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

CHARGE Inflammation working group; 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; Brenda Penninx; Meena Kumari; Harold Snieder; Behrooz Z Alizadeh

doi:10.1093/hmg/ddab023

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

CHARGE Inflammation working group, 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 KempChen 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, Brenda Penninx, Meena Kumari, Harold Snieder, Behrooz Z Alizadeh^*

^*Corresponding author for this work

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

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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 - 27-Apr-2021

Keywords

C-REACTIVE PROTEIN
SYSTEMIC-LUPUS-ERYTHEMATOSUS
RECEPTOR IL-6R GENE
SUSCEPTIBILITY LOCI
RHEUMATOID-ARTHRITIS
CHRONIC INFLAMMATION
PRODUCE IL-6
DISEASE
CELLS
ARCHITECTURE

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Genome-wide association study of circulating interleukin 6 levels identifies novel lociFinal publisher's version, 1.26 MBLicence: CC BY

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CHARGE Inflammation working group, 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., ... 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{42b9253f2e0343e3b51c10e4f1143efe,

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 = "C-REACTIVE PROTEIN, SYSTEMIC-LUPUS-ERYTHEMATOSUS, RECEPTOR IL-6R GENE, SUSCEPTIBILITY LOCI, RHEUMATOID-ARTHRITIS, CHRONIC INFLAMMATION, PRODUCE IL-6, DISEASE, CELLS, ARCHITECTURE",

author = "\{CHARGE Inflammation working group\} and 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 Brenda Penninx and Meena Kumari and Harold Snieder and Alizadeh, \{Behrooz Z\}",

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

year = "2021",

month = apr,

day = "27",

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",

}

CHARGE Inflammation working group, 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, Penninx, B, Kumari, M, 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 - CHARGE Inflammation working group

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 - Penninx, Brenda

AU - Kumari, Meena

AU - Snieder, Harold

AU - Alizadeh, Behrooz Z

PY - 2021/4/27

Y1 - 2021/4/27

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 - C-REACTIVE PROTEIN

KW - SYSTEMIC-LUPUS-ERYTHEMATOSUS

KW - RECEPTOR IL-6R GENE

KW - SUSCEPTIBILITY LOCI

KW - RHEUMATOID-ARTHRITIS

KW - CHRONIC INFLAMMATION

KW - PRODUCE IL-6

KW - DISEASE

KW - CELLS

KW - ARCHITECTURE

U2 - 10.1093/hmg/ddab023

DO - 10.1093/hmg/ddab023

M3 - Article

C2 - 33517400

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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Keywords

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