Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

Nikolaos A. Patsopoulos; Sergio E. Baranzini; Adam Santaniello; Parisa Shoostari; Chris Cotsapas; Garrett Wong; Ashley H. Beecham; Tojo James; Joseph Replogle; Ioannis S. Vlachos; Cristin McCabe; Tune H. Pers; Aaron Brandes; Charles White; Brendan Keenan; Maria Cimpean; Phoebe Winn; Ioannis Pavlos Panteliadis; Allison Robbins; Till F.M. Andlauer; Onigiusz Zarzycki; Bénédicte Dubois; An Goris; Helle Bach Søndergaard; Finn Sellebjerg; Per Soelberg Sorensen; Henrik Ullum; Lise Wegner Thørner; Janna Saarela; Isabelle Cournu-Rebeix; Vincent Damotte; Bertrand Fontaine; Lena Guillot-Noel; Mark Lathrop; Sandra Vukusic; Achim Berthele; Viola Pongratz; Dorothea Buck; Christiane Gasperi; Christiane Graetz; Verena Grummel; Bernhard Hemmer; Muni Hoshi; Benjamin Knier; Thomas Korn; Christina M. Lill; Felix Luessi; Mark Mühlau; Frauke Zipp; Efthimios Dardiotis; Cristina Agliardi; Antonio Amoroso; Nadia Barizzone; Maria D. Benedetti; Luisa Bernardinelli; Paola Cavalla; Ferdinando Clarelli; Giancarlo Comi; Daniele Cusi; Federica Esposito; Laura Ferrè; Daniela Galimberti; Clara Guaschino; Maurizio A. Leone; Vittorio Martinelli; Lucia Moiola; Marco Salvetti; Melissa Sorosina; Domizia Vecchio; Andrea Zauli; Silvia Santoro; Nicasio Mancini; Miriam Zuccalà; Julia Mescheriakova; Cornelia Van Duijn; Steffan D. Bos; Elisabeth G. Celius; Anne Spurkland; Manuel Comabella; Xavier Montalban; Lars Alfredsson; Izaura L. Bomfim; David Gomez-Cabrero; Jan Hillert; Maja Jagodic; Magdalena Lindén; Fredrik Piehl; Ilijas Jelčić; Roland Martin; Mirela Sospedra; Amie Baker; Maria Ban; Clive Hawkins; Pirro Hysi; Seema Kalra; Fredrik Karpe; Jyoti Khadake; Genevieve Lachance; Paul Molyneux; Matthew Neville; John Thorpe; Elizabeth Bradshaw; Stacy J. Caillier; Peter Calabresi; Bruce A.C. Cree; Anne Cross; Mary Davis; Paul W.I. De Bakker; Silvia Delgado; Marieme Dembele; Keith Edwards; Kate Fitzgerald; Irene Y. Frohlich; Pierre Antoine Gourraud; Jonathan L. Haines; Hakon Hakonarson; Dorlan Kimbrough; Noriko Isobe; Ioanna Konidari; Ellen Lathi; Michelle H. Lee; Taibo Li; David An; Andrew Zimmer; Lohith Madireddy; Clara P. Manrique; Mitja Mitrovic; Marta Olah; Ellis Patrick; Margaret A. Pericak-Vance; Laura Piccio; Cathy Schaefer; Howard Weiner; Kasper Lage; Alastair Compston; David Hafler; Hanne F. Harbo; Stephen L. Hauser; Graeme Stewart; Sandra D’Alfonso; Georgios Hadjigeorgiou; Bruce Taylor; Lisa F. Barcellos; David Booth; Rogier Hintzen; Ingrid Kockum; Filippo Martinelli-Boneschi; Jacob L. McCauley; Jorge R. Oksenberg; Annette Oturai; Stephen Sawcer; Adrian J. Ivinson; Tomas Olsson; Philip L. De Jager

doi:10.1126/science.aav7188

Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

Nikolaos A. Patsopoulos, Sergio E. Baranzini, Adam Santaniello, Parisa Shoostari, Chris Cotsapas, Garrett Wong, Ashley H. Beecham, Tojo James, Joseph Replogle, Ioannis S. Vlachos, Cristin McCabe, Tune H. Pers, Aaron Brandes, Charles White, Brendan Keenan, Maria Cimpean, Phoebe Winn, Ioannis Pavlos Panteliadis, Allison Robbins, Till F.M. AndlauerOnigiusz Zarzycki, Bénédicte Dubois, An Goris, Helle Bach Søndergaard, Finn Sellebjerg, Per Soelberg Sorensen, Henrik Ullum, Lise Wegner Thørner, Janna Saarela, Isabelle Cournu-Rebeix, Vincent Damotte, Bertrand Fontaine, Lena Guillot-Noel, Mark Lathrop, Sandra Vukusic, Achim Berthele, Viola Pongratz, Dorothea Buck, Christiane Gasperi, Christiane Graetz, Verena Grummel, Bernhard Hemmer, Muni Hoshi, Benjamin Knier, Thomas Korn, Christina M. Lill, Felix Luessi, Mark Mühlau, Frauke Zipp, Efthimios Dardiotis, Cristina Agliardi, Antonio Amoroso, Nadia Barizzone, Maria D. Benedetti, Luisa Bernardinelli, Paola Cavalla, Ferdinando Clarelli, Giancarlo Comi, Daniele Cusi, Federica Esposito, Laura Ferrè, Daniela Galimberti, Clara Guaschino, Maurizio A. Leone, Vittorio Martinelli, Lucia Moiola, Marco Salvetti, Melissa Sorosina, Domizia Vecchio, Andrea Zauli, Silvia Santoro, Nicasio Mancini, Miriam Zuccalà, Julia Mescheriakova, Cornelia Van Duijn, Steffan D. Bos, Elisabeth G. Celius, Anne Spurkland, Manuel Comabella, Xavier Montalban, Lars Alfredsson, Izaura L. Bomfim, David Gomez-Cabrero, Jan Hillert, Maja Jagodic, Magdalena Lindén, Fredrik Piehl, Ilijas Jelčić, Roland Martin, Mirela Sospedra, Amie Baker, Maria Ban, Clive Hawkins, Pirro Hysi, Seema Kalra, Fredrik Karpe, Jyoti Khadake, Genevieve Lachance, Paul Molyneux, Matthew Neville, John Thorpe, Elizabeth Bradshaw, Stacy J. Caillier, Peter Calabresi, Bruce A.C. Cree, Anne Cross, Mary Davis, Paul W.I. De Bakker, Silvia Delgado, Marieme Dembele, Keith Edwards, Kate Fitzgerald, Irene Y. Frohlich, Pierre Antoine Gourraud, Jonathan L. Haines, Hakon Hakonarson, Dorlan Kimbrough, Noriko Isobe, Ioanna Konidari, Ellen Lathi, Michelle H. Lee, Taibo Li, David An, Andrew Zimmer, Lohith Madireddy, Clara P. Manrique, Mitja Mitrovic, Marta Olah, Ellis Patrick, Margaret A. Pericak-Vance, Laura Piccio, Cathy Schaefer, Howard Weiner, Kasper Lage, Alastair Compston, David Hafler, Hanne F. Harbo, Stephen L. Hauser, Graeme Stewart, Sandra D’Alfonso, Georgios Hadjigeorgiou, Bruce Taylor, Lisa F. Barcellos, David Booth, Rogier Hintzen, Ingrid Kockum, Filippo Martinelli-Boneschi, Jacob L. McCauley, Jorge R. Oksenberg, Annette Oturai, Stephen Sawcer, Adrian J. Ivinson, Tomas Olsson, Philip L. De Jager

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

828 Scopus citations

Abstract

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses.

Original language	English (US)
Journal	Science
Volume	365
Issue number	6460
DOIs	https://doi.org/10.1126/science.aav7188
State	Published - Sep 27 2019
Externally published	Yes

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10.1126/science.aav7188

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Patsopoulos, N. A., Baranzini, S. E., Santaniello, A., Shoostari, P., Cotsapas, C., Wong, G., Beecham, A. H., James, T., Replogle, J., Vlachos, I. S., McCabe, C., Pers, T. H., Brandes, A., White, C., Keenan, B., Cimpean, M., Winn, P., Panteliadis, I. P., Robbins, A., ... De Jager, P. L. (2019). Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science, 365(6460). https://doi.org/10.1126/science.aav7188

@article{aee53a70e461484e83d6e990dbec1870,

title = "Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility",

abstract = "We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses.",

author = "Patsopoulos, {Nikolaos A.} and Baranzini, {Sergio E.} and Adam Santaniello and Parisa Shoostari and Chris Cotsapas and Garrett Wong and Beecham, {Ashley H.} and Tojo James and Joseph Replogle and Vlachos, {Ioannis S.} and Cristin McCabe and Pers, {Tune H.} and Aaron Brandes and Charles White and Brendan Keenan and Maria Cimpean and Phoebe Winn and Panteliadis, {Ioannis Pavlos} and Allison Robbins and Andlauer, {Till F.M.} and Onigiusz Zarzycki and B{\'e}n{\'e}dicte Dubois and An Goris and S{\o}ndergaard, {Helle Bach} and Finn Sellebjerg and Sorensen, {Per Soelberg} and Henrik Ullum and Th{\o}rner, {Lise Wegner} and Janna Saarela and Isabelle Cournu-Rebeix and Vincent Damotte and Bertrand Fontaine and Lena Guillot-Noel and Mark Lathrop and Sandra Vukusic and Achim Berthele and Viola Pongratz and Dorothea Buck and Christiane Gasperi and Christiane Graetz and Verena Grummel and Bernhard Hemmer and Muni Hoshi and Benjamin Knier and Thomas Korn and Lill, {Christina M.} and Felix Luessi and Mark M{\"u}hlau and Frauke Zipp and Efthimios Dardiotis and Cristina Agliardi and Antonio Amoroso and Nadia Barizzone and Benedetti, {Maria D.} and Luisa Bernardinelli and Paola Cavalla and Ferdinando Clarelli and Giancarlo Comi and Daniele Cusi and Federica Esposito and Laura Ferr{\`e} and Daniela Galimberti and Clara Guaschino and Leone, {Maurizio A.} and Vittorio Martinelli and Lucia Moiola and Marco Salvetti and Melissa Sorosina and Domizia Vecchio and Andrea Zauli and Silvia Santoro and Nicasio Mancini and Miriam Zuccal{\`a} and Julia Mescheriakova and {Van Duijn}, Cornelia and Bos, {Steffan D.} and Celius, {Elisabeth G.} and Anne Spurkland and Manuel Comabella and Xavier Montalban and Lars Alfredsson and Bomfim, {Izaura L.} and David Gomez-Cabrero and Jan Hillert and Maja Jagodic and Magdalena Lind{\'e}n and Fredrik Piehl and Ilijas Jel{\v c}i{\'c} and Roland Martin and Mirela Sospedra and Amie Baker and Maria Ban and Clive Hawkins and Pirro Hysi and Seema Kalra and Fredrik Karpe and Jyoti Khadake and Genevieve Lachance and Paul Molyneux and Matthew Neville and John Thorpe and Elizabeth Bradshaw and Caillier, {Stacy J.} and Peter Calabresi and Cree, {Bruce A.C.} and Anne Cross and Mary Davis and {De Bakker}, {Paul W.I.} and Silvia Delgado and Marieme Dembele and Keith Edwards and Kate Fitzgerald and Frohlich, {Irene Y.} and Gourraud, {Pierre Antoine} and Haines, {Jonathan L.} and Hakon Hakonarson and Dorlan Kimbrough and Noriko Isobe and Ioanna Konidari and Ellen Lathi and Lee, {Michelle H.} and Taibo Li and David An and Andrew Zimmer and Lohith Madireddy and Manrique, {Clara P.} and Mitja Mitrovic and Marta Olah and Ellis Patrick and Pericak-Vance, {Margaret A.} and Laura Piccio and Cathy Schaefer and Howard Weiner and Kasper Lage and Alastair Compston and David Hafler and Harbo, {Hanne F.} and Hauser, {Stephen L.} and Graeme Stewart and Sandra D{\textquoteright}Alfonso and Georgios Hadjigeorgiou and Bruce Taylor and Barcellos, {Lisa F.} and David Booth and Rogier Hintzen and Ingrid Kockum and Filippo Martinelli-Boneschi and McCauley, {Jacob L.} and Oksenberg, {Jorge R.} and Annette Oturai and Stephen Sawcer and Ivinson, {Adrian J.} and Tomas Olsson and {De Jager}, {Philip L.}",

note = "Generated from Scopus record by KAUST IRTS on 2021-02-16",

year = "2019",

month = sep,

day = "27",

doi = "10.1126/science.aav7188",

language = "English (US)",

volume = "365",

journal = "Science",

issn = "1095-9203",

publisher = "American Association for the Advancement of Science",

number = "6460",

}

Patsopoulos, NA, Baranzini, SE, Santaniello, A, Shoostari, P, Cotsapas, C, Wong, G, Beecham, AH, James, T, Replogle, J, Vlachos, IS, McCabe, C, Pers, TH, Brandes, A, White, C, Keenan, B, Cimpean, M, Winn, P, Panteliadis, IP, Robbins, A, Andlauer, TFM, Zarzycki, O, Dubois, B, Goris, A, Søndergaard, HB, Sellebjerg, F, Sorensen, PS, Ullum, H, Thørner, LW, Saarela, J, Cournu-Rebeix, I, Damotte, V, Fontaine, B, Guillot-Noel, L, Lathrop, M, Vukusic, S, Berthele, A, Pongratz, V, Buck, D, Gasperi, C, Graetz, C, Grummel, V, Hemmer, B, Hoshi, M, Knier, B, Korn, T, Lill, CM, Luessi, F, Mühlau, M, Zipp, F, Dardiotis, E, Agliardi, C, Amoroso, A, Barizzone, N, Benedetti, MD, Bernardinelli, L, Cavalla, P, Clarelli, F, Comi, G, Cusi, D, Esposito, F, Ferrè, L, Galimberti, D, Guaschino, C, Leone, MA, Martinelli, V, Moiola, L, Salvetti, M, Sorosina, M, Vecchio, D, Zauli, A, Santoro, S, Mancini, N, Zuccalà, M, Mescheriakova, J, Van Duijn, C, Bos, SD, Celius, EG, Spurkland, A, Comabella, M, Montalban, X, Alfredsson, L, Bomfim, IL, Gomez-Cabrero, D, Hillert, J, Jagodic, M, Lindén, M, Piehl, F, Jelčić, I, Martin, R, Sospedra, M, Baker, A, Ban, M, Hawkins, C, Hysi, P, Kalra, S, Karpe, F, Khadake, J, Lachance, G, Molyneux, P, Neville, M, Thorpe, J, Bradshaw, E, Caillier, SJ, Calabresi, P, Cree, BAC, Cross, A, Davis, M, De Bakker, PWI, Delgado, S, Dembele, M, Edwards, K, Fitzgerald, K, Frohlich, IY, Gourraud, PA, Haines, JL, Hakonarson, H, Kimbrough, D, Isobe, N, Konidari, I, Lathi, E, Lee, MH, Li, T, An, D, Zimmer, A, Madireddy, L, Manrique, CP, Mitrovic, M, Olah, M, Patrick, E, Pericak-Vance, MA, Piccio, L, Schaefer, C, Weiner, H, Lage, K, Compston, A, Hafler, D, Harbo, HF, Hauser, SL, Stewart, G, D’Alfonso, S, Hadjigeorgiou, G, Taylor, B, Barcellos, LF, Booth, D, Hintzen, R, Kockum, I, Martinelli-Boneschi, F, McCauley, JL, Oksenberg, JR, Oturai, A, Sawcer, S, Ivinson, AJ, Olsson, T & De Jager, PL 2019, 'Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility', Science, vol. 365, no. 6460. https://doi.org/10.1126/science.aav7188

TY - JOUR

T1 - Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

AU - Patsopoulos, Nikolaos A.

AU - Baranzini, Sergio E.

AU - Santaniello, Adam

AU - Shoostari, Parisa

AU - Cotsapas, Chris

AU - Wong, Garrett

AU - Beecham, Ashley H.

AU - James, Tojo

AU - Replogle, Joseph

AU - Vlachos, Ioannis S.

AU - McCabe, Cristin

AU - Pers, Tune H.

AU - Brandes, Aaron

AU - White, Charles

AU - Keenan, Brendan

AU - Cimpean, Maria

AU - Winn, Phoebe

AU - Panteliadis, Ioannis Pavlos

AU - Robbins, Allison

AU - Andlauer, Till F.M.

AU - Zarzycki, Onigiusz

AU - Dubois, Bénédicte

AU - Goris, An

AU - Søndergaard, Helle Bach

AU - Sellebjerg, Finn

AU - Sorensen, Per Soelberg

AU - Ullum, Henrik

AU - Thørner, Lise Wegner

AU - Saarela, Janna

AU - Cournu-Rebeix, Isabelle

AU - Damotte, Vincent

AU - Fontaine, Bertrand

AU - Guillot-Noel, Lena

AU - Lathrop, Mark

AU - Vukusic, Sandra

AU - Berthele, Achim

AU - Pongratz, Viola

AU - Buck, Dorothea

AU - Gasperi, Christiane

AU - Graetz, Christiane

AU - Grummel, Verena

AU - Hemmer, Bernhard

AU - Hoshi, Muni

AU - Knier, Benjamin

AU - Korn, Thomas

AU - Lill, Christina M.

AU - Luessi, Felix

AU - Mühlau, Mark

AU - Zipp, Frauke

AU - Dardiotis, Efthimios

AU - Agliardi, Cristina

AU - Amoroso, Antonio

AU - Barizzone, Nadia

AU - Benedetti, Maria D.

AU - Bernardinelli, Luisa

AU - Cavalla, Paola

AU - Clarelli, Ferdinando

AU - Comi, Giancarlo

AU - Cusi, Daniele

AU - Esposito, Federica

AU - Ferrè, Laura

AU - Galimberti, Daniela

AU - Guaschino, Clara

AU - Leone, Maurizio A.

AU - Martinelli, Vittorio

AU - Moiola, Lucia

AU - Salvetti, Marco

AU - Sorosina, Melissa

AU - Vecchio, Domizia

AU - Zauli, Andrea

AU - Santoro, Silvia

AU - Mancini, Nicasio

AU - Zuccalà, Miriam

AU - Mescheriakova, Julia

AU - Van Duijn, Cornelia

AU - Bos, Steffan D.

AU - Celius, Elisabeth G.

AU - Spurkland, Anne

AU - Comabella, Manuel

AU - Montalban, Xavier

AU - Alfredsson, Lars

AU - Bomfim, Izaura L.

AU - Gomez-Cabrero, David

AU - Hillert, Jan

AU - Jagodic, Maja

AU - Lindén, Magdalena

AU - Piehl, Fredrik

AU - Jelčić, Ilijas

AU - Martin, Roland

AU - Sospedra, Mirela

AU - Baker, Amie

AU - Ban, Maria

AU - Hawkins, Clive

AU - Hysi, Pirro

AU - Kalra, Seema

AU - Karpe, Fredrik

AU - Khadake, Jyoti

AU - Lachance, Genevieve

AU - Molyneux, Paul

AU - Neville, Matthew

AU - Thorpe, John

AU - Bradshaw, Elizabeth

AU - Caillier, Stacy J.

AU - Calabresi, Peter

AU - Cree, Bruce A.C.

AU - Cross, Anne

AU - Davis, Mary

AU - De Bakker, Paul W.I.

AU - Delgado, Silvia

AU - Dembele, Marieme

AU - Edwards, Keith

AU - Fitzgerald, Kate

AU - Frohlich, Irene Y.

AU - Gourraud, Pierre Antoine

AU - Haines, Jonathan L.

AU - Hakonarson, Hakon

AU - Kimbrough, Dorlan

AU - Isobe, Noriko

AU - Konidari, Ioanna

AU - Lathi, Ellen

AU - Lee, Michelle H.

AU - Li, Taibo

AU - An, David

AU - Zimmer, Andrew

AU - Madireddy, Lohith

AU - Manrique, Clara P.

AU - Mitrovic, Mitja

AU - Olah, Marta

AU - Patrick, Ellis

AU - Pericak-Vance, Margaret A.

AU - Piccio, Laura

AU - Schaefer, Cathy

AU - Weiner, Howard

AU - Lage, Kasper

AU - Compston, Alastair

AU - Hafler, David

AU - Harbo, Hanne F.

AU - Hauser, Stephen L.

AU - Stewart, Graeme

AU - D’Alfonso, Sandra

AU - Hadjigeorgiou, Georgios

AU - Taylor, Bruce

AU - Barcellos, Lisa F.

AU - Booth, David

AU - Hintzen, Rogier

AU - Kockum, Ingrid

AU - Martinelli-Boneschi, Filippo

AU - McCauley, Jacob L.

AU - Oksenberg, Jorge R.

AU - Oturai, Annette

AU - Sawcer, Stephen

AU - Ivinson, Adrian J.

AU - Olsson, Tomas

AU - De Jager, Philip L.

N1 - Generated from Scopus record by KAUST IRTS on 2021-02-16

PY - 2019/9/27

Y1 - 2019/9/27

N2 - We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses.

AB - We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses.

UR - https://www.sciencemag.org/lookup/doi/10.1126/science.aav7188

UR - http://www.scopus.com/inward/record.url?scp=85072692374&partnerID=8YFLogxK

U2 - 10.1126/science.aav7188

DO - 10.1126/science.aav7188

M3 - Article

SN - 1095-9203

VL - 365

JO - Science

JF - Science

IS - 6460

ER -

Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

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