New genes with cholesterol-regulatory function identified

Scientists from EMBL Heidelberg and University of Heidelberg used RNAi–based functional profiling of loci from blood lipid genome-wide association studies to identify genes with cholesterol-regulatory function.

Complex traits and diseases are assumed to result from interactions between multiple genes in relevant biological processes. Recent genome-wide association studies have uncovered many novel genomic loci where genes with functional significance are expected. However, functional validation of such genes has thus far remained confined to single gene approaches. The researchers here used RNA interference and high-content screening microscopy to profile 133 genes at 56 loci associated with blood lipid traits, cardiovascular disease, and/or myocardial infarction for a function in regulating cellular free cholesterol levels and the efficiency of low-density lipoprotein uptake. The results suggest that a high number of trait-associated genes have conserved cholesterol-regulatory functions in cells, with several GWAS loci harboring more than one gene of likely functional significance. For a number of genes without previously known lipid-regulatory functions, consequences upon siRNA knockdown positively correlated with cellular levels of LDL receptor, a major determinant of blood LDL levels. Moreover, GFP–tagged fusion proteins of several candidates shifted cellular cholesterol levels to inverse directions than knockdown, and subcellular localization of some candidates was sterol-dependent. The study generates a valuable resource for prioritization of lipid-trait/CAD/MI-associated genes for future in-depth mechanistic analyses and introduces cell-based RNAi as a scalable and unbiased tool for functional follow-up of GWAS loci.

Copyright: CC Attribution licence.

Cover image: Modified figure from original publication.

References

Blattmann P, Schuberth C, Pepperkok R, Runz H (2013) RNAi–Based Functional Profiling of Loci from Blood Lipid Genome-Wide Association Studies Identifies Genes with Cholesterol-Regulatory Function. PLoS Genet 9(2): e1003338. DOI: 10.1371/journal.pgen.1003338.

Documents for download

• Full article by Blattmann et al.

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