Editors' ChoiceHuman Genetics

SORTing Out Lipids

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Science Translational Medicine  01 Sep 2010:
Vol. 2, Issue 47, pp. 47ec136
DOI: 10.1126/scitranslmed.3001624

To date, genome-wide association studies (GWASs) have identified over 800 DNA sequence variants that are strongly tied to over 150 polygenic traits. Many of these studies have illuminated previously unrecognized pathways in disease pathobiology. Two recent reports by Musunuru et al. and Teslovich et al. are exemplary of such transformative findings and clarify a highly heritable and important phenotype: plasma lipids. In the first, a GWAS meta-analysis assessed 2.6 million single -nucleotide polymorphisms (SNPs) in over 100,000 individuals from diverse ancestries and found an impressive 95 loci strongly linked to low-density lipoprotein (LDL), high-density lipoprotein (HDL), and plasma triglyceride concentrations. Of these, 59 were newly described, 39 were in previously established lipid-related genes, and 18 were in genes involved in classic Mendelian lipid disorders.

In an accompanying report, the investigators further defined the genomic region on chromosome 1p13, which was where the most significantly associated LDL SNP (rs12740374; P = 1 × 10–170) resided. This protective allele is in a noncoding region between two genes—CELSR2 and PSRC1—and near another gene, SORT1, which is a cell-surface receptor–sorting protein. Before this study, none of these genes were known to participate in lipid metabolism. Accordingly, the authors designed a set of rigorous experiments to determine conclusively which of these genes actually regulate plasma LDL and how they exert their effects. They first found that individuals that carried the protective SNP exhibited 12 times more liver SORT1 expression but showed no elevation in CELSR2. Second, enhanced binding of the liver-specific transcription factor CEBPA was seen in the promoter region of SORT1. Third, transfection of mice with human SORT1 resulted in substantially reduced concentrations of small dense and total LDL cholesterol, which mirrored the human phenotype. As final confirmation of SORT as the culprit gene, knockdown of SORT by means of small interfering RNA completely reversed the protective LDL phenotype. Together, these two studies incontrovertibly demonstrate that the most important common genetic contributor to plasma LDL concentrations acts through SORT1 by creating a binding site for a transcription factor. The power of integrating GWAS results with functional experiments to “SORT” out the complexities behind complex phenotypes is now clear.

K. Musunuru et al., From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 466, 714–719 (2010). [Abstract]

T. M. Teslovich et al., Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010). [Abstract]

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