Skip to main content
Log in

Novel non-HLA-susceptible regions determined by meta-analysis of four genomewide scans for ankylosing spondylitis

  • Research Article
  • Published:
Journal of Genetics Aims and scope Submit manuscript

Abstract

We identified novel non-HLA-susceptible regions for ankylosing spondylitis (AS) by applying the genome-search-meta-analysis (GSMA) method to combine the previous four AS genomewide scan studies including 479 families with 1175 affected individuals. Three original genomescans were mainly analysed for Caucasian families and one analysed for Han Mongolian families. Ten bins had both Psumrnk and Pord < 0.05, suggesting these bins most likely contain AS-linked loci. The 10 bins are 6.2, 16.3, 6.1, 3.3, 6.3, 16.4, 10.5, 17.1, 2.5 and 2.9. The most significant result of linkage was on chromosome 6p22.3-p21.1 (bin 6.2, Psumrnk < 0.000417), where HLA loci are located. By addition of a genome scan of Chinese origin, our GSMA result further confirmed the HLA loci as the greatest susceptible region to AS and suggested that non-HLA loci chromosome 16q, 3p, 10q, 2p, 2q and 17p, may also contain AS-linked loci. The novel loci identified in our result give hints to further studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Braun J., Bollow M., Remlinger G., Eggens U., Rudwaleit M., Distler A. et al. 1998 Prevalence of spondylarthropathies in HLAB27 positive and negative blood donors. Arthritis Rheum. 41, 58–67.

    Article  PubMed  CAS  Google Scholar 

  • Brown M. A., Laval S. H., Brophy S. and Calin A. 2000 Recurrence risk modeling of the genetic susceptibility to ankylosing spondylitis. Ann. Rheum. Dis. 59, 883–886.

    Article  PubMed  CAS  Google Scholar 

  • Brown M. A., Kennedy L. G., MacGregor A. J., Darke C., Duncan E., Shatford J. L. et al. 1997 Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA and the environment. Arthritis Rheum. 40, 1823–1828.

    Article  PubMed  CAS  Google Scholar 

  • Brown M. A., Pile K. D., Kennedy L. G., MacGregor A. J., Darke C., Duncan E. et al. 1998a A genome-wide screen for susceptibility loci in ankylosing spondylitis. Arthritis Rheum. 41, 588–595.

    Article  PubMed  CAS  Google Scholar 

  • Brown M. A., Kennedy L. G., Darke C., Gibson K., Pile K. D., Shatford J. L. et al. 1998b The effect of HLA-DR genes on susceptibility to and severity of ankylosing spondylitis. Arthritis Rheum. 41, 4460–4465.

    Google Scholar 

  • Brown M. A., Brophy S., Bradbury L., Hamersma J., Timms A., Laval S. et al. 2003 Identification of major loci controlling clinical manifestations of ankylosing spondylitis. Arthritis Rheum. 48, 2234–2239.

    Article  PubMed  Google Scholar 

  • de Juan M. D., Reta A., Belzunegui J., Figueroa M., Maruri N. and Cuadrado E. 2004 HLA-A*2402 and a microsatellite (D6S248) are secondary independent susceptibility markers to ankylosing spondylitis in Basque patients. Hum. Immun. 65, 175–180.

    Article  PubMed  Google Scholar 

  • Fisher S. A., Abecasis G. R., Yashar B. M., Zareparsi S., Swaroop A., Iyengar S. K. et al. 2005 meta-analysis of genome scans of age-related mascular degeneration. Hum. Mol. Genet. 14, 2257–2264.

    Article  PubMed  CAS  Google Scholar 

  • Gu M. M., Yuan W. T., Yang J. Q., Zhang J., Xiong X. Y., Yao F. J. et al. 2004 A genome wide scan for the ankylosing spondylitis in susceptibility gene loci to Chinese Han population. Acta Gervetica Sinica 31, 217–220.

    CAS  Google Scholar 

  • Hoyle E., Laval S. H., Calin A., Wordsworth B.P. and Brown M. A. 2000 The X-Chromosome and susceptibility to ankylosing spondylitis. Arthritis Rheum. 43, 1353–1355.

    Article  PubMed  CAS  Google Scholar 

  • Jin L., Weisman M., Zhang G., Ward M., Luo J., Bruckel J. et al. 2005 Lack of association of matrix metalloproteinase 3 (MMP3) genotypes with ankylosing spondylitis susceptibility and severity. Rheumatol. 44, 55–60.

    Article  CAS  Google Scholar 

  • Johnson L., Luke A., Deng H.-W., Mitchell B. D., Comuzzie A. G., Cole S. A. et al. 2005 Meta-analysis of five genome-wide linkage studies for body mass index reveals significant evidence for linkage to chromosome 8p. Int. J. Obes. 29, 413–419.

    Article  CAS  Google Scholar 

  • Koziol J. A. and Feng A. C. 2005 A note on generalized genome scan meta-analysis statistics, BMC Bioinformatics 32.

  • Laval S. H., Timms A., Edwards S., Bradbury L., Brophy S., Milicic A., Rubin L. et al. 2001 Whole-genome screening in ankylosing spondylitis: evidence of non-MHC genetic susceptibility loci. Am. J. Hum. Genet. 68, 918–926.

    Article  PubMed  CAS  Google Scholar 

  • Lee Y. H., Rho Y. H., Choi S. J., Ji J. D. and Song G. G. 2005 Ankylosing spondylitis susceptibility loci defined by genome-search meta-analysis. J. Hum. Genet. 50, 453–459.

    Article  PubMed  CAS  Google Scholar 

  • Maksymowych W. P., Rahman P., Reeve J. P., Gladman D. D., Peddle L. and Inman R. D. 2006 Association of the IL1 gene cluster with susceptibility to ankylosing spondylitis. Arthritis Rheum. 54, 974–985.

    Article  PubMed  CAS  Google Scholar 

  • Maksymowych W. P., Reeve J. P., Reveille J. D., Akey J. M., Buenviaje H. O’Brien L. et al. 2003 High-throughput single — nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondylitis by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. Arthritis Rheum. 48, 2011–2018.

    Article  PubMed  CAS  Google Scholar 

  • Martin T. M., Zhang G., Luo J., Jin L., Doyle T. M., Rajska B. M. et al. 2005 A locus on chromosome 9p predisposes to a specific disease manifestation, acute anterior uveitis, in ankylosing spondylitis, a genetically complex, multisystem, inflammatory disease. Arthritis Rheum. 52, 269–274.

    Article  PubMed  CAS  Google Scholar 

  • McGarry F., Neilly J., Anderson N., Sturrock R. and Field M. 2001 A polymorphism within the interleukin 1 receptor antagonist (IL1Ra) gene is associated with ankylosing spondylitis. Rheumatol. 40, 1359–1364.

    Article  CAS  Google Scholar 

  • Miceli-Richard C., Zouali H., Said-Nahal R., Lesage S., Merlin F., Toma C. et al. 2004 Significant linkage to spondyloarthropathy on 9q31–34. Hum. Mol. Genet. 13, 1641–1648.

    Article  PubMed  CAS  Google Scholar 

  • Pardi F., Levinson D. F. and Lewis C. M. 2005 GSMA: Software implementation of the genome search meta-analysis method. Bioinformatics 21, 4430–4431.

    Article  PubMed  CAS  Google Scholar 

  • Timms A. E., Crane A. M., Sims A. M., Cordell H. J., Bradbury L. A. Abbott A. et al. 2004 The interlukin 1 gene cluster contains a major susceptibility locus for ankylosing spondylitis. Am. J. Hum. Genet. 75, 585–595.

    Article  Google Scholar 

  • Van der Linden S., Valkenburg H. A. and Cats A. 1984 Evaluation of diagnostic criteria for ankylosing spondylitis: a proposal for modification of the New York criteria. Arthritis Rheum. 27, 361–368.

    Article  PubMed  Google Scholar 

  • Van der Paardt M., Crusius J. B., Garcia-Gonzalez M. A., Baudoin P. et al. 2002 Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms in ankylosing spondylitis. Rheumatol. 41, 1419–1423.

    Article  Google Scholar 

  • Van der Paardt M., Crusius J. B., de Koning M. H. M. T., Morre S. A., van de Stadt R. J., Dijkmans B. A. C. et al. 2005 No evidence for involvement of the Toll-like receptor 4 (TLR4)A896G and CD14-C260T polymorphisms in susceptibility to ankylosing spondylitis. Ann. Rheum. Dis. 64, 235–238.

    Article  PubMed  Google Scholar 

  • Wise L. H., Lanchbury J. S. and Lewis C. M. 1999 Meta-analysis of genome searches. Ann. Hum. Genet. 63, 263–272.

    Article  PubMed  CAS  Google Scholar 

  • Zhang G., Luo J., Bruckel J., Weisman M. A., Schumacher H. R., Khan M. A. et al. 2004 Genetic studies in familial ankylosing spondylitis susceptibility. Arthritis Rheum. 50, 2246–2254.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jieruo Gu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, J., Li, C., Xu, H. et al. Novel non-HLA-susceptible regions determined by meta-analysis of four genomewide scans for ankylosing spondylitis. J Genet 87, 75–81 (2008). https://doi.org/10.1007/s12041-008-0010-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12041-008-0010-x

Keywords

Navigation