Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis

Alexandre Wagschal; S. Hani Najafi-Shoushtari; Lifeng Wang; Leigh Goedeke; Sumita Sinha; Andrew S. Delemos; Josh C. Black; Cristina M. Ramírez; Yingxia Li; Ryan Tewhey; Ida Hatoum; Naisha Shah; Yong Lu; Fjoralba Kristo; Nikolaos Psychogios; Vladimir Vrbanac; Yi Chien Lu; Timothy Hla; Rafael De Cabo; John S. Tsang; Eric Schadt; Pardis C. Sabeti; Sekar Kathiresan; David E. Cohen; Johnathan Whetstine; Raymond T. Chung; Carlos Fernández-Hernando; Lee M. Kaplan; Andre Bernards; Robert E. Gerszten; Anders M. Näär

doi:10.1038/nm.3980

Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis

Alexandre Wagschal, S. Hani Najafi-Shoushtari, Lifeng Wang, Leigh Goedeke, Sumita Sinha, Andrew S. Delemos, Josh C. Black, Cristina M. Ramírez, Yingxia Li, Ryan Tewhey, Ida Hatoum, Naisha Shah, Yong Lu, Fjoralba Kristo, Nikolaos Psychogios, Vladimir Vrbanac, Yi Chien Lu, Timothy Hla, Rafael De Cabo, John S. TsangEric Schadt, Pardis C. Sabeti, Sekar Kathiresan, David E. Cohen, Johnathan Whetstine, Raymond T. Chung, Carlos Fernández-Hernando, Lee M. Kaplan, Andre Bernards, Robert E. Gerszten, Anders M. Näär

Research output: Contribution to journal › Article › peer-review

223 Scopus citations

Abstract

Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet-fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.

Original language	English
Pages (from-to)	1290-1297
Number of pages	8
Journal	Nature Medicine
Volume	21
Issue number	11
DOIs	https://doi.org/10.1038/nm.3980
State	Published - Nov 1 2015
Externally published	Yes

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Wagschal, A., Najafi-Shoushtari, S. H., Wang, L., Goedeke, L., Sinha, S., Delemos, A. S., Black, J. C., Ramírez, C. M., Li, Y., Tewhey, R., Hatoum, I., Shah, N., Lu, Y., Kristo, F., Psychogios, N., Vrbanac, V., Lu, Y. C., Hla, T., De Cabo, R., ... Näär, A. M. (2015). Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. Nature Medicine, 21(11), 1290-1297. https://doi.org/10.1038/nm.3980

@article{b08b2079688f4558b16c42a377ac4461,

title = "Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis",

abstract = "Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet-fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.",

author = "Alexandre Wagschal and Najafi-Shoushtari, {S. Hani} and Lifeng Wang and Leigh Goedeke and Sumita Sinha and Delemos, {Andrew S.} and Black, {Josh C.} and Ram{\'i}rez, {Cristina M.} and Yingxia Li and Ryan Tewhey and Ida Hatoum and Naisha Shah and Yong Lu and Fjoralba Kristo and Nikolaos Psychogios and Vladimir Vrbanac and Lu, {Yi Chien} and Timothy Hla and {De Cabo}, Rafael and Tsang, {John S.} and Eric Schadt and Sabeti, {Pardis C.} and Sekar Kathiresan and Cohen, {David E.} and Johnathan Whetstine and Chung, {Raymond T.} and Carlos Fern{\'a}ndez-Hernando and Kaplan, {Lee M.} and Andre Bernards and Gerszten, {Robert E.} and N{\"a}{\"a}r, {Anders M.}",

year = "2015",

month = nov,

day = "1",

doi = "10.1038/nm.3980",

language = "English",

volume = "21",

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Wagschal, A, Najafi-Shoushtari, SH, Wang, L, Goedeke, L, Sinha, S, Delemos, AS, Black, JC, Ramírez, CM, Li, Y, Tewhey, R, Hatoum, I, Shah, N, Lu, Y, Kristo, F, Psychogios, N, Vrbanac, V, Lu, YC, Hla, T, De Cabo, R, Tsang, JS, Schadt, E, Sabeti, PC, Kathiresan, S, Cohen, DE, Whetstine, J, Chung, RT, Fernández-Hernando, C, Kaplan, LM, Bernards, A, Gerszten, RE & Näär, AM 2015, 'Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis', Nature Medicine, vol. 21, no. 11, pp. 1290-1297. https://doi.org/10.1038/nm.3980

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AU - Wagschal, Alexandre

AU - Najafi-Shoushtari, S. Hani

AU - Wang, Lifeng

AU - Goedeke, Leigh

AU - Sinha, Sumita

AU - Delemos, Andrew S.

AU - Black, Josh C.

AU - Ramírez, Cristina M.

AU - Li, Yingxia

AU - Tewhey, Ryan

AU - Hatoum, Ida

AU - Shah, Naisha

AU - Lu, Yong

AU - Kristo, Fjoralba

AU - Psychogios, Nikolaos

AU - Vrbanac, Vladimir

AU - Lu, Yi Chien

AU - Hla, Timothy

AU - De Cabo, Rafael

AU - Tsang, John S.

AU - Schadt, Eric

AU - Sabeti, Pardis C.

AU - Kathiresan, Sekar

AU - Cohen, David E.

AU - Whetstine, Johnathan

AU - Chung, Raymond T.

AU - Fernández-Hernando, Carlos

AU - Kaplan, Lee M.

AU - Bernards, Andre

AU - Gerszten, Robert E.

AU - Näär, Anders M.

PY - 2015/11/1

Y1 - 2015/11/1

N2 - Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet-fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.

AB - Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet-fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.

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DO - 10.1038/nm.3980

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EP - 1297

JO - Nature Medicine

JF - Nature Medicine

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ER -

Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis

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