Needles in the genetic haystack of lipid disorders: single nucleotide polymorphisms in the microRNA regulome

In recent years, microRNAs (miRNA) have emerged as important posttranscriptional regulators of gene expression in a wide variety of biological pathways. Since the discovery of the liver-specific miRNA-122 (miR-122) and its critical role in hepatic function, numerous additional miRNAs have been implicated in lipid metabolism. It is now apparent that lipid homeostasis is governed in part by an intricate web of miRNA activity. miRNAs are thought to confer robustness against environmental changes, such as diet modifications. Therefore, naturally occurring genetic variation that perturbs miRNA expression and/or function is likely to contribute to interindividual variability in lipid phenotypes. Although the field is still in its infancy, this review describes the growing evidence for miRNA-related genetic variation as etiological factors in lipid disorders. Specific examples, including a variant in a miRNA transcriptional control element that leads to dyslipidemia as well as a variant in a miRNA target site that modulates the effect of diet on plasma lipid levels, are discussed. Finally, the utility of recent systems genetics approaches to uncover hidden miRNA-related genetic associations with lipid disorders are considered, thereby illuminating the needles in the genetic haystack.