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Circulation: Genomic and Precision Medicine

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Original Article

The WWOX Gene Modulates High-Density Lipoprotein and Lipid MetabolismClinical Perspective

Iulia Iatan, Hong Y. Choi, Isabelle Ruel, M.V. Prasad Linga Reddy, Hyunsuk Kil, Jaeho Lee, Mohammad Abu Odeh, Zaidoun Salah, Muhannad Abu-Remaileh, Daphna Weissglas-Volkov, Elina Nikkola, Mete Civelek, Zuhier Awan, Carlo M. Croce, Rami I. Aqeilan, Päivi Pajukanta, C. Marcelo Aldaz, Jacques Genest
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https://doi.org/10.1161/CIRCGENETICS.113.000248
Circulation: Genomic and Precision Medicine. 2014;7:491-504
Originally published May 28, 2014
Iulia Iatan
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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Hong Y. Choi
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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Isabelle Ruel
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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M.V. Prasad Linga Reddy
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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Hyunsuk Kil
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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Jaeho Lee
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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Mohammad Abu Odeh
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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Zaidoun Salah
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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Muhannad Abu-Remaileh
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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Daphna Weissglas-Volkov
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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Elina Nikkola
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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Mete Civelek
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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Zuhier Awan
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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Carlo M. Croce
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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Rami I. Aqeilan
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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Päivi Pajukanta
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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C. Marcelo Aldaz
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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Jacques Genest
From the Cardiovascular Research Laboratories, Department of Biochemistry, Faculty of Medicine, Division of Cardiology, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada (I.I., H.Y.C., I.R., Z.A., J.G.); Department of Human Genetics (M.V.P.L.R., D.W.-V., E.N., P.P.) and Department of Medicine (M.V.P.L.R., D.W.-V., E.N., P.P.), David Geffen School of Medicine at University of California at Los Angeles; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville (H.K., J.L., C.M.A.); The Lautenberg Cancer Research Center, Department of Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel (M.A.O., M.A.-R., R.I.A.); The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel and Al-Quds-Bard College for Arts and Sciences, Al-Quds University, East Jerusalem-Abu Dis, Palestine (Z.S.); and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus (M.C., C.M.C., R.I.A.).
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Abstract

Background—Low levels of high-density lipoprotein (HDL) cholesterol constitutes a major risk factor for atherosclerosis. Recent studies from our group reported a genetic association between the WW domain-containing oxidoreductase (WWOX) gene and HDL cholesterol levels. Here, through next-generation resequencing, in vivo functional studies and gene microarray analyses, we investigated the role of WWOX in HDL and lipid metabolism.

Methods and Results—Using next-generation resequencing of the WWOX region, we first identified 8 variants significantly associated and perfectly segregating with the low-HDL trait in 2 multigenerational French Canadian dyslipidemic families. To understand in vivo functions of WWOX, we used liver-specific Wwoxhep−/− and total Wwox−/− mice models, where we found decreased ApoA-I and Abca1 levels in hepatic tissues. Analyses of lipoprotein profiles in Wwox−/−, but not Wwoxhep−/− littermates, also showed marked reductions in serum HDL cholesterol concentrations, concordant with the low-HDL findings observed in families. We next obtained evidence of a sex-specific effect in female Wwoxhep−/− mice, where microarray analyses revealed an increase in plasma triglycerides and altered lipid metabolic pathways. We further identified a significant reduction in ApoA-I and Lpl and an upregulation in Fas, Angptl4, and Lipg, suggesting that the effects of Wwox involve multiple pathways, including cholesterol homeostasis, ApoA-I/ABCA1 pathway, and fatty acid biosynthesis/triglyceride metabolism.

Conclusions—Our data indicate that WWOX disruption alters HDL and lipoprotein metabolism through several mechanisms and may account for the low-HDL phenotype observed in families expressing the WWOX variants. These findings thus describe a novel gene involved in cellular lipid homeostasis, which effects may impact atherosclerotic disease development.

  • ABCA1
  • Apolopoprotein A-I
  • cardiovascular diseases
  • genetics
  • HDL cholesterol
  • lipids
  • WWOX protein
  • Received July 3, 2013.
  • Accepted April 23, 2014.
  • © 2014 American Heart Association, Inc.
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August 2014, Volume 7, Issue 4
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    The WWOX Gene Modulates High-Density Lipoprotein and Lipid MetabolismClinical Perspective
    Iulia Iatan, Hong Y. Choi, Isabelle Ruel, M.V. Prasad Linga Reddy, Hyunsuk Kil, Jaeho Lee, Mohammad Abu Odeh, Zaidoun Salah, Muhannad Abu-Remaileh, Daphna Weissglas-Volkov, Elina Nikkola, Mete Civelek, Zuhier Awan, Carlo M. Croce, Rami I. Aqeilan, Päivi Pajukanta, C. Marcelo Aldaz and Jacques Genest
    Circulation: Genomic and Precision Medicine. 2014;7:491-504, originally published May 28, 2014
    https://doi.org/10.1161/CIRCGENETICS.113.000248

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    The WWOX Gene Modulates High-Density Lipoprotein and Lipid MetabolismClinical Perspective
    Iulia Iatan, Hong Y. Choi, Isabelle Ruel, M.V. Prasad Linga Reddy, Hyunsuk Kil, Jaeho Lee, Mohammad Abu Odeh, Zaidoun Salah, Muhannad Abu-Remaileh, Daphna Weissglas-Volkov, Elina Nikkola, Mete Civelek, Zuhier Awan, Carlo M. Croce, Rami I. Aqeilan, Päivi Pajukanta, C. Marcelo Aldaz and Jacques Genest
    Circulation: Genomic and Precision Medicine. 2014;7:491-504, originally published May 28, 2014
    https://doi.org/10.1161/CIRCGENETICS.113.000248
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