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Common variants within the interleukin 4 receptor α gene (IL4R) are associated with susceptibility to osteoarthritis

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Abstract

Primary osteoarthritis (OA) is a common late-onset arthritis that demonstrates a complex mode of transmittance with both joint-site and gender-specific heterogeneity. We have previously linkage-mapped an OA susceptibility locus to a 12-cM interval at chromosome 16p12.3-p12.1 in a cohort of 146 affected female sibling-pair families ascertained by total hip replacement (female-THR families), with a maximum multipoint LOD score of 1.7. Despite the low LOD score, we were encouraged to investigate this interval further following the report of a linkage to the same interval in an Icelandic pedigree with an early-onset form of hip OA. Using public databases, we searched the interval for plausible candidates and concluded that the gene encoding the interleukin 4 receptor α chain (IL4R) was a particularly strong candidate based on its known role in cartilage homeostasis. We genotyped nine common single nucleotide polymorphisms (SNPs) from within IL4R, including six non-synonymous SNPs, in the 146 probands from our female-THR families (stage 1) and in an independent cohort of 310 female-THR cases (stage 2). We compared allele frequencies with those of 399 age-matched female controls. All individuals were UK Caucasians. The minor alleles of two SNPs demonstrated association in both stages, with the most significant association having a P-value of 0.004 with an odds ratio (OR) of 2.1. These two SNPs defined two associated SNP groups. Inheriting a minor SNP allele from both groups was a particular risk factor (OR=2.4, P=0.0008). Our data suggest that functional variants within the IL4R gene predispose to hip OA in Caucasian females.

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Acknowledgements

This work was funded by Research into Ageing and the Arthritis Research Campaign. We thank Professor Andrew Carr and Ms Kim Clipsham who organised the collection of the patient and family samples used in this study. We also thank Professor Tim Spector for providing additional female control samples.

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Authors and Affiliations

  1. Institute of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, University of Oxford, Oxford, OX3 7LD, UK

    Tracy Forster, Kay Chapman & John Loughlin

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  1. Tracy Forster
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  2. Kay Chapman
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  3. John Loughlin
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Correspondence to John Loughlin.

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Forster, T., Chapman, K. & Loughlin, J. Common variants within the interleukin 4 receptor α gene (IL4R) are associated with susceptibility to osteoarthritis. Hum Genet 114, 391–395 (2004). https://doi.org/10.1007/s00439-004-1083-0

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  • DOI: https://doi.org/10.1007/s00439-004-1083-0

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