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From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus


Recent genome-wide association studies (GWASs) have identified a locus on chromosome 1p13 strongly associated with both plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) in humans. Here we show through a series of studies in human cohorts and human-derived hepatocytes that a common noncoding polymorphism at the 1p13 locus, rs12740374, creates a C/EBP (CCAAT/enhancer binding protein) transcription factor binding site and alters the hepatic expression of the SORT1 gene. With small interfering RNA (siRNA) knockdown and viral overexpression in mouse liver, we demonstrate that Sort1 alters plasma LDL-C and very low-density lipoprotein (VLDL) particle levels by modulating hepatic VLDL secretion. Thus, we provide functional evidence for a novel regulatory pathway for lipoprotein metabolism and suggest that modulation of this pathway may alter risk for MI in humans. We also demonstrate that common noncoding DNA variants identified by GWASs can directly contribute to clinical phenotypes.

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Figure 1: Human chromosome 1p13 locus is preferentially associated with very small LDL and liver gene expression.
Figure 2: rs12740374 is responsible for haplotype-specific difference in transcriptional activity.
Figure 3: rs12740374 alters a C/EBP transcription factor binding site.
Figure 4: Overexpression or knockdown of Sort1 in mouse liver alters plasma lipids and lipoproteins.


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We thank D. Altshuler, E. Fisher and J. Maraganore for advice and guidance, and A. Akinc, J. Billheimer, R. Brown, R. Camahort, D. Cromley, E. Eduoard, I. Fuki, C. Geaney, G. Hinkle, I. Kohaar, S. Kuchimanchi, W. Lagor, F. Lau, D. Lum, M. Maier, D. Marchadier, R. Meyers, J. Millar, S. Milstein, D. Nguyen, D. Perez, D. Peters, V. Redon, A. Rigamonti, R. Schinzel, M.-S. Sun, S.-A. Toh, A. Wilson and K. Wojnoonski for assistance and suggestions. We acknowledge the National Heart, Lung, and Blood Institute (NHLBI) Gene Therapy Resource Program for providing support for viral vector production as well as the Vector Core laboratory of the University of Pennsylvania for producing the vectors. We acknowledge the members of the NHLBI Candidate Gene Association Resource (CARe) lipids working group for the contribution of association data in African Americans. This work was supported in part by a T32 grant in Cell and Molecular Training for Cardiovascular Biology from the United States National Institutes of Health (NIH), K99-HL098364 from the NIH, and the Clinician Scientist Program of the Harvard Stem Cell Institute (K.M.); a Medical Scientist Training Program grant from the NIH (A.S.); the intramural research program of the Division of Cancer Epidemiology & Genetics, National Cancer Institute, NIH (L.P.-O.); the Swedish Medical Research Council, Heart-Lung Foundation, and Påhlsson Foundation (M.O.-M., O.M.); U01-HL069757 from the NIH and research support from Quest Diagnostics, Inc. (R.M.K.); RC2-HL101864 from the NIH (S.K.); and P01-HL059407 and RC2-HL101864 from the NIH and a “Freedom to Discover” Unrestricted Cardiovascular Research Grant from Bristol-Myers Squibb (D.J.R.).

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Authors and Affiliations



K.M., A.S., M.F.-K., N.E.L., T.A., K.V.S., X.L., H.L., N.K., V.M.R., J.J.P., B.M., L.P.-O., J.L.H., E.E.S., C.R.M., S.L.-K., M.C.P., J.W., W.C., T.R., K.G.E., M.O.-M., O.M. and R.M.K. carried out experimental work and/or performed data analysis. V.K., K.F., C.A.C., S.K. and D.J.R. supervised the study. K.M., A.S., S.K. and D.J.R. conceived and designed the study. K.M. wrote the manuscript.

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Correspondence to Sekar Kathiresan or Daniel J. Rader.

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Competing interests

Competing interests: M.F.-K., J.W., W.C., T.R., V.K. and K.F. are employees of Alnylam Pharmaceuticals. R.M.K. has received research support from Quest Diagnostics related to work presented in this manuscript The other authors declare no competing financial interests.

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Musunuru, K., Strong, A., Frank-Kamenetsky, M. et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 466, 714–719 (2010).

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