Abstract 219: Tissue-Specific RNAseq Identifies Novel and Cardiometabolic Disease--Associated Long Intergenic Noncoding RNAs in Human Adipose
Objective: The purpose is to identify novel long intergenic noncoding RNAs (lincRNAs) in human adipose, examine the association of their genetic variants with cardiometabolic traits, and explore their function in adipocytes.
Methods and results: We performed deep high-throughput RNAseq (>200 million reads/sample) in adipose tissues of 13 volunteers. Of 54,944 human lincRNAs, 6,558 were detected in adipose. We utilized multiple GWAS meta-analysis of adipose-related cardiometabolic traits (e.g. BMI, triglyceride and HDL cholesterol) and interrogated 6,558 adipose LincRNAs for their overlap with GWAS SNPs. After performing Bonferroni correction for the number of adipose lincRNA SNPs tested, we identified 46 SNPs in 9 lincRNAs, 28 SNPs in 13 lincRNAs and 13 SNPs in 6 lincRNAs that were significantly associated with waist-hip ratio adjusted BMI, HDL and triglyceride respectively. Notably, RP11-392O17.1, more abundantly expressed in adipose, and linc-NFE2L3-1, predominantly detected in adipose and skeleton muscle, contain 22 and 4 SNPs reaching genome wide significance for BMI (lead SNPs rs12031603, P=2.15х10-9 and rs10267498, P=2.73х10-8 respectively). Linkage disequilibrium analysis confirmed RP11-392O17.1 and linc-NFE2L3-1 harbor the strongest GWAS signals in the loci, suggesting causality for GWAS association with BMI. Several adipose lincRNAs, including RP11-392O17.1, linc-NFE2L3-1 and linc-AQPEP, were induced during in vitro human adipocyte differentiation. As an example of adipose lincRNA functional impacts, Linc-AQPEP, an abundant adipose-specific lincRNA, was knocked down by 70% with lentiviral-based short hairpin RNAs, resulting in ~35% decrease of triglyceride content in human adipocytes. RNAseq analysis demonstrated differential expression (DE) in 3,291 of 13,653 adipocyte genes with Linc-AQPEP knockdown (FDR<0.01) and significant enrichments of DE genes in lipid biosynthesis, fatty acid metabolism and mitochondrion pathways. Additional studies are ongoing to further investigate biological roles of human lincRNAs in adipocytes.
Conclusion: Our data suggest human LincRNAs may play specific roles in adipocyte biology and that their genetic variations may contribute to cardiometabolic traits.
Author Disclosures: X. Zhang: None. R. Ballantyne: None. J.F. Ferguson: None. C. Xue: None. S. Gosai: None. B. Gregory: None. M. Li: None. M.P. Reilly: None.
- © 2014 by American Heart Association, Inc.