A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity
Por:
van der Lee, SJ, Conway, OJ, Jansen, I, Carrasquillo, MM, Kleineidam, L, van den Akker, E, Hernandez, I, van Eijk, KR, Stringa, N, Chen, JA, Zettergren, A, Andlauer, TFM, Diez-Fairen, M, Simon-Sanchez, J, Lleo, A, Zetterberg, H, Nygaard, M, Blauwendraat, C, Savage, JE, Mengel-From, J, Moreno-Grau, S, Wagner, M, Fortea, J, Keogh, MJ, Blennow, K, Skoog, I, Friese, MA, Pletnikova, O, Zulaica, M, Lage, C, de Rojas, I, Riedel-Heller, S, Illan-Gala, I, Wei, W, Jeune, B, Orellana, A, Bergh, FT, Wang, X, Hulsman, M, Beker, N, Tesi, N, Morris, CM, Indakoetxea, B, Collij, LE, Scherer, M, Morenas-Rodriguez, E, Ironside, JW, van Berckel, BNM, Alcolea, D, Wiendl, H, Strickland, SL, Pastor, P, Rodriguez Rodriguez, E, Boeve, BF, Petersen, RC, Ferman, TJ, van Gerpen, JA, Reinders, MJT, Uitti, RJ, Tarraga, L, Maier, W, Dols-Icardo, O, Kawalia, A, Dalmasso, MC, Boada, M, Zettl, UK, van Schoor, NM, Beekman, M, Allen, M, Masliah, E, de Munain, AL, Pantelyat, A, Wszolek, ZK, Ross, OA, Dickson, DW, Graff-Radford, NR, Knopman, D, Rademakers, R, Lemstra, AW, Pijnenburg, YAL, Scheltens, P, Gasser, T, Chinnery, PF, Hemmer, B, Huisman, MA, Troncoso, J, Moreno, F, Nohr, EA, Sorensen, TIA, Heutink, P, Sanchez-Juan, P, Posthuma, D, Clarimon, J, Christensen, K, Ertekin-Taner, N, Scholz, SW, Ramirez, A, Ruiz, A, Slagboom, E, van der Flier, WM, Holstege, H
Publicada:
1 ago 2019
Resumen:
The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLC gamma 2 pathway as drug-target.
Filiaciones:
van der Lee, SJ:
Vrije Univ Amsterdam, Dept Neurol, Alzheimer Ctr Amsterdam, Amsterdam Neurosci,Amsterdam UMC, Amsterdam, Netherlands
Vrije Univ Amsterdam, Dept Clin Genet, Amsterdam UMC, Amsterdam, Netherlands
Conway, OJ:
Mayo Clin Florida, Dept Neurosci, Jacksonville, FL 32224 USA
Jansen, I:
Vrije Univ Amsterdam, Dept Neurol, Alzheimer Ctr Amsterdam, Amsterdam Neurosci,Amsterdam UMC, Amsterdam, Netherlands
Vrije Univ Amsterdam, Dept Complex Trait Genet, Ctr Neurogen & Cognit Res, Amsterdam Neurosci,Amsterdam UMC, Amsterdam, Netherlands
Carrasquillo, MM:
Mayo Clin Florida, Dept Neurosci, Jacksonville, FL 32224 USA
Kleineidam, L:
Univ Bonn, Dept Neurodegenerat Dis & Geriatr Psychiat, Bonn, Germany
German Ctr Neurodegenerat Dis, DZNE, Bonn, Germany
Univ Hosp Cologne, Div Neurogenet & Mol Psychiat, Dept Psychiat & Psychotherapy, Fac Med, Cologne, Germany
van den Akker, E:
Leiden Univ, Mol Epidemiol, Med Ctr, Leiden, Netherlands
Delft Univ Technol, Pattern Recognit & Bioinformat, Delft, Netherlands
Hernandez, I:
Univ Int Catalunya, Res Ctr, Inst Catala Neurociencies Aplicades, Fundacio ACE, Barcelona, Spain
Univ Int Catalunya, Memory Clin, Inst Catala Neurociencies Aplicades, Fundacio ACE, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
van Eijk, KR:
Univ Med Ctr Utrecht, Dept Neurol, Brain Ctr Rudolf Magnus, Utrecht, Netherlands
Stringa, N:
Vrije Univ Amsterdam, Amsterdam UMC, Dept Epidemiol & Biostat, Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands
Chen, JA:
Univ Calif Los Angeles, Interdept Program Bioinformat, Los Angeles, CA USA
Zettergren, A:
Univ Gothenburg, Ctr Ageing & Hlth AgeCap, Sahlgrenska Acad,Inst Neurosci & Physiol, Neuropsychiat Epidemiol Unit,Dept Psychiat & Neur, Gothenburg, Sweden
Andlauer, TFM:
Max Planck Inst Psychiat, Munich, Germany
Tech Univ Munich, Dept Neurol, Klinikum Rechts Isar, Munich, Germany
German Competence Network Multiple Sclerosis KKNM, Munich, Germany
Diez-Fairen, M:
Univ Hosp Mutua de Terrassa, Dept Neurol, Movement Disorders & Memory Unit, Barcelona, Spain
Fundacio Recerca Biomed I Social Mutua Terrassa, Barcelona, Spain
Simon-Sanchez, J:
German Ctr Neurodegenerat Dis DZNE Tubingen, Tubingen, Germany
Univ Tubingen, Hertie Inst Clin Brain Res, Tubingen, Germany
Lleo, A:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, IIB St Pau, Memory Unit,Dept Neurol, Barcelona, Spain
Zetterberg, H:
Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Gothenburg, Sweden
UCL Inst Neurol, Dept Mol Neurosci, Queen Sq, London, England
Nygaard, M:
Univ Southern Denmark, Dept Publ Hlth, Danish Aging Res Ctr, Epidemiol Biostat & Biodemog, Odense, Denmark
Blauwendraat, C:
NINDS, Neurodegenerat Dis Res Unit, Bethesda, MD 20892 USA
Savage, JE:
Vrije Univ Amsterdam, Dept Complex Trait Genet, Ctr Neurogen & Cognit Res, Amsterdam Neurosci,Amsterdam UMC, Amsterdam, Netherlands
Mengel-From, J:
Univ Southern Denmark, Dept Publ Hlth, Epidemiol Biostat & Biodemog, Odense, Denmark
Moreno-Grau, S:
Univ Int Catalunya, Res Ctr, Inst Catala Neurociencies Aplicades, Fundacio ACE, Barcelona, Spain
Univ Int Catalunya, Memory Clin, Inst Catala Neurociencies Aplicades, Fundacio ACE, Barcelona, Spain
Wagner, M:
Univ Bonn, Dept Neurodegenerat Dis & Geriatr Psychiat, Bonn, Germany
German Ctr Neurodegenerat Dis, DZNE, Bonn, Germany
Fortea, J:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, IIB St Pau, Memory Unit,Dept Neurol, Barcelona, Spain
Keogh, MJ:
Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England
Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 0QQ, England
Blennow, K:
Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Gothenburg, Sweden
Skoog, I:
Univ Gothenburg, Ctr Ageing & Hlth AgeCap, Sahlgrenska Acad,Inst Neurosci & Physiol, Neuropsychiat Epidemiol Unit,Dept Psychiat & Neur, Gothenburg, Sweden
Friese, MA:
German Competence Network Multiple Sclerosis KKNM, Munich, Germany
Univ Klinikum Hamburg Eppendorf, Inst Neuroimmunol & Multiple Sklerose INIMS, Hamburg, Germany
Pletnikova, O:
Johns Hopkins Univ, Med Ctr, Dept Pathol Neuropathol, Baltimore, MD 21218 USA
Zulaica, M:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Inst Biodonostia, San Sebastian, Spain
Lage, C:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Univ Hosp Marques de Valdecilla, Santander, Spain
IDIVAL, Santander, Spain
de Rojas, I:
Univ Int Catalunya, Res Ctr, Inst Catala Neurociencies Aplicades, Fundacio ACE, Barcelona, Spain
Univ Int Catalunya, Memory Clin, Inst Catala Neurociencies Aplicades, Fundacio ACE, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Riedel-Heller, S:
Univ Leipzig, Inst Social Med Occupat Hlth & Publ Hlth ISAP, Leipzig, Germany
Illan-Gala, I:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, IIB St Pau, Memory Unit,Dept Neurol, Barcelona, Spain
Wei, W:
Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 0QQ, England
Jeune, B:
Univ Southern Denmark, Dept Publ Hlth, Epidemiol Biostat & Biodemog, Odense, Denmark
Orellana, A:
Univ Int Catalunya, Res Ctr, Inst Catala Neurociencies Aplicades, Fundacio ACE, Barcelona, Spain
Univ Int Catalunya, Memory Clin, Inst Catala Neurociencies Aplicades, Fundacio ACE, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Bergh, FT:
German Competence Network Multiple Sclerosis KKNM, Munich, Germany
Univ Leipzig, Dept Neurol, Leipzig, Germany
Wang, X:
Mayo Clin Florida, Dept Neurosci, Jacksonville, FL 32224 USA
Hulsman, M:
Vrije Univ Amsterdam, Dept Neurol, Alzheimer Ctr Amsterdam, Amsterdam Neurosci,Amsterdam UMC, Amsterdam, Netherlands
Vrije Univ Amsterdam, Dept Clin Genet, Amsterdam UMC, Amsterdam, Netherlands
Delft Univ Technol, Pattern Recognit & Bioinformat, Delft, Netherlands
Beker, N:
Vrije Univ Amsterdam, Dept Neurol, Alzheimer Ctr Amsterdam, Amsterdam Neurosci,Amsterdam UMC, Amsterdam, Netherlands
Tesi, N:
Vrije Univ Amsterdam, Dept Neurol, Alzheimer Ctr Amsterdam, Amsterdam Neurosci,Amsterdam UMC, Amsterdam, Netherlands
Vrije Univ Amsterdam, Dept Clin Genet, Amsterdam UMC, Amsterdam, Netherlands
Delft Univ Technol, Pattern Recognit & Bioinformat, Delft, Netherlands
Morris, CM:
Newcastle Univ, Inst Neurosci, Newcastle Brain Tissue Resource, Edwardson Bldg, Newcastle Upon Tyne NE4 5PL, Tyne & Wear, England
Indakoetxea, B:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Inst Biodonostia, San Sebastian, Spain
Hosp Univ San Sebastian, Dept Neurol, Cognit Disorders Unit, San Sebastian, Spain
Collij, LE:
Vrije Univ Amsterdam, Amsterdam Neurosci, Dept Radiol & Nucl Med, Amsterdam UMC, Amsterdam, Netherlands
Scherer, M:
Univ Med Ctr, Dept Primary Med Care, Ctr Psychosocial Med, Hamburg, Germany
Morenas-Rodriguez, E:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, IIB St Pau, Memory Unit,Dept Neurol, Barcelona, Spain
Ironside, JW:
Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH4 2XU, Midlothian, Scotland
van Berckel, BNM:
Vrije Univ Amsterdam, Amsterdam Neurosci, Dept Radiol & Nucl Med, Amsterdam UMC, Amsterdam, Netherlands
Alcolea, D:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, IIB St Pau, Memory Unit,Dept Neurol, Barcelona, Spain
Wiendl, H:
German Competence Network Multiple Sclerosis KKNM, Munich, Germany
Univ Munster, Inst Translat Neurol, Neurol Klin, Dept Neurol, Munster, Germany
Strickland, SL:
Mayo Clin Florida, Dept Neurosci, Jacksonville, FL 32224 USA
Pastor, P:
Univ Hosp Mutua de Terrassa, Dept Neurol, Movement Disorders & Memory Unit, Barcelona, Spain
Fundacio Recerca Biomed I Social Mutua Terrassa, Barcelona, Spain
Rodriguez Rodriguez, E:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Univ Hosp Marques de Valdecilla, Santander, Spain
IDIVAL, Santander, Spain
Boeve, BF:
Mayo Clin Minnesota, Dept Neurol, Rochester, MN 55905 USA
Petersen, RC:
Mayo Clin Minnesota, Dept Neurol, Rochester, MN 55905 USA
Ferman, TJ:
Mayo Clin Florida, Dept Psychiat & Psychol, Jacksonville, FL 32224 USA
van Gerpen, JA:
Mayo Clin Florida, Dept Neurol, Jacksonville, FL 32224 USA
Reinders, MJT:
Delft Univ Technol, Delft Bioinformat Lab, Delft, Netherlands
Uitti, RJ:
Mayo Clin Florida, Dept Neurol, Jacksonville, FL 32224 USA
Tarraga, L:
Univ Int Catalunya, Res Ctr, Inst Catala Neurociencies Aplicades, Fundacio ACE, Barcelona, Spain
Univ Int Catalunya, Memory Clin, Inst Catala Neurociencies Aplicades, Fundacio ACE, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Maier, W:
Univ Bonn, Dept Neurodegenerat Dis & Geriatr Psychiat, Bonn, Germany
German Ctr Neurodegenerat Dis, DZNE, Bonn, Germany
Dols-Icardo, O:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, IIB St Pau, Memory Unit,Dept Neurol, Barcelona, Spain
Kawalia, A:
Univ Hosp Cologne, Div Neurogenet & Mol Psychiat, Dept Psychiat & Psychotherapy, Fac Med, Cologne, Germany
Dalmasso, MC:
Univ Hosp Cologne, Div Neurogenet & Mol Psychiat, Dept Psychiat & Psychotherapy, Fac Med, Cologne, Germany
Consejo Nacl Invest Cient & Tecn, IIBBA, Fdn Inst Leloir, Buenos Aires, DF, Argentina
Boada, M:
Univ Int Catalunya, Res Ctr, Inst Catala Neurociencies Aplicades, Fundacio ACE, Barcelona, Spain
Univ Int Catalunya, Memory Clin, Inst Catala Neurociencies Aplicades, Fundacio ACE, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Zettl, UK:
German Competence Network Multiple Sclerosis KKNM, Munich, Germany
Univ Rostock, Dept Neurol, Rostock, Germany
van Schoor, NM:
Vrije Univ Amsterdam, Amsterdam UMC, Dept Epidemiol & Biostat, Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands
Beekman, M:
Leiden Univ, Mol Epidemiol, Med Ctr, Leiden, Netherlands
Allen, M:
Mayo Clin Florida, Dept Neurosci, Jacksonville, FL 32224 USA
Masliah, E:
NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA
de Munain, AL:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Inst Biodonostia, San Sebastian, Spain
Hosp Univ San Sebastian, Dept Neurol, San Sebastian, Spain
Pantelyat, A:
Johns Hopkins Univ, Med Ctr, Dept Neurol, Baltimore, MD 21287 USA
Wszolek, ZK:
Mayo Clin Florida, Dept Neurol, Jacksonville, FL 32224 USA
Ross, OA:
Mayo Clin Florida, Dept Neurosci, Jacksonville, FL 32224 USA
Dickson, DW:
Mayo Clin Florida, Dept Neurosci, Jacksonville, FL 32224 USA
Graff-Radford, NR:
Mayo Clin Florida, Dept Neurol, Jacksonville, FL 32224 USA
Knopman, D:
Mayo Clin Minnesota, Dept Neurol, Rochester, MN 55905 USA
Rademakers, R:
Mayo Clin Florida, Dept Neurosci, Jacksonville, FL 32224 USA
Lemstra, AW:
Vrije Univ Amsterdam, Dept Neurol, Alzheimer Ctr Amsterdam, Amsterdam Neurosci,Amsterdam UMC, Amsterdam, Netherlands
Pijnenburg, YAL:
Vrije Univ Amsterdam, Dept Neurol, Alzheimer Ctr Amsterdam, Amsterdam Neurosci,Amsterdam UMC, Amsterdam, Netherlands
Scheltens, P:
Vrije Univ Amsterdam, Dept Neurol, Alzheimer Ctr Amsterdam, Amsterdam Neurosci,Amsterdam UMC, Amsterdam, Netherlands
Gasser, T:
Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Ctr Neurol, Tubingen, Germany
Chinnery, PF:
Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 0QQ, England
Univ Cambridge, MRC, Mitochondrial Biol Unit, Cambridge CB2 0QQ, England
Hemmer, B:
Tech Univ Munich, Dept Neurol, Klinikum Rechts Isar, Munich, Germany
German Competence Network Multiple Sclerosis KKNM, Munich, Germany
Munich Cluster Syst Neurol SyNergy, Munich, Germany
Huisman, MA:
Vrije Univ Amsterdam, Amsterdam UMC, Dept Epidemiol & Biostat, Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands
Vrije Univ Amsterdam, Dept Sociol, Amsterdam, Netherlands
Troncoso, J:
Johns Hopkins Univ, Med Ctr, Dept Pathol Neuropathol, Baltimore, MD 21218 USA
Moreno, F:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Inst Biodonostia, San Sebastian, Spain
Hosp Univ San Sebastian, Dept Neurol, Cognit Disorders Unit, San Sebastian, Spain
Nohr, EA:
Univ Southern Denmark, Dept Clin Res, Res Unit Gynecol & Obstet, Odense, Denmark
Sorensen, TIA:
Novo Nordisk Fdn, Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark
Univ Copenhagen, Fac Hlth & Med Sci, Epidemiol Sect, Dept Publ Hlth, Copenhagen, Denmark
Univ Bristol, MRC, Integrat Epidemiol Unit, Bristol, Avon, England
Heutink, P:
German Ctr Neurodegenerat Dis DZNE Tubingen, Tubingen, Germany
Univ Tubingen, Hertie Inst Clin Brain Res, Tubingen, Germany
Sanchez-Juan, P:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Univ Hosp Marques de Valdecilla, Santander, Spain
IDIVAL, Santander, Spain
Posthuma, D:
Vrije Univ Amsterdam, Dept Clin Genet, Amsterdam UMC, Amsterdam, Netherlands
Vrije Univ Amsterdam, Dept Complex Trait Genet, Ctr Neurogen & Cognit Res, Amsterdam Neurosci,Amsterdam UMC, Amsterdam, Netherlands
Clarimon, J:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, IIB St Pau, Memory Unit,Dept Neurol, Barcelona, Spain
Christensen, K:
Univ Southern Denmark, Dept Publ Hlth, Danish Aging Res Ctr, Epidemiol Biostat & Biodemog, Odense, Denmark
Odense Univ Hosp, Clin Biochem & Pharmacol, Odense, Denmark
Odense Univ Hosp, Dept Clin Genet, Odense, Denmark
Ertekin-Taner, N:
Mayo Clin Florida, Dept Neurosci, Jacksonville, FL 32224 USA
Mayo Clin Florida, Dept Neurol, Jacksonville, FL 32224 USA
Scholz, SW:
NINDS, Neurodegenerat Dis Res Unit, Bethesda, MD 20892 USA
Johns Hopkins Univ, Med Ctr, Dept Neurol, Baltimore, MD 21287 USA
Ramirez, A:
Univ Bonn, Dept Neurodegenerat Dis & Geriatr Psychiat, Bonn, Germany
Univ Hosp Cologne, Div Neurogenet & Mol Psychiat, Dept Psychiat & Psychotherapy, Fac Med, Cologne, Germany
Ruiz, A:
Univ Int Catalunya, Res Ctr, Inst Catala Neurociencies Aplicades, Fundacio ACE, Barcelona, Spain
Univ Int Catalunya, Memory Clin, Inst Catala Neurociencies Aplicades, Fundacio ACE, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Slagboom, E:
Leiden Univ, Mol Epidemiol, Med Ctr, Leiden, Netherlands
Dutch Soc Res Ageing, Leiden, Netherlands
van der Flier, WM:
Vrije Univ Amsterdam, Dept Neurol, Alzheimer Ctr Amsterdam, Amsterdam Neurosci,Amsterdam UMC, Amsterdam, Netherlands
Holstege, H:
Vrije Univ Amsterdam, Dept Neurol, Alzheimer Ctr Amsterdam, Amsterdam Neurosci,Amsterdam UMC, Amsterdam, Netherlands
Vrije Univ Amsterdam, Dept Clin Genet, Amsterdam UMC, Amsterdam, Netherlands
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