Genome-wide association study of circulating interleukin 6 levels identifies novel loci
Authors: Ahluwalia Tarunveer S , Prins Bram P , Abdollahi Mohammadreza , Armstrong Nicola J , Aslibekyan Stella , Bain Lisa , Jefferis Barbara , Baumert Jens , Beekman Marian , Ben-Shlomo Yoav , Bis Joshua C , Mitchell Braxton D , de Geus Eco , Delgado Graciela E , Marek Diana , Eriksson Joel , Kajantie Eero , Kanoni Stavroula , Kemp John P , Lu Chen , Marioni Riccardo E , McLachlan Stela , Milaneschi Yuri , Nolte Ilja M , Petrelis Alexandros M , Porcu Eleonora , Sabater-Lleal Maria , Naderi Elnaz , Seppälä Ilkka , Shah Tina , Singhal Gaurav , Standl Marie , Teumer Alexander , Thalamuthu Anbupalam , Thiering Elisabeth , Trompet Stella , Ballantyne Christie M , Benjamin Emelia J , Casas Juan P , Toben Catherine , Dedoussis George , Deelen Joris , Durda Peter , Engmann Jorgen , Feitosa Mary F , Grallert Harald , Hammarstedt Ann , Harris Sarah E , Homuth Georg , Hottenga Jouke-Jan , Jalkanen Sirpa , Jamshidi Yalda , Jawahar Magdalene C , Jess Tine , Kivimaki Mika , Kleber Marcus E , Lahti Jari , Liu Yongmei , Marques-Vidal Pedro , Mellström Dan , Mooijaart Simon P , Müller-Nurasyid Martina , Penninx Brenda , Revez Joana A , Rossing Peter , Räikkönen Katri , Sattar Naveed , Scharnagl Hubert , Sennblad Bengt , Silveira Angela , Pourcain Beate St , Timpson Nicholas J , Trollor Julian ,   CHARGE Inflammation Working Group, van Dongen Jenny , Van Heemst Diana , Visvikis-Siest Sophie , Vollenweider Peter , Völker Uwe , Waldenberger Melanie , Willemsen Gonneke , Zabaneh Delilah , Morris Richard W , Arnett Donna K , Baune Bernhard T , Boomsma Dorret I , Chang Yen-Pei C , Deary Ian J , Deloukas Panos , Eriksson Johan G , Evans David M , Ferreira Manuel A , Gaunt Tom , Gudnason Vilmundur , Hamsten Anders , Heinrich Joachim , Hingorani Aroon , Humphries Steve E , Jukema J Wouter , Koenig Wolfgang , Kumari Meena , Kutalik Zoltan , Lawlor Deborah A , Lehtimäki Terho , März Winfried , Mather Karen A , Naitza Silvia , Nauck Matthias , Ohlsson Claes , Price Jackie F , Raitakari Olli , Rice Ken , Sachdev Perminder S , Slagboom Eline , Sørensen Thorkild I A , Spector Tim , Stacey David , Stathopoulou Maria G , Tanaka Toshiko , Wannamethee S Goya , Whincup Peter , Rotter Jerome I , Dehghan Abbas , Boerwinkle Eric , Psaty Bruce M , Snieder Harold , Alizadeh Behrooz Z 
Published: January 2021

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.