression. We examined natural variation of miRNA expression in adipose tissue in a population of 200 men who have been carefully characterized for metabolic syndrome phenotypes as part of the METSIM study. We genotyped the subjects using high-density SNP microarrays and quantified the mRNA abundance using genome-wide expression arrays and miRNA abundance using next generation sequencing. We reliably quantified 356 miRNA species that were expressed in human adipose tissue, a limited number of which made up most of the expressed miRNAs. We mapped the miRNA abundance as an expression quantitative trait and determined cis regulation of expression for 9 of the miRNAs and of the processing of one miRNA (miR-28). The degree of genetic variation of miRNA expression was substantially less than that of mRNAs. For the majority of the miRNAs, genetic regulation of expression was independent of the host mRNA transcript expression. We also showed that for 108 miRNAs, mapped reads displayed widespread variation from the canonical sequence. We found a total of 24 miRNAs to be significantly associated with metabolic syndrome traits. We suggest a regulatory role for miR-204-5p which was predicted to inhibit ACACB, a key fatty acid oxidation enzyme that has been shown to play a role in regulating body fat and insulin resistance in adipose tissue.