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A new regulatory variant in the interleukin-6 receptor gene associates with asthma risk

Genes & Immunity volume 14, pages 441–446 (2013)Cite this article

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Abstract

The main genetic determinant of soluble interleukin 6 receptor (sIL-6R) levels is the missense variant rs2228145 that maps to the cleavage site of IL-6R. For each Ala allele, sIL-6R serum levels increase by ∼20 ng ml−1 and asthma risk by 1.09-fold. However, this variant does not explain the total heritability for sIL-6R levels. Additional independent variants in IL6R may therefore contribute to variation in sIL-6R levels and influence asthma risk. We imputed 471 variants in IL6R and tested these for association with sIL-6R serum levels in 360 individuals. An intronic variant (rs12083537) was associated with sIL-6R levels independently of rs4129267 (P=0.0005), a proxy single-nucleotide polymorphism for rs2228145. A significant and consistent association for rs12083537 was observed in a replication panel of 354 individuals (P=0.033). Each rs12083537:A allele increased sIL-6R serum levels by 2.4 ng ml−1. Analysis of mRNA levels in two cohorts did not identify significant associations between rs12083537 and IL6R transcription levels. On the other hand, results from 16 705 asthmatics and 30 809 controls showed that the rs12083537:A allele increased asthma risk by 1.04-fold (P=0.0419). Genetic risk scores based on IL6R regulatory variants may prove useful in explaining variation in clinical response to tocilizumab, an anti-IL-6R monoclonal antibody.

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Acknowledgements

We thank all the participants of the Asthma and Twin moles studies: Ann Eldridge, Marlene Grace, Kerrie McAloney (sample collection); Melinda Richter, Lisa Bowdler, Steven Crooks (DNA processing); David Smyth, Harry Beeby, Daniel Park (IT support). Funding was provided by the Australian National Health and Medical Research Council (NHMRC, 613627). The NTR/NESDA data described in this paper were funded by the US National Institute of Mental Health (RC2 MH089951, PI Sullivan) as part of the American Recovery and Reinvestment Act of 2009. MARF is supported by a Career Development Fellowship from the NHMRC.

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Authors and Affiliations

  1. Queensland Institute of Medical Research, Brisbane, Queensland, Australia

    J A Revez, L Bain, B Chapman, D L Duffy, N G Martin, G W Montgomery & M A R Ferreira

  2. University of Queensland Diamantina Institute, Brisbane, Queensland, Australia

    J E Powell & P M Visscher

  3. Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands

    R Jansen & B W Penninx

  4. Neuroscience Campus Amsterdam, Amsterdam, The Netherlands

    R Jansen, B W Penninx & D I Boomsma

  5. 23andMe, Inc., Mountain View California, CA, USA

    J Y Tung & D A Hinds

  6. Queensland Brain Institute, Brisbane, Queensland, Australia

    P M Visscher

  7. Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands

    E J C De Geus & D I Boomsma

  8. EMGO institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands

    E J C De Geus & D I Boomsma

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AAGC Collaborators

  • Melanie C Matheson
  • , Guy B Marks
  • , Jennie Hui
  • , Peter Le Souëf
  • , Patrick Danoy
  • , Svetlana Baltic
  • , Dale R Nyholt
  • , Mark Jenkins
  • , Catherine Hayden
  • , John Beilby
  • , Faang Cheah
  • , Pamela A Madden
  • , Andrew C Heath
  • , John L Hopper
  • , Bill Musk
  • , Stephen R Leeder
  • , Eugene H Walters
  • , Alan James
  • , Graham Jones
  • , Michael J Abramson
  • , Colin F Robertson
  • , Shyamali C Dharmage
  • , Matthew A Brown
  •  & Philip J Thompson

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Correspondence to M A R Ferreira.

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Contributors Melanie C Matheson, Guy B Marks, Jennie Hui, Peter Le Souëf, Patrick Danoy, Svetlana Baltic, Dale R Nyholt, Mark Jenkins, Catherine Hayden, John Beilby, Faang Cheah, Pamela A Madden, Andrew C Heath, John L Hopper, Bill Musk, Stephen R Leeder, Eugene H Walters, Alan James, Graham Jones, Michael J Abramson, Colin F Robertson, Shyamali C Dharmage, Matthew A Brown and Philip J Thompson. Affiliation details for this group can be found in the supplementary information.

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Revez, J., Bain, L., Chapman, B. et al. A new regulatory variant in the interleukin-6 receptor gene associates with asthma risk. Genes Immun 14, 441–446 (2013). https://doi.org/10.1038/gene.2013.38

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