Long Noncoding RNA TRIBAL Links the 8q24.13 Locus to Hepatic Lipid Metabolism and Coronary Artery Disease.

BACKGROUND

Genome-wide association studies identified a 20-Kb region of chromosome 8 (8q24.13) associated with plasma lipids, hepatic steatosis, and risk for coronary artery disease. The region is proximal to , and given its well-established role in lipid regulation in animal models, TRIB1 has been proposed to mediate the contribution of the 8q24.13 locus to these traits. This region overlaps a gene encoding the primate-specific long noncoding RNA transcript / (-associated locus), but the contribution of TRIBAL to coronary artery disease risk remains untested.

METHODS

Using recently available expression quantitative trait loci data and hepatocyte models, we further investigated this locus by Mendelian randomization analysis. Following antisense oligonucleotide targeting of TRIBAL, transcription array, quantitative reverse transcription polymerase chain reaction, and enrichment analyses were performed and effects on apoB and triglyceride secretion were determined.

RESULTS

Mendelian randomization analysis supports a causal relationship between genetically determined hepatic expression and markers of hepatic steatosis and coronary artery disease risk. By contrast, expression data sets did not support expression quantitative trait loci relationships between coronary artery disease-associated variants and . suppression reduced the expression of key regulators of triglyceride metabolism and bile acid synthesis. Enrichment analyses identified patterns consistent with impaired metabolic functions, including reduced triglyceride and cholesterol handling ability. Furthermore, suppression was associated with reduced hepatocyte secretion of triglycerides.

CONCLUSIONS

This work identifies as a gene bridging the genotype-phenotype relationship at the 8q24.13 locus with effects on genes regulating hepatocyte lipid metabolism and triglyceride secretion.