title: Identification of IL6R and chromosome 11q13.5 as risk loci for asthma.
abstract: BACKGROUND
  We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease.
  
  
  METHODS
  We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26,475), and these were tested in an additional 25,358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset.
  
  
  RESULTS
  Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57,800): rs4129267 (OR 1·09, combined p=2·4×10(-8)) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1·09, p=1·8×10(-8)) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1·33, p=7×10(-4)), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2.
  
  
  CONCLUSIONS
  The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma.
  
  
  BACKGROUND
  National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix.
authors: The Queensland Institute of Medical Research, Brisbane, QLD, Australia. manuel.ferreira@qimr.edu.au
authors: Manuel A R
authors: MA
authors: Ferreira
authors: Melanie C
authors: MC
authors: Matheson
authors: David L
authors: DL
authors: Duffy
authors: Guy B
authors: GB
authors: Marks
authors: Jennie
authors: J
authors: Hui
authors: Peter
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authors: Le Souëf
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authors: Danoy
authors: Svetlana
authors: S
authors: Baltic
authors: Dale R
authors: DR
authors: Nyholt
authors: Mark
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authors: Jenkins
authors: Catherine
authors: C
authors: Hayden
authors: Gonneke
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authors: Willemsen
authors: Wei
authors: W
authors: Ang
authors: Mikko
authors: M
authors: Kuokkanen
authors: John
authors: J
authors: Beilby
authors: Faang
authors: F
authors: Cheah
authors: Eco J C
authors: EJ
authors: de Geus
authors: Adaikalavan
authors: A
authors: Ramasamy
authors: Sailaja
authors: S
authors: Vedantam
authors: Veikko
authors: V
authors: Salomaa
authors: Pamela A
authors: PA
authors: Madden
authors: Andrew C
authors: AC
authors: Heath
authors: John L
authors: JL
authors: Hopper
authors: Peter M
authors: PM
authors: Visscher
authors: Bill
authors: B
authors: Musk
authors: Stephen R
authors: SR
authors: Leeder
authors: Marjo-Riitta
authors: MR
authors: Jarvelin
authors: Craig
authors: C
authors: Pennell
authors: Dorret I
authors: DI
authors: Boomsma
authors: Joel N
authors: JN
authors: Hirschhorn
authors: Haydn
authors: H
authors: Walters
authors: Nicholas G
authors: NG
authors: Martin
authors: Alan
authors: A
authors: James
authors: Graham
authors: G
authors: Jones
authors: Michael J
authors: MJ
authors: Abramson
authors: Colin F
authors: CF
authors: Robertson
authors: Shyamali C
authors: SC
authors: Dharmage
authors: Matthew A
authors: MA
authors: Brown
authors: Grant W
authors: GW
authors: Montgomery
authors: Philip J
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authors: Thompson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001249:Asthma / Q000235:genetics* / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019947:Receptors, Interleukin-6 / Q000235:genetics*; D055815:Young Adult
chemical_list: C087215:LRRC32 protein, human; D008565:Membrane Proteins; D019947:Receptors, Interleukin-6