Genome-Wide Association Study of Circulating Interleukin 6 Levels Identifies Novel Loci

Tarunveer S Ahluwalia; Eco De Geus; Yuri Milaneschi; Jouke-Jan Hottenga; Jenny Van Dongen; Gonneke Willemsen; Dorret I Boomsma; Behrooz Z Alizadeh; CHARGE Inflammation Working Group

doi:10.1093/hmg/ddab023

Genome-Wide Association Study of Circulating Interleukin 6 Levels Identifies Novel Loci

Tarunveer S Ahluwalia
, Eco De Geus
, Yuri Milaneschi
, Jouke-Jan Hottenga
, Jenny Van Dongen
, Gonneke Willemsen
, Dorret I Boomsma
, Behrooz Z Alizadeh
, CHARGE Inflammation Working Group

Research output: Contribution to Journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	393-409
Number of pages	17
Journal	Human molecular genetics
Volume	30
Issue number	5
Early online date	30 Jan 2021
DOIs	https://doi.org/10.1093/hmg/ddab023
Publication status	Published - 1 Mar 2021

Funding

Funders	Funder number
National Heart, Lung, and Blood Institute	R01HL120393

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10.1093/hmg/ddab023

https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddab023/6124523

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@article{044392b6ae0c41d3a5b40eba21d7aa01,

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.",

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\} and \{CHARGE Inflammation Working Group\}",

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",

}

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

AU - CHARGE Inflammation Working Group

PY - 2021/3/1

Y1 - 2021/3/1

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.

U2 - 10.1093/hmg/ddab023

DO - 10.1093/hmg/ddab023

M3 - Article

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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