BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease. Previous studies have revealed shared genetic determinants among different inflammatory disorders, suggesting that markers associated with immune-related traits might also play a role in AD. OBJECTIVE: We sought to identify novel genetic risk factors for AD. METHODS: We examined the results of all genome-wide association studies from a public repository and selected 318 genetic markers that were significantly associated with any inflammatory trait. These markers were considered candidates and tested for association with AD in a 3-step approach including 7 study populations with 7130 patients with AD and 9253 control subjects. RESULTS: A functional amino acid change in the IL-6 receptor (IL-6R Asp358Ala; rs2228145) was significantly associated with AD (odds ratio [OR], 1.15; P = 5 × 10(-9)). Interestingly, investigation of 2 independent population-based birth cohorts showed that IL-6R 358Ala specifically predisposes to the persistent form of AD (ORpersistent AD = 1.22, P = .0008; ORtransient AD = 1.04, P = .54). This variant determines the balance between the classical membrane-bound versus soluble IL-6R signaling pathways. Carriers of 358Ala had increased serum levels of soluble IL-6R (P = 4 × 10(-14)), with homozygote carriers showing a 2-fold increase. Moreover, we demonstrate that soluble IL-6R levels were higher in patients with AD than in control subjects (46.0 vs 37.8 ng/mL, P = .001). Additional AD risk variants were identified in RAD50, RUNX3, and ERBB3. CONCLUSION: Our study supports the importance of genetic variants influencing inflammation in the etiology of AD. Moreover, we identified a functional genetic variant in IL6R influencing disease prognosis and specifically predisposing to persistent AD.
BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease. Previous studies have revealed shared genetic determinants among different inflammatory disorders, suggesting that markers associated with immune-related traits might also play a role in AD. OBJECTIVE: We sought to identify novel genetic risk factors for AD. METHODS: We examined the results of all genome-wide association studies from a public repository and selected 318 genetic markers that were significantly associated with any inflammatory trait. These markers were considered candidates and tested for association with AD in a 3-step approach including 7 study populations with 7130 patients with AD and 9253 control subjects. RESULTS: A functional amino acid change in the IL-6 receptor (IL-6R Asp358Ala; rs2228145) was significantly associated with AD (odds ratio [OR], 1.15; P = 5 × 10(-9)). Interestingly, investigation of 2 independent population-based birth cohorts showed that IL-6R 358Ala specifically predisposes to the persistent form of AD (ORpersistent AD = 1.22, P = .0008; ORtransient AD = 1.04, P = .54). This variant determines the balance between the classical membrane-bound versus soluble IL-6R signaling pathways. Carriers of 358Ala had increased serum levels of soluble IL-6R (P = 4 × 10(-14)), with homozygote carriers showing a 2-fold increase. Moreover, we demonstrate that soluble IL-6R levels were higher in patients with AD than in control subjects (46.0 vs 37.8 ng/mL, P = .001). Additional AD risk variants were identified in RAD50, RUNX3, and ERBB3. CONCLUSION: Our study supports the importance of genetic variants influencing inflammation in the etiology of AD. Moreover, we identified a functional genetic variant in IL6R influencing disease prognosis and specifically predisposing to persistent AD.
Authors: Laura Polányi; Carien M Niessen; Christina Vohlen; Julia Stinn; Tobias Kretschmer; Vanessa Jentgen; Dharmesh Hirani; Silke V Koningsbruggen-Rietschel; Jörg Dötsch; Miguel A Alejandre Alcazar Journal: J Mol Med (Berl) Date: 2020-01-07 Impact factor: 4.599
Authors: Avanti Desai; Mi-Yeon Jung; Ana Olivera; Alasdair M Gilfillan; Calman Prussin; Arnold S Kirshenbaum; Michael A Beaven; Dean D Metcalfe Journal: J Allergy Clin Immunol Date: 2016-01-07 Impact factor: 10.793
Authors: Juan Manuel Leyva-Castillo; Haifa H Jabara; Joerg Wenzel; Alex McGurk; Daniel Wong; Thomas Bieber; Raif S Geha Journal: Clin Immunol Date: 2020-08-08 Impact factor: 3.969
Authors: Lavinia Paternoster; Marie Standl; Johannes Waage; Hansjörg Baurecht; Melanie Hotze; David P Strachan; John A Curtin; Klaus Bønnelykke; Chao Tian; Atsushi Takahashi; Jorge Esparza-Gordillo; Alexessander Couto Alves; Jacob P Thyssen; Herman T den Dekker; Manuel A Ferreira; Elisabeth Altmaier; Patrick Ma Sleiman; Feng Li Xiao; Juan R Gonzalez; Ingo Marenholz; Birgit Kalb; Maria Pino Yanes; Cheng-Jian Xu; Lisbeth Carstensen; Maria M Groen-Blokhuis; Cristina Venturini; Craig E Pennell; Sheila J Barton; Albert M Levin; Ivan Curjuric; Mariona Bustamante; Eskil Kreiner-Møller; Gabrielle A Lockett; Jonas Bacelis; Supinda Bunyavanich; Rachel A Myers; Anja Matanovic; Ashish Kumar; Joyce Y Tung; Tomomitsu Hirota; Michiaki Kubo; Wendy L McArdle; A J Henderson; John P Kemp; Jie Zheng; George Davey Smith; Franz Rüschendorf; Anja Bauerfeind; Min Ae Lee-Kirsch; Andreas Arnold; Georg Homuth; Carsten O Schmidt; Elisabeth Mangold; Sven Cichon; Thomas Keil; Elke Rodríguez; Annette Peters; Andre Franke; Wolfgang Lieb; Natalija Novak; Regina Fölster-Holst; Momoko Horikoshi; Juha Pekkanen; Sylvain Sebert; Lise L Husemoen; Niels Grarup; Johan C de Jongste; Fernando Rivadeneira; Albert Hofman; Vincent Wv Jaddoe; Suzanne Gma Pasmans; Niels J Elbert; André G Uitterlinden; Guy B Marks; Philip J Thompson; Melanie C Matheson; Colin F Robertson; Janina S Ried; Jin Li; Xian Bo Zuo; Xiao Dong Zheng; Xian Yong Yin; Liang Dan Sun; Maeve A McAleer; Grainne M O'Regan; Caoimhe Mr Fahy; Linda E Campbell; Milan Macek; Michael Kurek; Donglei Hu; Celeste Eng; Dirkje S Postma; Bjarke Feenstra; Frank Geller; Jouke Jan Hottenga; Christel M Middeldorp; Pirro Hysi; Veronique Bataille; Tim Spector; Carla Mt Tiesler; Elisabeth Thiering; Badri Pahukasahasram; James J Yang; Medea Imboden; Scott Huntsman; Natàlia Vilor-Tejedor; Caroline L Relton; Ronny Myhre; Wenche Nystad; Adnan Custovic; Scott T Weiss; Deborah A Meyers; Cilla Söderhäll; Erik Melén; Carole Ober; Benjamin A Raby; Angela Simpson; Bo Jacobsson; John W Holloway; Hans Bisgaard; Jordi Sunyer; Nicole M Probst Hensch; L Keoki Williams; Keith M Godfrey; Carol A Wang; Dorret I Boomsma; Mads Melbye; Gerard H Koppelman; Deborah Jarvis; Wh Irwin McLean; Alan D Irvine; Xue Jun Zhang; Hakon Hakonarson; Christian Gieger; Esteban G Burchard; Nicholas G Martin; Liesbeth Duijts; Allan Linneberg; Marjo-Riitta Jarvelin; Markus M Noethen; Susanne Lau; Norbert Hübner; Young-Ae Lee; Mayumi Tamari; David A Hinds; Daniel Glass; Sara J Brown; Joachim Heinrich; David M Evans; Stephan Weidinger Journal: Nat Genet Date: 2015-10-19 Impact factor: 38.330