Advertisement

Multiple microRNA regulation of lipoprotein lipase gene abolished by 3′UTR polymorphisms in a triglyceride-lowering haplotype harboring p.Ser474Ter

  • Cyrielle Caussy
    Affiliations
    Hospices Civils de Lyon, Hôpital Louis Pradel, Fédération d'endocrinologie, maladies métaboliques, diabète et nutrition, 28 Avenue Doyen Lépine, Bron Cedex F-69677, France

    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, Bâtiment IMBL, INSA-Lyon, 11 Avenue Jean Capelle, 69621 Villeurbanne Cedex, France
    Search for articles by this author
  • Sybil Charrière
    Correspondence
    Corresponding author. Fédération d'endocrinologie, maladies métaboliques, diabète et nutrition, Hôpital Louis Pradel, 28 Avenue Doyen Lépine, 69677 Bron Cedex, France.
    Affiliations
    Hospices Civils de Lyon, Hôpital Louis Pradel, Fédération d'endocrinologie, maladies métaboliques, diabète et nutrition, 28 Avenue Doyen Lépine, Bron Cedex F-69677, France

    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, Bâtiment IMBL, INSA-Lyon, 11 Avenue Jean Capelle, 69621 Villeurbanne Cedex, France
    Search for articles by this author
  • Aline Meirhaeghe
    Affiliations
    INSERM, U1167, Institut Pasteur de Lille, Université de Lille, 1 rue du Pr. Calmette, BP 245, F-59019 Lille Cedex, France
    Search for articles by this author
  • Jean Dallongeville
    Affiliations
    INSERM, U1167, Institut Pasteur de Lille, Université de Lille, 1 rue du Pr. Calmette, BP 245, F-59019 Lille Cedex, France
    Search for articles by this author
  • Etienne Lefai
    Affiliations
    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, Bâtiment IMBL, INSA-Lyon, 11 Avenue Jean Capelle, 69621 Villeurbanne Cedex, France
    Search for articles by this author
  • Sophie Rome
    Affiliations
    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, Bâtiment IMBL, INSA-Lyon, 11 Avenue Jean Capelle, 69621 Villeurbanne Cedex, France
    Search for articles by this author
  • Charlotte Cuerq
    Affiliations
    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, Bâtiment IMBL, INSA-Lyon, 11 Avenue Jean Capelle, 69621 Villeurbanne Cedex, France

    Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Centre de Biologie Sud, Laboratoire de Biochimie moléculaire et métabolique, 165 chemin du Grand Revoyet, Pierre-Bénite Cedex F-69495, France
    Search for articles by this author
  • Vanessa Euthine
    Affiliations
    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, Bâtiment IMBL, INSA-Lyon, 11 Avenue Jean Capelle, 69621 Villeurbanne Cedex, France
    Search for articles by this author
  • Mireille Delay
    Affiliations
    Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Centre de Biologie Sud, Laboratoire de Biochimie moléculaire et métabolique, 165 chemin du Grand Revoyet, Pierre-Bénite Cedex F-69495, France
    Search for articles by this author
  • Oriane Marmontel
    Affiliations
    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, Bâtiment IMBL, INSA-Lyon, 11 Avenue Jean Capelle, 69621 Villeurbanne Cedex, France

    Hospices Civils de Lyon, Centre de Biologie et de Pathologie Est, Département de biochimie et biologie moléculaire, 59 Boulevard Pinel, Bron Cedex F-69677, France
    Search for articles by this author
  • Mathilde Di Filippo
    Affiliations
    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, Bâtiment IMBL, INSA-Lyon, 11 Avenue Jean Capelle, 69621 Villeurbanne Cedex, France

    Hospices Civils de Lyon, Centre de Biologie et de Pathologie Est, Département de biochimie et biologie moléculaire, 59 Boulevard Pinel, Bron Cedex F-69677, France
    Search for articles by this author
  • Michel Lagarde
    Affiliations
    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, Bâtiment IMBL, INSA-Lyon, 11 Avenue Jean Capelle, 69621 Villeurbanne Cedex, France
    Search for articles by this author
  • Philippe Moulin
    Affiliations
    Hospices Civils de Lyon, Hôpital Louis Pradel, Fédération d'endocrinologie, maladies métaboliques, diabète et nutrition, 28 Avenue Doyen Lépine, Bron Cedex F-69677, France

    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, Bâtiment IMBL, INSA-Lyon, 11 Avenue Jean Capelle, 69621 Villeurbanne Cedex, France

    CENS, Centre de Recherche en Nutrition Humaine Rhône-Alpes, Centre Hospitalier Lyon Sud, 165 chemin du Grand Revoyet, 69310 Pierre-Bénite, France
    Search for articles by this author
  • Christophe Marçais
    Affiliations
    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, Bâtiment IMBL, INSA-Lyon, 11 Avenue Jean Capelle, 69621 Villeurbanne Cedex, France

    Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Centre de Biologie Sud, Laboratoire de Biochimie moléculaire et métabolique, 165 chemin du Grand Revoyet, Pierre-Bénite Cedex F-69495, France

    CENS, Centre de Recherche en Nutrition Humaine Rhône-Alpes, Centre Hospitalier Lyon Sud, 165 chemin du Grand Revoyet, 69310 Pierre-Bénite, France
    Search for articles by this author

      Highlights

      • A LPL 3′UTR haplotype (Hap4) is associated with lower triglyceride concentrations.
      • This LPL Haplotype 4 induces a loss of several functional microRNA binding sites.
      • The p.Ser474Ter hypoTG effect could be due to its linkage disequilibrium with Hap4.

      Abstract

      Background

      Lipoprotein lipase (LPL) is a key enzyme in triglyceride (TG) metabolism. LPL gene single nucleotide polymorphisms (SNPs) are associated with TG concentrations however the functionality of many of these SNPs remains poorly understood. MicroRNAs (miR) exert post-transcriptional down-regulation and their target sequence on the 3′UTR may be altered by SNPs. We therefore investigated whether LPL 3′UTR SNPs could modulate plasma TG concentration through the alteration of miR binding-sites.

      Methods and results

      We performed genetic association studies of LPL 3′UTR SNPs with TG concentrations in 271 type 2 diabetic patients and in general population samples (2997 individuals). A specific LPL haplotype (Hap4) was associated with lower plasma TG concentration (TG-0.18, IC95% [−0.30, −0.07] mmol/L or logTG-0.13, IC95% [−0.18, −0.08], p = 4.77·10−8) in the meta-analysis. Hap4 comprises seven 3′UTR SNP minor alleles and p.Ser474Ter (rs328) a well-documented nonsense mutation associated with low TG concentration although by an unknown mechanism so far. Bio-informatic studies identified several putative miRNA binding-sites on the wild-type Hap1 haplotype, lost on Hap4. Functional validation performed in HEK-293T cells using luciferase expression constructs with various LPL 3′UTR allele combinations demonstrated a binding of miR-29, miR-1277 and miR-410 on Hap1, lost on Hap4. This loss of specific miR binding-site in presence of Hap4 was independent of the allelic variation of p.Ser474Ter (rs328).

      Conclusions

      We report the regulation of LPL by the miR-29, miR-1277 and miR-410 that is lost in presence of Hap4, a specific LPL TG-lowering haplotype. Consequently p.Ser474Ter association with TG concentration could be at least partially explained by its strong linkage disequilibrium with these functional 3′UTR SNPs.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Li Y.
        • He P.-P.
        • Zhang D.-W.
        • et al.
        Lipoprotein lipase: from gene to atherosclerosis.
        Atherosclerosis. 2014; 237: 597-608https://doi.org/10.1016/j.atherosclerosis.2014.10.016
        • Hensley L.L.
        • Ranganathan G.
        • Wagner E.M.
        • et al.
        Transgenic mice expressing lipoprotein lipase in adipose tissue. absence of the proximal 3’-untranslated region causes translational upregulation.
        J. Biol. Chem. 2003; 278: 32702-32709https://doi.org/10.1074/jbc.M304200200
        • Ranganathan G.
        • Vu D.
        • Kern P.A.
        Translational regulation of lipoprotein lipase by epinephrine involves a trans-acting binding protein interacting with the 3’ untranslated region.
        J. Biol. Chem. 1997; 272: 2515-2519
        • Bartel D.P.
        MicroRNAs: genomics, biogenesis, mechanism, and function.
        Cell. 2004; 116: 281-297
        • Richardson K.
        • Nettleton J.A.
        • Rotllan N.
        • et al.
        Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site.
        Am. J. Hum. Genet. 2013; 92: 5-14https://doi.org/10.1016/j.ajhg.2012.10.020
        • Gong J.
        • Tong Y.
        • Zhang H.-M.
        • et al.
        Genome-wide identification of SNPs in microRNA genes and the SNP effects on microRNA target binding and biogenesis.
        Hum. Mutat. 2012; 33: 254-263https://doi.org/10.1002/humu.21641
        • Caussy C.
        • Charrière S.
        • Marçais C.
        • et al.
        An APOA5 3’ UTR variant associated with plasma triglycerides triggers APOA5 downregulation by creating a functional miR-485-5p binding site.
        Am. J. Hum. Genet. 2014; 94: 129-134https://doi.org/10.1016/j.ajhg.2013.12.001
        • Kraja A.T.
        • Vaidya D.
        • Pankow J.S.
        • et al.
        A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium.
        Diabetes. 2011; 60: 1329-1339https://doi.org/10.2337/db10-1011
        • Kathiresan S.
        • Manning A.K.
        • Demissie S.
        • et al.
        A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study.
        BMC Med. Genet. 2007; 8: S17https://doi.org/10.1186/1471-2350-8-S1-S17
        • Middelberg R.P.S.
        • Ferreira M.A.R.
        • Henders A.K.
        • et al.
        Genetic variants in LPL, OASL and TOMM40/APOE-C1-C2-C4 genes are associated with multiple cardiovascular-related traits.
        BMC Med. Genet. 2011; 12: 123https://doi.org/10.1186/1471-2350-12-123
        • Rip J.
        • Nierman M.C.
        • Ross C.J.
        • et al.
        Lipoprotein lipase S447X: a naturally occurring gain-of-function mutation.
        Arterioscler. Thromb. Vasc. Biol. 2006; 26: 1236-1245https://doi.org/10.1161/01.ATV.0000219283.10832.43
        • Groenemeijer B.E.
        • Hallman M.D.
        • Reymer P.W.
        • et al.
        Genetic variant showing a positive interaction with beta-blocking agents with a beneficial influence on lipoprotein lipase activity, HDL cholesterol, and triglyceride levels in coronary artery disease patients. The Ser447-stop substitution in the lipoprotein lipase gene. REGRESS Study Group.
        Circulation. 1997; 95: 2628-2635
        • Ross C.J.D.
        • Liu G.
        • Kuivenhoven J.A.
        • et al.
        Complete rescue of lipoprotein lipase-deficient mice by somatic gene transfer of the naturally occurring LPLS447X beneficial mutation.
        Arterioscler. Thromb. Vasc. Biol. 2005; 25: 2143-2150https://doi.org/10.1161/01.ATV.0000176971.27302.b0
        • Bernard S.
        • Sérusclat A.
        • Targe F.
        • et al.
        Incremental predictive value of carotid ultrasonography in the assessment of coronary risk in a cohort of asymptomatic type 2 diabetic subjects.
        Diabetes Care. 2005; 28: 1158-1162
        • Charriere S.
        • Bernard S.
        • Aqallal M.
        • et al.
        Association of APOA5 -1131T>C and S19W gene polymorphisms with both mild hypertriglyceridemia and hyperchylomicronemia in type 2 diabetic patients.
        Clin. Chim. Acta Int. J. Clin. Chem. 2008; 394: 99-103https://doi.org/10.1016/j.cca.2008.04.013
        • Marçais C.
        • Bernard S.
        • Merlin M.
        • et al.
        Severe hypertriglyceridaemia in type II diabetes: involvement of apoC-III Sst-I polymorphism, LPL mutations and apo E3 deficiency.
        Diabetologia. 2000; 43: 1346-1352https://doi.org/10.1007/s001250051537
        • Stephens M.
        • Smith N.J.
        • Donnelly P.
        A new statistical method for haplotype reconstruction from population data.
        Am. J. Hum. Genet. 2001; 68: 978-989https://doi.org/10.1086/319501
        • Meirhaeghe A.
        • Helbecque N.
        • Cottel D.
        • Amouyel P.
        Impact of polymorphisms of the human beta2-adrenoceptor gene on obesity in a French population.
        Int. J. Obes. Relat. Metab. Disord. J. Int. Assoc. Study Obes. 2000; 24: 382-387
        • Goumidi L.
        • Cottel D.
        • Dallongeville J.
        • Amouyel P.
        • Meirhaeghe A.
        Effects of established BMI-associated loci on obesity-related traits in a French representative population sample.
        BMC Genet. 2014; 15: 62https://doi.org/10.1186/1471-2156-15-62
        • Luc G.
        • Empana J.-P.
        • Morange P.
        • et al.
        Adipocytokines and the risk of coronary heart disease in healthy middle aged men: the PRIME Study.
        Int. J. Obes. 2010; 34: 118-126https://doi.org/10.1038/ijo.2009.204
        • Kertesz M.
        • Iovino N.
        • Unnerstall U.
        • Gaul U.
        • Segal E.
        The role of site accessibility in microRNA target recognition.
        Nat. Genet. 2007; 39: 1278-1284https://doi.org/10.1038/ng2135
        • Enright A.J.
        • John B.
        • Gaul U.
        • Tuschl T.
        • Sander C.
        • Marks D.S.
        MicroRNA targets in Drosophila.
        Genome Biol. 2003; 5: R1https://doi.org/10.1186/gb-2003-5-1-r1
        • Goodarzi M.O.
        • Wong H.
        • Quiñones M.J.
        • et al.
        The 3’ untranslated region of the lipoprotein lipase gene: haplotype structure and association with post-heparin plasma lipase activity.
        J. Clin. Endocrinol. Metab. 2005; 90: 4816-4823https://doi.org/10.1210/jc.2005-0389
        • Smith A.J.P.
        • Palmen J.
        • Putt W.
        • Talmud P.J.
        • Humphries S.E.
        • Drenos F.
        Application of statistical and functional methodologies for the investigation of genetic determinants of coronary heart disease biomarkers: lipoprotein lipase genotype and plasma triglycerides as an exemplar.
        Hum. Mol. Genet. 2010; 19: 3936-3947https://doi.org/10.1093/hmg/ddq308
        • Tang W.
        • Apostol G.
        • Schreiner P.J.
        • Jacobs D.R.
        • Boerwinkle E.
        • Fornage M.
        Associations of lipoprotein lipase gene polymorphisms with longitudinal plasma lipid trends in young adults: the Coronary Artery Risk Development in Young Adults (CARDIA) study.
        Circ. Cardiovasc. Genet. 2010; 3: 179-186https://doi.org/10.1161/CIRCGENETICS.109.913426
        • Lanktree M.B.
        • Anand S.S.
        • Yusuf S.
        • Hegele R.A.
        • SHARE Investigators
        Replication of genetic associations with plasma lipoprotein traits in a multiethnic sample.
        J. Lipid Res. 2009; 50: 1487-1496https://doi.org/10.1194/jlr.P900008-JLR200
        • Evans D.
        • Beil F.U.
        • Aberle J.
        Resequencing the untranslated regions of the lipoprotein lipase (LPL) gene reveals that variants in microRNA target sequences are associated with triglyceride levels.
        J. Clin. Lipidol. 2013; 7: 610-614https://doi.org/10.1016/j.jacl.2013.09.006
        • Garcia-Rios A.
        • Delgado-Lista J.
        • Perez-Martinez P.
        • et al.
        Genetic variations at the lipoprotein lipase gene influence plasma lipid concentrations and interact with plasma n-6 polyunsaturated fatty acids to modulate lipid metabolism.
        Atherosclerosis. 2011; 218: 416-422https://doi.org/10.1016/j.atherosclerosis.2011.07.092
        • Mo X.
        • Liu X.
        • Wang L.
        • et al.
        Lipoprotein lipase gene polymorphism rs1059611 functionally influences serum lipid concentrations.
        Atherosclerosis. 2013; 229: 511-516https://doi.org/10.1016/j.atherosclerosis.2013.05.005
        • Krek A.
        • Grün D.
        • Poy M.N.
        • et al.
        Combinatorial microRNA target predictions.
        Nat. Genet. 2005; 37: 495-500https://doi.org/10.1038/ng1536
        • John B.
        • Enright A.J.
        • Aravin A.
        • Tuschl T.
        • Sander C.
        • Marks D.S.
        Human microRNA targets.
        PLoS Biol. 2004; 2: e363https://doi.org/10.1371/journal.pbio.0020363
        • Zhang H.
        • Henderson H.
        • Gagne S.E.
        • et al.
        Common sequence variants of lipoprotein lipase: standardized studies of in vitro expression and catalytic function.
        Biochim. Biophys. Acta. 1996; 1302: 159-166
        • Turlo K.
        • Leung C.S.
        • Seo J.J.
        • et al.
        Equivalent binding of wild-type lipoprotein lipase (LPL) and S447X-LPL to GPIHBP1, the endothelial cell LPL transporter.
        Biochim. Biophys. Acta. 2014; 1841: 963-969https://doi.org/10.1016/j.bbalip.2014.03.011
        • Ranganathan G.
        • Unal R.
        • Pokrovskaya I.D.
        • et al.
        The lipoprotein lipase (LPL) S447X gain of function variant involves increased mRNA translation.
        Atherosclerosis. 2012; 221: 143-147https://doi.org/10.1016/j.atherosclerosis.2011.12.028
        • Deo R.C.
        • Reich D.
        • Tandon A.
        • et al.
        Genetic differences between the determinants of lipid profile phenotypes in African and European Americans: the Jackson Heart Study.
        PLoS Genet. 2009; 5: e1000342https://doi.org/10.1371/journal.pgen.1000342