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 Räikkönen; 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 Koeing; Meena Kumari; Zoltan Kutalik; Deborah A Lawlor; Terho Lehtimäki; Winfried März; Karen Mather; Silvia Naitza; Mathias 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 LuRiccardo 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 Räikkönen, 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 Koeing, Meena Kumari, Zoltan Kutalik, Deborah A Lawlor, Terho Lehtimäki, Winfried März, Karen Mather, Silvia Naitza, Mathias 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

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

Abstract / Description of output

Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and 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
Article number	ddab023
Journal	Human Molecular Genetics
Early online date	30 Jan 2021
DOIs	https://doi.org/10.1093/hmg/ddab023
Publication status	E-pub ahead of print - 30 Jan 2021

Keywords / Materials (for Non-textual outputs)

anti-inflammatory agents
cytokine
chromosomes
interleukin-6
genome-wide association study
hla-drb1 gene

Access to Document

10.1093/hmg/ddab023Licence: Creative Commons: Attribution (CC-BY)

AhluwaliaEtalHMG2021GenomeWideAssociationAccepted author manuscript, 1.69 MBLicence: Creative Commons: Attribution (CC-BY)

Cite this

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, Article ddab023. Advance online publication. https://doi.org/10.1093/hmg/ddab023

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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- and 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.",

keywords = "anti-inflammatory agents, cytokine, chromosomes, interleukin-6, genome-wide association study, hla-drb1 gene",

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 Jouke-jan Hottenga 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 R{\"a}ikk{\"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 Koeing and Meena Kumari and Zoltan Kutalik and Lawlor, {Deborah A} and Terho Lehtim{\"a}ki and Winfried M{\"a}rz and Karen Mather and Silvia Naitza and Mathias 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}",

year = "2021",

month = jan,

day = "30",

doi = "10.1093/hmg/ddab023",

language = "English",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

}

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, J, 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, Räikkönen, 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, YC, Deary, IJ, Deloukas, P, Eriksson, JG, Evans, DM, Ferreira, MA, Gaunt, T, Gudnason, V, Hamsten, A, Heinrich, J, Hingorani, A, Humphries, SE, Jukema, JW, Koeing, W, Kumari, M, Kutalik, Z, Lawlor, DA, Lehtimäki, T, März, W, Mather, K, 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. 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 - Räikkönen, 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 - Koeing, Wolfgang

AU - Kumari, Meena

AU - Kutalik, Zoltan

AU - Lawlor, Deborah A

AU - Lehtimäki, Terho

AU - März, Winfried

AU - Mather, Karen

AU - Naitza, Silvia

AU - Nauck, Mathias

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 - 2021/1/30

Y1 - 2021/1/30

N2 - Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and 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- and 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.

KW - anti-inflammatory agents

KW - cytokine

KW - chromosomes

KW - interleukin-6

KW - genome-wide association study

KW - hla-drb1 gene

U2 - 10.1093/hmg/ddab023

DO - 10.1093/hmg/ddab023

M3 - Article

SN - 0964-6906

JO - Human Molecular Genetics

JF - Human Molecular Genetics

M1 - ddab023

ER -

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

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

Access to Document

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Cite this