Genome-wide association study of circulating interleukin 6 levels identifies novel loci

Tarunveer S. Ahluwalia; Bram P. Prins; Mohammadreza Abdollahi; Nicola J. Armstrong; Stella Aslibekyan; Lisa Bain; Barbara Jefferis; Jens Baumert; Marian Beekman; Yoav Ben-Shlomo; Joshua C. Bis; Braxton D. Mitchell; Eco De Geus; Graciela E. Delgado; Diana Marek; Joel Eriksson; Eero Kajantie; Stavroula Kanoni; John P. Kemp; Chen Lu; Riccardo E. Marioni; Stela McLachlan; Yuri Milaneschi; Ilja M. Nolte; Alexandros M. Petrelis; Eleonora Porcu; Maria Sabater-Lleal; Elnaz Naderi; Ilkka Seppälä; Tina Shah; Gaurav Singhal; Marie Standl; Alexander Teumer; Anbupalam Thalamuthu; Elisabeth Thiering; Stella Trompet; Christie M. Ballantyne; Emelia J. Benjamin; Juan P. Casas; Catherine Toben; George Dedoussis; Joris Deelen; Peter Durda; Jorgen Engmann; Mary F. Feitosa; Harald Grallert; Ann Hammarstedt; Sarah E. Harris; Georg Homuth; Jouke Jan Hottenga; Sirpa Jalkanen; Yalda Jamshidi; Magdalene C. Jawahar; Tine Jess; Mika Kivimaki; Marcus E. Kleber; Jari Lahti; Yongmei Liu; Pedro Marques-Vidal; Dan Mellström; Simon P. Mooijaart; Martina Müller-Nurasyid; Brenda Penninx; Joana A. Revez; Peter Rossing; Katri Raïkkönen; Naveed Sattar; Hubert Scharnagl; Bengt Sennblad; Angela Silveira; Beate St Pourcain; Nicholas J. Timpson; Julian Trollor; Jenny Van Dongen; Diana Van Heemst; Sophie Visvikis-Siest; Peter Vollenweider; Uwe Völker; Melanie Waldenberger; Gonneke Willemsen; Delilah Zabaneh; Richard W. Morris; Donna K. Arnett; Bernhard T. Baune; Dorret I. Boomsma; Yen Pei C. Chang; Ian J. Deary; Panos Deloukas; Johan G. Eriksson; David M. Evans; Manuel A. Ferreira; Tom Gaunt; Vilmundur Gudnason; Anders Hamsten; Joachim Heinrich; Aroon Hingorani; Steve E. Humphries; J. Wouter Jukema; Wolfgang Koenig; Meena Kumari; Zoltan Kutalik; Deborah A. Lawlor; Terho Lehtimäki; Winfried März; Karen A. Mather; Silvia Naitza; Matthias Nauck; Claes Ohlsson; Jackie F. Price; Olli Raitakari; Ken Rice; Perminder S. Sachdev; Eline Slagboom; Thorkild I.A. Sørensen; Tim Spector; David Stacey; Maria G. Stathopoulou; Toshiko Tanaka; S. Goya Wannamethee; Peter Whincup; Jerome I. Rotter; Abbas Dehghan; Eric Boerwinkle; Bruce M. Psaty; Harold Snieder; Behrooz Z. Alizadeh

doi:10.1093/hmg/ddab023

Genome-wide association study of circulating interleukin 6 levels identifies novel loci

Tarunveer S. Ahluwalia
, Bram P. Prins
, Mohammadreza Abdollahi
, Nicola J. Armstrong
, Stella Aslibekyan
, Lisa Bain
, Barbara Jefferis
, Jens Baumert
, Marian Beekman
, Yoav Ben-Shlomo
, Joshua C. Bis
, Braxton D. Mitchell
, Eco De Geus
, Graciela E. Delgado
, Diana Marek
, Joel Eriksson
, Eero Kajantie
, Stavroula Kanoni
, John P. Kemp
, Chen Lu

Riccardo E. Marioni, Stela McLachlan, Yuri Milaneschi, Ilja M. Nolte, Alexandros M. Petrelis, Eleonora Porcu, Maria Sabater-Lleal, Elnaz Naderi, Ilkka Seppälä, Tina Shah, Gaurav Singhal, Marie Standl, Alexander Teumer, Anbupalam Thalamuthu, Elisabeth Thiering, Stella Trompet, Christie M. Ballantyne, Emelia J. Benjamin, Juan P. Casas, Catherine Toben, George Dedoussis, Joris Deelen, Peter Durda, Jorgen Engmann, Mary F. Feitosa, Harald Grallert, Ann Hammarstedt, Sarah E. Harris, Georg Homuth, Jouke Jan Hottenga, Sirpa Jalkanen, Yalda Jamshidi, Magdalene C. Jawahar, Tine Jess, Mika Kivimaki, Marcus E. Kleber, Jari Lahti, Yongmei Liu, Pedro Marques-Vidal, Dan Mellström, Simon P. Mooijaart, Martina Müller-Nurasyid, Brenda Penninx, Joana A. Revez, Peter Rossing, Katri Raïkkönen, Naveed Sattar, Hubert Scharnagl, Bengt Sennblad, Angela Silveira, Beate St Pourcain, Nicholas J. Timpson, Julian Trollor, Jenny Van Dongen, Diana Van Heemst, Sophie Visvikis-Siest, Peter Vollenweider, Uwe Völker, Melanie Waldenberger, Gonneke Willemsen, Delilah Zabaneh, Richard W. Morris, Donna K. Arnett, Bernhard T. Baune, Dorret I. Boomsma, Yen Pei C. Chang, Ian J. Deary, Panos Deloukas, Johan G. Eriksson, David M. Evans, Manuel A. Ferreira, Tom Gaunt, Vilmundur Gudnason, Anders Hamsten, Joachim Heinrich, Aroon Hingorani, Steve E. Humphries, J. Wouter Jukema, Wolfgang Koenig, Meena Kumari, Zoltan Kutalik, Deborah A. Lawlor, Terho Lehtimäki, Winfried März, Karen A. Mather, Silvia Naitza, Matthias Nauck, Claes Ohlsson, Jackie F. Price, Olli Raitakari, Ken Rice, Perminder S. Sachdev, Eline Slagboom, Thorkild I.A. Sørensen, Tim Spector, David Stacey, Maria G. Stathopoulou, Toshiko Tanaka, S. Goya Wannamethee, Peter Whincup, Jerome I. Rotter, Abbas Dehghan, Eric Boerwinkle, Bruce M. Psaty, Harold Snieder, Behrooz Z. Alizadeh^*

^*Corresponding author for this work

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

38 Citations (Scopus)

Abstract

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro-A nd anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

Original language	English
Pages (from-to)	393-409
Number of pages	17
Journal	Human Molecular Genetics
Volume	30
Issue number	5
DOIs	https://doi.org/10.1093/hmg/ddab023
Publication status	Published - 1 Mar 2021
Externally published	Yes

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10.1093/hmg/ddab023

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Ahluwalia, T. S., Prins, B. P., Abdollahi, M., Armstrong, N. J., Aslibekyan, S., Bain, L., Jefferis, B., Baumert, J., Beekman, M., Ben-Shlomo, Y., Bis, J. C., Mitchell, B. D., De Geus, E., Delgado, G. E., Marek, D., Eriksson, J., Kajantie, E., Kanoni, S., Kemp, J. P., ... Alizadeh, B. Z. (2021). Genome-wide association study of circulating interleukin 6 levels identifies novel loci. Human Molecular Genetics, 30(5), 393-409. https://doi.org/10.1093/hmg/ddab023

@article{fd75bc3242c94d99b6e6b95b6b3b8970,

title = "Genome-wide association study of circulating interleukin 6 levels identifies novel loci",

abstract = "Interleukin 6 (IL-6) is a multifunctional cytokine with both pro-A nd anti-inflammatory properties with a heritability estimate of up to 61\%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.",

author = "Ahluwalia, \{Tarunveer S.\} and Prins, \{Bram P.\} and Mohammadreza Abdollahi and Armstrong, \{Nicola J.\} and Stella Aslibekyan and Lisa Bain and Barbara Jefferis and Jens Baumert and Marian Beekman and Yoav Ben-Shlomo and Bis, \{Joshua C.\} and Mitchell, \{Braxton D.\} and \{De Geus\}, Eco and Delgado, \{Graciela E.\} and Diana Marek and Joel Eriksson and Eero Kajantie and Stavroula Kanoni and Kemp, \{John P.\} and Chen Lu and Marioni, \{Riccardo E.\} and Stela McLachlan and Yuri Milaneschi and Nolte, \{Ilja M.\} and Petrelis, \{Alexandros M.\} and Eleonora Porcu and Maria Sabater-Lleal and Elnaz Naderi and Ilkka Sepp{\"a}l{\"a} and Tina Shah and Gaurav Singhal and Marie Standl and Alexander Teumer and Anbupalam Thalamuthu and Elisabeth Thiering and Stella Trompet and Ballantyne, \{Christie M.\} and Benjamin, \{Emelia J.\} and Casas, \{Juan P.\} and Catherine Toben and George Dedoussis and Joris Deelen and Peter Durda and Jorgen Engmann and Feitosa, \{Mary F.\} and Harald Grallert and Ann Hammarstedt and Harris, \{Sarah E.\} and Georg Homuth and Hottenga, \{Jouke Jan\} and Sirpa Jalkanen and Yalda Jamshidi and Jawahar, \{Magdalene C.\} and Tine Jess and Mika Kivimaki and Kleber, \{Marcus E.\} and Jari Lahti and Yongmei Liu and Pedro Marques-Vidal and Dan Mellstr{\"o}m and Mooijaart, \{Simon P.\} and Martina M{\"u}ller-Nurasyid and Brenda Penninx and Revez, \{Joana A.\} and Peter Rossing and Katri Ra{\"i}kk{\"o}nen and Naveed Sattar and Hubert Scharnagl and Bengt Sennblad and Angela Silveira and Pourcain, \{Beate St\} and Timpson, \{Nicholas J.\} and Julian Trollor and \{Van Dongen\}, Jenny and \{Van Heemst\}, Diana and Sophie Visvikis-Siest and Peter Vollenweider and Uwe V{\"o}lker and Melanie Waldenberger and Gonneke Willemsen and Delilah Zabaneh and Morris, \{Richard W.\} and Arnett, \{Donna K.\} and Baune, \{Bernhard T.\} and Boomsma, \{Dorret I.\} and Chang, \{Yen Pei C.\} and Deary, \{Ian J.\} and Panos Deloukas and Eriksson, \{Johan G.\} and Evans, \{David M.\} and Ferreira, \{Manuel A.\} and Tom Gaunt and Vilmundur Gudnason and Anders Hamsten and Joachim Heinrich and Aroon Hingorani and Humphries, \{Steve E.\} and Jukema, \{J. Wouter\} and Wolfgang Koenig and Meena Kumari and Zoltan Kutalik and Lawlor, \{Deborah A.\} and Terho Lehtim{\"a}ki and Winfried M{\"a}rz and Mather, \{Karen A.\} and Silvia Naitza and Matthias Nauck and Claes Ohlsson and Price, \{Jackie F.\} and Olli Raitakari and Ken Rice and Sachdev, \{Perminder S.\} and Eline Slagboom and S{\o}rensen, \{Thorkild I.A.\} and Tim Spector and David Stacey and Stathopoulou, \{Maria G.\} and Toshiko Tanaka and Wannamethee, \{S. Goya\} and Peter Whincup and Rotter, \{Jerome I.\} and Abbas Dehghan and Eric Boerwinkle and Psaty, \{Bruce M.\} and Harold Snieder and Alizadeh, \{Behrooz Z.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2021. Published by Oxford University Press.",

year = "2021",

month = mar,

day = "1",

doi = "10.1093/hmg/ddab023",

language = "English",

volume = "30",

pages = "393--409",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "5",

}

Ahluwalia, TS, Prins, BP, Abdollahi, M, Armstrong, NJ, Aslibekyan, S, Bain, L, Jefferis, B, Baumert, J, Beekman, M, Ben-Shlomo, Y, Bis, JC, Mitchell, BD, De Geus, E, Delgado, GE, Marek, D, Eriksson, J, Kajantie, E, Kanoni, S, Kemp, JP, Lu, C, Marioni, RE, McLachlan, S, Milaneschi, Y, Nolte, IM, Petrelis, AM, Porcu, E, Sabater-Lleal, M, Naderi, E, Seppälä, I, Shah, T, Singhal, G, Standl, M, Teumer, A, Thalamuthu, A, Thiering, E, Trompet, S, Ballantyne, CM, Benjamin, EJ, Casas, JP, Toben, C, Dedoussis, G, Deelen, J, Durda, P, Engmann, J, Feitosa, MF, Grallert, H, Hammarstedt, A, Harris, SE, Homuth, G, Hottenga, JJ, Jalkanen, S, Jamshidi, Y, Jawahar, MC, Jess, T, Kivimaki, M, Kleber, ME, Lahti, J, Liu, Y, Marques-Vidal, P, Mellström, D, Mooijaart, SP, Müller-Nurasyid, M, Penninx, B, Revez, JA, Rossing, P, Raïkkönen, K, Sattar, N, Scharnagl, H, Sennblad, B, Silveira, A, Pourcain, BS, Timpson, NJ, Trollor, J, Van Dongen, J, Van Heemst, D, Visvikis-Siest, S, Vollenweider, P, Völker, U, Waldenberger, M, Willemsen, G, Zabaneh, D, Morris, RW, Arnett, DK, Baune, BT, Boomsma, DI, Chang, YPC, Deary, IJ, Deloukas, P, Eriksson, JG, Evans, DM, Ferreira, MA, Gaunt, T, Gudnason, V, Hamsten, A, Heinrich, J, Hingorani, A, Humphries, SE, Jukema, JW, Koenig, W, Kumari, M, Kutalik, Z, Lawlor, DA, Lehtimäki, T, März, W, Mather, KA, Naitza, S, Nauck, M, Ohlsson, C, Price, JF, Raitakari, O, Rice, K, Sachdev, PS, Slagboom, E, Sørensen, TIA, Spector, T, Stacey, D, Stathopoulou, MG, Tanaka, T, Wannamethee, SG, Whincup, P, Rotter, JI, Dehghan, A, Boerwinkle, E, Psaty, BM, Snieder, H & Alizadeh, BZ 2021, 'Genome-wide association study of circulating interleukin 6 levels identifies novel loci', Human Molecular Genetics, vol. 30, no. 5, pp. 393-409. https://doi.org/10.1093/hmg/ddab023

TY - JOUR

T1 - Genome-wide association study of circulating interleukin 6 levels identifies novel loci

AU - Ahluwalia, Tarunveer S.

AU - Prins, Bram P.

AU - Abdollahi, Mohammadreza

AU - Armstrong, Nicola J.

AU - Aslibekyan, Stella

AU - Bain, Lisa

AU - Jefferis, Barbara

AU - Baumert, Jens

AU - Beekman, Marian

AU - Ben-Shlomo, Yoav

AU - Bis, Joshua C.

AU - Mitchell, Braxton D.

AU - De Geus, Eco

AU - Delgado, Graciela E.

AU - Marek, Diana

AU - Eriksson, Joel

AU - Kajantie, Eero

AU - Kanoni, Stavroula

AU - Kemp, John P.

AU - Lu, Chen

AU - Marioni, Riccardo E.

AU - McLachlan, Stela

AU - Milaneschi, Yuri

AU - Nolte, Ilja M.

AU - Petrelis, Alexandros M.

AU - Porcu, Eleonora

AU - Sabater-Lleal, Maria

AU - Naderi, Elnaz

AU - Seppälä, Ilkka

AU - Shah, Tina

AU - Singhal, Gaurav

AU - Standl, Marie

AU - Teumer, Alexander

AU - Thalamuthu, Anbupalam

AU - Thiering, Elisabeth

AU - Trompet, Stella

AU - Ballantyne, Christie M.

AU - Benjamin, Emelia J.

AU - Casas, Juan P.

AU - Toben, Catherine

AU - Dedoussis, George

AU - Deelen, Joris

AU - Durda, Peter

AU - Engmann, Jorgen

AU - Feitosa, Mary F.

AU - Grallert, Harald

AU - Hammarstedt, Ann

AU - Harris, Sarah E.

AU - Homuth, Georg

AU - Hottenga, Jouke Jan

AU - Jalkanen, Sirpa

AU - Jamshidi, Yalda

AU - Jawahar, Magdalene C.

AU - Jess, Tine

AU - Kivimaki, Mika

AU - Kleber, Marcus E.

AU - Lahti, Jari

AU - Liu, Yongmei

AU - Marques-Vidal, Pedro

AU - Mellström, Dan

AU - Mooijaart, Simon P.

AU - Müller-Nurasyid, Martina

AU - Penninx, Brenda

AU - Revez, Joana A.

AU - Rossing, Peter

AU - Raïkkönen, Katri

AU - Sattar, Naveed

AU - Scharnagl, Hubert

AU - Sennblad, Bengt

AU - Silveira, Angela

AU - Pourcain, Beate St

AU - Timpson, Nicholas J.

AU - Trollor, Julian

AU - Van Dongen, Jenny

AU - Van Heemst, Diana

AU - Visvikis-Siest, Sophie

AU - Vollenweider, Peter

AU - Völker, Uwe

AU - Waldenberger, Melanie

AU - Willemsen, Gonneke

AU - Zabaneh, Delilah

AU - Morris, Richard W.

AU - Arnett, Donna K.

AU - Baune, Bernhard T.

AU - Boomsma, Dorret I.

AU - Chang, Yen Pei C.

AU - Deary, Ian J.

AU - Deloukas, Panos

AU - Eriksson, Johan G.

AU - Evans, David M.

AU - Ferreira, Manuel A.

AU - Gaunt, Tom

AU - Gudnason, Vilmundur

AU - Hamsten, Anders

AU - Heinrich, Joachim

AU - Hingorani, Aroon

AU - Humphries, Steve E.

AU - Jukema, J. Wouter

AU - Koenig, Wolfgang

AU - Kumari, Meena

AU - Kutalik, Zoltan

AU - Lawlor, Deborah A.

AU - Lehtimäki, Terho

AU - März, Winfried

AU - Mather, Karen A.

AU - Naitza, Silvia

AU - Nauck, Matthias

AU - Ohlsson, Claes

AU - Price, Jackie F.

AU - Raitakari, Olli

AU - Rice, Ken

AU - Sachdev, Perminder S.

AU - Slagboom, Eline

AU - Sørensen, Thorkild I.A.

AU - Spector, Tim

AU - Stacey, David

AU - Stathopoulou, Maria G.

AU - Tanaka, Toshiko

AU - Wannamethee, S. Goya

AU - Whincup, Peter

AU - Rotter, Jerome I.

AU - Dehghan, Abbas

AU - Boerwinkle, Eric

AU - Psaty, Bruce M.

AU - Snieder, Harold

AU - Alizadeh, Behrooz Z.

PY - 2021/3/1

Y1 - 2021/3/1

N2 - Interleukin 6 (IL-6) is a multifunctional cytokine with both pro-A nd anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

AB - Interleukin 6 (IL-6) is a multifunctional cytokine with both pro-A nd anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

UR - https://www.scopus.com/pages/publications/85106143662

U2 - 10.1093/hmg/ddab023

DO - 10.1093/hmg/ddab023

M3 - Article

C2 - 33517400

AN - SCOPUS:85106143662

SN - 0964-6906

VL - 30

SP - 393

EP - 409

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 5

ER -

Genome-wide association study of circulating interleukin 6 levels identifies novel loci

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