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

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From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. / Musunuru, Kiran; Strong, Alanna; Frank-Kamenetsky, Maria; Lee, Noemi E.; Ahfeldt, Tim; Sachs, Katherine V.; Li, Xiaoyu; Li, Hui; Kuperwasser, Nicolas; Ruda, Vera M.; Pirruccello, James P.; Muchmore, Brian; Prokunina-Olsson, Ludmila; Hall, Jennifer L.; Schadt, Eric E.; Morales, Carlos R.; Lund-Katz, Sissel; Phillips, Michael C.; Wong, Jamie; Cantley, William; Racie, Timothy; Ejebe, Kenechi G.; Orho-Melander, Marju; Melander, Olle; Koteliansky, Victor; Fitzgerald, Kevin; Krauss, Ronald M.; Cowan, Chad A.; Kathiresan, Sekar; Rader, Daniel J.

In: Nature, Vol. 466, No. 7307, 2010, p. 714-U2.

Research output: Contribution to journalArticle

Harvard

Musunuru, K, Strong, A, Frank-Kamenetsky, M, Lee, NE, Ahfeldt, T, Sachs, KV, Li, X, Li, H, Kuperwasser, N, Ruda, VM, Pirruccello, JP, Muchmore, B, Prokunina-Olsson, L, Hall, JL, Schadt, EE, Morales, CR, Lund-Katz, S, Phillips, MC, Wong, J, Cantley, W, Racie, T, Ejebe, KG, Orho-Melander, M, Melander, O, Koteliansky, V, Fitzgerald, K, Krauss, RM, Cowan, CA, Kathiresan, S & Rader, DJ 2010, 'From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus', Nature, vol. 466, no. 7307, pp. 714-U2. https://doi.org/10.1038/nature09266

APA

Musunuru, K., Strong, A., Frank-Kamenetsky, M., Lee, N. E., Ahfeldt, T., Sachs, K. V., ... Rader, D. J. (2010). From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature, 466(7307), 714-U2. https://doi.org/10.1038/nature09266

CBE

Musunuru K, Strong A, Frank-Kamenetsky M, Lee NE, Ahfeldt T, Sachs KV, Li X, Li H, Kuperwasser N, Ruda VM, Pirruccello JP, Muchmore B, Prokunina-Olsson L, Hall JL, Schadt EE, Morales CR, Lund-Katz S, Phillips MC, Wong J, Cantley W, Racie T, Ejebe KG, Orho-Melander M, Melander O, Koteliansky V, Fitzgerald K, Krauss RM, Cowan CA, Kathiresan S, Rader DJ. 2010. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature. 466(7307):714-U2. https://doi.org/10.1038/nature09266

MLA

Vancouver

Musunuru K, Strong A, Frank-Kamenetsky M, Lee NE, Ahfeldt T, Sachs KV et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature. 2010;466(7307):714-U2. https://doi.org/10.1038/nature09266

Author

Musunuru, Kiran ; Strong, Alanna ; Frank-Kamenetsky, Maria ; Lee, Noemi E. ; Ahfeldt, Tim ; Sachs, Katherine V. ; Li, Xiaoyu ; Li, Hui ; Kuperwasser, Nicolas ; Ruda, Vera M. ; Pirruccello, James P. ; Muchmore, Brian ; Prokunina-Olsson, Ludmila ; Hall, Jennifer L. ; Schadt, Eric E. ; Morales, Carlos R. ; Lund-Katz, Sissel ; Phillips, Michael C. ; Wong, Jamie ; Cantley, William ; Racie, Timothy ; Ejebe, Kenechi G. ; Orho-Melander, Marju ; Melander, Olle ; Koteliansky, Victor ; Fitzgerald, Kevin ; Krauss, Ronald M. ; Cowan, Chad A. ; Kathiresan, Sekar ; Rader, Daniel J. / From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. In: Nature. 2010 ; Vol. 466, No. 7307. pp. 714-U2.

RIS

TY - JOUR

T1 - From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus

AU - Musunuru, Kiran

AU - Strong, Alanna

AU - Frank-Kamenetsky, Maria

AU - Lee, Noemi E.

AU - Ahfeldt, Tim

AU - Sachs, Katherine V.

AU - Li, Xiaoyu

AU - Li, Hui

AU - Kuperwasser, Nicolas

AU - Ruda, Vera M.

AU - Pirruccello, James P.

AU - Muchmore, Brian

AU - Prokunina-Olsson, Ludmila

AU - Hall, Jennifer L.

AU - Schadt, Eric E.

AU - Morales, Carlos R.

AU - Lund-Katz, Sissel

AU - Phillips, Michael C.

AU - Wong, Jamie

AU - Cantley, William

AU - Racie, Timothy

AU - Ejebe, Kenechi G.

AU - Orho-Melander, Marju

AU - Melander, Olle

AU - Koteliansky, Victor

AU - Fitzgerald, Kevin

AU - Krauss, Ronald M.

AU - Cowan, Chad A.

AU - Kathiresan, Sekar

AU - Rader, Daniel J.

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

U2 - 10.1038/nature09266

DO - 10.1038/nature09266

M3 - Article

VL - 466

SP - 714-U2

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7307

ER -