• Open Access

Common genetic variants associated with disease from genome-wide association studies are mutually exclusive in prostate cancer and rheumatoid arthritis

Authors

  • Gisela Orozco,

    1. Arthritis Research UK Epidemiology Unit, School of Translational Medicine, University of Manchester, Manchester, UK
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    • Joint first authors.
  • Chee L. Goh,

    1. Oncogenetics Team, The Institute of Cancer Research, Sutton, Surrey, UK
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  • Ali Amin Al Olama,

    1. Cancer Research UK Centre for Cancer Genetic Epidemiology, Strangeways Laboratory, University of Cambridge, Cambridge, UK
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  • Sara Benlloch-Garcia,

    1. Cancer Research UK Centre for Cancer Genetic Epidemiology, Strangeways Laboratory, University of Cambridge, Cambridge, UK
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  • Koveela Govindasami,

    1. Oncogenetics Team, The Institute of Cancer Research, Sutton, Surrey, UK
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  • Michelle Guy,

    1. Oncogenetics Team, The Institute of Cancer Research, Sutton, Surrey, UK
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  • Kenneth R. Muir,

    1. Health Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry, UK
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  • Graham G. Giles,

    1. Cancer Epidemiology Centre, The Cancer Council Victoria, Carlton, Vic, Australia
    2. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Melbourne, Vic, Australia
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  • Gianluca Severi,

    1. Cancer Epidemiology Centre, The Cancer Council Victoria, Carlton, Vic, Australia
    2. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Melbourne, Vic, Australia
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  • David E. Neal,

    1. Surgical Oncology (Uro-Oncology: S4), University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
    2. Cancer Research UK Cambridge Research Institute, Cambridge, UK
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  • Freddie C. Hamdy,

    1. Nuffield Department of Surgery, University of Oxford, Oxford, UK
    2. Faculty of Medical Science, University of Oxford, John Radcliffe Hospital, Oxford, UK
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  • Jenny L. Donovan,

    1. School of Social and Community Medicine, University of Bristol, Bristol, UK
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  • Zsofia Kote-Jarai,

    1. Oncogenetics Team, The Institute of Cancer Research, Sutton, Surrey, UK
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  • Douglas F. Easton,

    1. Cancer Research UK Centre for Cancer Genetic Epidemiology, Strangeways Laboratory, University of Cambridge, Cambridge, UK
    2. Department of Public Health, University of Cambridge, Cambridge, UK
    3. Department of Primary Care, University of Cambridge, Cambridge, UK
    4. Department of Oncology, University of Cambridge, Cambridge, UK
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  • Steve Eyre,

    1. Arthritis Research UK Epidemiology Unit, School of Translational Medicine, University of Manchester, Manchester, UK
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  • Rosalind A. Eeles

    Corresponding author
    1. Oncogenetics Team, The Institute of Cancer Research, Sutton, Surrey, UK
    2. Academic Urology Unit, Royal Marsden Foundation NHS Trust, Sutton, Surrey, UK
    • Correspondence: Professor Rosalind Eeles, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Downs Road, Sutton SM2 5PT, UK.

      e-mail: Rosalind.eeles@icr.ac.uk

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Abstract

What's known on the subject? and What does the study add?

  • The link between inflammation and cancer has long been reported and inflammation is thought to play a role in the pathogenesis of many cancers, including prostate cancer (PrCa). Over the last 5 years, genome-wide association studies (GWAS) have reported numerous susceptibility loci that predispose individuals to many different traits.
  • The present study aims to ascertain if there are common genetic risk profiles that might predispose individuals to both PrCa and the autoimmune inflammatory condition, rheumatoid arthritis. These results could have potential public heath impact in terms of screening and chemoprevention.

Objectives

  • To investigate if potential common pathways exist for the pathogenesis of autoimmune disease and prostate cancer (PrCa).
  • To ascertain if the single nucleotide polymorphisms (SNPs) reported by genome-wide association studies (GWAS) as being associated with susceptibility to PrCa are also associated with susceptibility to the autoimmune disease rheumatoid arthritis (RA).

Materials and Methods

  • The original Wellcome Trust Case Control Consortium (WTCCC) UK RA GWAS study was expanded to include a total of 3221 cases and 5272 controls.
  • In all, 37 germline autosomal SNPs at genome-wide significance associated with PrCa risk were identified from a UK/Australian PrCa GWAS.
  • Allele frequencies were compared for these 37 SNPs between RA cases and controls using a chi-squared trend test and corrected for multiple testing (Bonferroni).

Results

  • In all, 33 SNPs were able to be analysed in the RA dataset. Proxies could not be located for the SNPs in 3q26, 5p15 and for two SNPs in 17q12.
  • After applying a Bonferroni correction for the number of SNPs tested, the SNP mapping to CCHCR1 (rs130067) retained statistically significant evidence for association (P = 6 × 10–4; odds ratio [OR] = 1.15, 95% CI: 1.06–1.24); this has also been associated with psoriasis.
  • However, further analyses showed that the association of this allele was due to confounding by RA-associated HLA-DRB1 alleles.

Conclusions

  • There is currently no evidence that SNPs associated with PrCa at genome-wide significance are associated with the development of RA.
  • Studies like this are important in determining if common genetic risk profiles might predispose individuals to many diseases, which could have implications for public health in terms of screening and chemoprevention.

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