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Extended haplotypes and linkage disequilibrium in the IL1R1–IL1A–IL1B–IL1RN gene cluster: association with knee osteoarthritis

Genes & Immunity volume 5, pages 451–460 (2004)Cite this article

Abstract

The interleukin-1 gene cluster is a key regulator in a number of chronic disease processes. We explored the linkage between nine polymorphic loci in the IL1R1 promoter, eight in the IL1A–IL1B–IL1RN gene complex, and their association with osteoarthritis (OA), a common complex disease associated with low-level inflammation. Using 195 healthy controls, we identified eight novel polymorphisms in the IL1R1 exon 1A region. We found limited LD between IL1R1 and the IL1A–IL1B–IL1RN cluster, although LD within these two individual groups was high. To test association with knee OA, we genotyped 141 patients from Bristol (UK) at the 17 loci. IL1R1 promoter haplotypes showed no association with disease. However, within the IL1A–IL1B–IL1RN complex, we identified a common haplotype conferring a four-fold risk of OA (P=0.00043; Pc=0.0043) and one IL1B–IL1RN haplotype conferring a four-fold reduced risk (P=0.0036; Pc=0.029). To replicate these associations, we subsequently examined 163 knee OA patients from London. Here, the effects of the haplotypes were confirmed: the risk IL1A–IL1B–IL1RN haplotype conferred a two-fold risk of OA (P=0.02), and the protective IL1B–IL1RN haplotype conferred a five-fold reduced risk of OA (P=0.0000008). These results may help to explain the genome-wide scan linkage data and functional observations concerning association between IL-1 and OA.

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Acknowledgements

We thank Dr Nigel Wood for oligonucleotide synthesis, Doris Culpan for nucleotide sequencing and Gabriela Surdulescu for sample preparation from the London OA cohort.

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Authors and Affiliations

  1. University of Bristol Department of Pathology and Microbiology, Homoeopathic Hospital Site, Cotham, Bristol, UK

    A J P Smith, L J Keen, C J Elson & J L Bidwell

  2. University of Bristol Division of Medicine, Veterinary Anatomy, Southwell Street, Bristol, UK

    M J Billingham

  3. Department of Orthopaedic Surgery, Avon Orthopaedic Centre, Southmead Hospital, Bristol, UK

    M J Perry

  4. Rheumatology Unit, Bristol Royal Infirmary, Marlborough Street, Bristol, UK

    J R Kirwan

  5. Molecular Genetics Department, Amgen, 51 University Street, Seattle, Washington, USA

    J E Sims

  6. Academic Rheumatology Unit, University of Nottingham, Nottingham City Hospital, Nottingham, UK

    M Doherty

  7. Twin Research & Genetic Epidemiology Unit, St Thomas Hospital, London, UK

    T D Spector

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  1. A J P Smith
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Correspondence to A J P Smith.

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Smith, A., Keen, L., Billingham, M. et al. Extended haplotypes and linkage disequilibrium in the IL1R1–IL1A–IL1B–IL1RN gene cluster: association with knee osteoarthritis. Genes Immun 5, 451–460 (2004). https://doi.org/10.1038/sj.gene.6364107

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