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A common variant of the interleukin 6 receptor (IL-6r) gene increases IL-6r and IL-6 levels, without other inflammatory effects

Genes & Immunity volume 8, pages 552–559 (2007)Cite this article

Abstract

Interleukin-6 (IL-6) is a key inflammatory cytokine, signalling to most tissues by binding to a soluble IL-6 receptor (sIL-6r), making a complex with gp130. We used 1273 subjects (mean age 68 years) from the InCHIANTI Italian cohort to study common variation in the IL-6r locus and associations with interleukin 6 receptor (IL-6r), IL-6, gp130 and a battery of inflammatory markers. The rs4537545 single nucleotide polymorphism (SNP) tags the functional non-synonymous Asp358Ala variant (rs8192284) in IL-6r (r2=0.89, n=343). Individuals homozygous for the rs4537545 SNP minor allele (frequency 40%) had a doubling of IL-6r levels (132.48 pg/ml, 95% CI 125.13–140.27) compared to the common allele homozygous group (68.31 pg/ml, 95% CI 65.35–71.41): in per allele regression models, the rs4537545 SNP accounted for 20% of the variance in sIL-6r, with P=5.1 × 10−62. The minor allele of rs4537545 was also associated with higher circulating IL-6 levels (P=1.9 × 10−4). There was no association of this variant with serum levels of gp130 or with any of the studied pro- and anti-inflammatory markers. A common variant of the IL-6r gene results in major changes in IL-6r and IL-6 serum levels, but with no apparent effect on gp130 levels or on inflammatory status in the general population.

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Acknowledgements

This work was supported in part by NIH/NIA Grant R01 AG24233-01 and by the Intramural Research Program, National Institute on Aging, NIH. DM is supported by an NHS Executive National Public Health Career Scientist Award, Ref: PHCSA/00/002. The InCHIANTI study was supported as a ‘targeted project’ (ICS 110.1RS97.71) by the Italian Ministry of Health, by the US National Institute on Aging (Contracts N01-AG-916413 and N01-AG-821336, and 263 MD 9164 13 and 263 MD 821336). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

  1. Peninsula Medical School, Institute of Biomedical and Clinical Science, Exeter, UK

    S Rafiq, T M Frayling, A Murray, A Hurst, K Stevens, M N Weedon & D Melzer

  2. School of Mathematics and Statistics, University of Plymouth, Plymouth, UK

    W Henley

  3. Longitudinal Studies Section, Clinical Research Branch, Gerontology Research Center, National Institute on Aging, Baltimore, MD, USA

    L Ferrucci

  4. Laboratory of Clinical Epidemiology, Italian National Research Council on Aging, Geriatric Rehabilitation Unit, ASF, Firenze, Italy

    S Bandinelli

  5. Department of Medical and Surgical Critical Care, Tuscany Regional Health Agency, IOT, Thrombosis Centre, University of Florence, Firenze, Italy

    A-M Corsi

  6. Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, MD, USA

    J M Guralnik

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  1. S Rafiq
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  8. L Ferrucci
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Corresponding author

Correspondence to D Melzer.

Additional information

Authors' contributions: SR, TF, KS and DM contributed to the design of this study, and led the statistical analysis, writing and editing of the manuscript. AM participated in the coordination and the design of the study, undertook the genotyping and contributed to the editing of the manuscript. AJH and WH assisted with the statistical analysis and editing of the manuscript. MNW undertook the analysis of the genotyping for quality control. SB, LF and JG led the InCHIANTI study including design and data collection, and contributed to the editing of the manuscript. AMC prepared the InCHIANTI DNA and contributed to the editing of the manuscript. All authors read and approved the final manuscript.

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The authors have declared that no competing interests exist.

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Rafiq, S., Frayling, T., Murray, A. et al. A common variant of the interleukin 6 receptor (IL-6r) gene increases IL-6r and IL-6 levels, without other inflammatory effects. Genes Immun 8, 552–559 (2007). https://doi.org/10.1038/sj.gene.6364414

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