Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Autophagy-related IRGM genes confer susceptibility to ankylosing spondylitis in a Chinese female population: a case–control study

Genes & Immunity volume 18, pages 42–47 (2017)Cite this article

Subjects

Abstract

It is known that ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) shared a common genetic component. The gist of current study is to assess the role of IBD-associated autophagy gene IRGM on AS susceptibility in a Chinese Han population. A total of 1270 unrelated subjects (643 AS and 627 controls) were enrolled. Two tag single-nucleotide polymorphisms (SNPs) (rs10065172 and rs4958846) were selected and were genotyped by iMLDR Assay technology. Genotypes and haplotype analysis were conducted by using SPSS 16.0 and haploview 4.2 software. Among two tag SNPs of IRGM, no correlation was observed between rs10065172 and AS susceptibility. For rs4958846, genotype and allelic frequencies were marginally discrepant between female cases and controls before, not after, Bonferroni correction (P=0.049; P=0.031). Logistic regression analysis revealed that carriers with CT+TT or CT genotype had a significantly decreased risk for developing AS among female subjects when compared with CC genotype (OR=0.514, 95% CI=0.301–0.876, P=0.014; OR=0.518, 95% CI=0.297–0.902, P=0.020, respectively). Additionally, a risk haplotype rs4958846C–rs10065172C (OR=2.093, 95% CI=1.301–3.368) and a protective haplotype rs4958846T–rs10065172C (OR=0.652, 95% CI=0.441–0.964) were also identified to be associated with female AS. IBD-associated IRGM gene is also associated with AS susceptibility in the Chinese female population, indicating that autophagy pathway may involve in AS genetic predisposition.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Brown MA, Kenna T, Wordsworth BP . Genetics of ankylosing spondylitis–insights into pathogenesis. Nat Rev Rheumatol 2016; 12: 81–91.

    Article  CAS  Google Scholar 

  2. Pedersen OB, Svendsen AJ, Ejstrup L, Skytthe A, Harris JR, Junker P . Ankylosing spondylitis in Danish and Norwegian twins: occurrence and the relative importance of genetic vs. environmental effectors in disease causation. Scand J Rheumatol 2008; 37: 120–126.

    Article  CAS  Google Scholar 

  3. Evans DM, Spencer CC, Pointon JJ, Su Z, Harvey D, Kochan G et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet 2011; 43: 761–767.

    Article  CAS  Google Scholar 

  4. Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 2007; 39: 1329–1337.

    Article  CAS  Google Scholar 

  5. Reveille JD, Sims AM, Danoy P, Evans DM, Leo P, Pointon JJ et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 2010; 42: 123–127.

    Article  CAS  Google Scholar 

  6. Chauhan S, Mandell MA, Deretic V . IRGM governs the core autophagy machinery to conduct antimicrobial defense. Mol Cell 2015; 58: 507–521.

    Article  CAS  Google Scholar 

  7. Deretic V, Saitoh T, Akira S . Autophagy in infection, inflammation and immunity. Nat Rev Immunol 2013; 13: 722–737.

    Article  CAS  Google Scholar 

  8. Brest P, Lapaquette P, Souidi M, Lebrigand K, Cesaro A, Vouret-Craviari V et al. A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease. Nat Genet 2011; 43: 242–245.

    Article  CAS  Google Scholar 

  9. Rufini S, Ciccacci C, Di Fusco D, Ruffa A, Pallone F, Novelli G et al. Autophagy and inflammatory bowel disease: association between variants of the autophagy-related IRGM gene and susceptibility to Crohn's disease. Dig Liver Dis 2015; 47: 744–750.

    Article  CAS  Google Scholar 

  10. Moon CM, Shin DJ, Kim SW, Son NH, Park A, Park B et al. Associations between genetic variants in the IRGM gene and inflammatory bowel diseases in the Korean population. Inflamm Bowel Dis 2013; 19: 106–114.

    Article  Google Scholar 

  11. Baskaran K, Pugazhendhi S, Ramakrishna BS . Association of IRGM gene mutations with inflammatory bowel disease in the Indian population. PLoS One 2014; 9: e106863.

    Article  Google Scholar 

  12. Thjodleifsson B, Geirsson AJ, Bjornsson S, Bjarnason I . A common genetic background for inflammatory bowel disease and ankylosing spondylitis: a genealogic study in Iceland. Arthritis Rheum 2007; 56: 2633–2639.

    Article  Google Scholar 

  13. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012; 491: 119–124.

    Article  CAS  Google Scholar 

  14. Parkes M, Cortes A, van Heel DA, Brown MA . Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet 2013; 14: 661–673.

    Article  CAS  Google Scholar 

  15. Asquith M, Elewaut D, Lin P, Rosenbaum JT . The role of the gut and microbes in the pathogenesis of spondyloarthritis. Best Pract Res Clin Rheumatol 2014; 28: 687–702.

    Article  Google Scholar 

  16. De Wilde K, Debusschere K, Beeckman S, Jacques P, Elewaut D . Integrating the pathogenesis of spondyloarthritis: gut and joint united? Curr Opin Rheumatol 2015; 27: 189–196.

    Article  CAS  Google Scholar 

  17. Costello ME, Ciccia F, Willner D, Warrington N, Robinson PC, Gardiner B et al. Intestinal dysbiosis in ankylosing spondylitis. Arthritis Rheumatol 2014, e-pub ahead of print 21 November 2014 doi:10.1002/art.38967.

    Article  Google Scholar 

  18. Halldorsson BV, Istrail S, De La Vega FM . Optimal selection of SNP markers for disease association studies. Hum Hered 2004; 58: 190–202.

    Article  CAS  Google Scholar 

  19. Mahdevar G, Zahiri J, Sadeghi M, Nowzari-Dalini A, Ahrabian H, Tag SN . selection via a genetic algorithm. J Biomed Inform 2010; 43: 800–804.

    Article  CAS  Google Scholar 

  20. Halperin E, Kimmel G, Shamir R, Tag SNP . selection in genotype data for maximizing SNP prediction accuracy. Bioinformatics 2005; 21 (Suppl 1): i195–i203.

    Article  CAS  Google Scholar 

  21. Reveille JD . Genetics of spondyloarthritis—beyond the MHC. Nat Rev Rheumatol 2012; 8: 296–304.

    Article  CAS  Google Scholar 

  22. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314: 1461–1463.

    Article  CAS  Google Scholar 

  23. Strange A, Capon F, Spencer CC, Knight J, Weale ME, Allen MH et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet 2010; 42: 985–990.

    Article  CAS  Google Scholar 

  24. Xiang YJ, Dai SM . Prevalence of rheumatic diseases and disability in China. Rheumatol Int 2009; 29: 481–490.

    Article  Google Scholar 

  25. Hughes GC, Choubey D . Modulation of autoimmune rheumatic diseases by oestrogen and progesterone. Nat Rev Rheumatol 2014; 10: 740–751.

    Article  CAS  Google Scholar 

  26. Schmidt M, Hartung R, Capellino S, Cutolo M, Pfeifer-Leeg A, Straub RH . Estrone/17beta-estradiol conversion to, and tumor necrosis factor inhibition by, estrogen metabolites in synovial cells of patients with rheumatoid arthritis and patients with osteoarthritis. Arthritis Rheum 2009; 60: 2913–2922.

    Article  CAS  Google Scholar 

  27. Jimenez-Balderas FJ, Tapia-Serrano R, Madero-Cervera JI, Murrieta S, Mintz G . Ovarian function studies in active ankylosing spondylitis in women. Clinical response to estrogen therapy. J Rheumatol 1990; 17: 497–502.

    CAS  Google Scholar 

  28. Sobolewska A, Gajewska M, Zarzynska J, Gajkowska B, Motyl T . IGF-1 EGF and sex steroids regulate autophagy in bovine mammary epithelial cells via the mTOR pathway. Eur J Cell Biol 2009; 88: 117–130.

    Article  CAS  Google Scholar 

  29. Lista P, Straface E, Brunelleschi S, Franconi F, Malorni W . On the role of autophagy in human diseases: a gender perspective. J Cell Mol Med 2011; 15: 1443–1457.

    Article  CAS  Google Scholar 

  30. Straface E, Gambardella L, Brandani M, Malorni W . Sex differences at cellular level: 'cells have a sex'. Handb Exp Pharmacol 2012: 49–65.

  31. Yuan L, Ke Z, Ma J, Guo Y, Li Y . IRGM gene polymorphisms and haplotypes associate with susceptibility of pulmonary tuberculosis in Chinese Hubei Han population. Tuberculosis (Edinb) 2016; 96: 58–64.

    Article  CAS  Google Scholar 

  32. Bahari G, Hashemi M, Taheri M, Naderi M, Eskandari-Nasab E, Atabaki M . Association of IRGM polymorphisms and susceptibility to pulmonary tuberculosis in Zahedan, Southeast Iran. ScientificWorldJournal 2012; 2012: 950801.

    PubMed Central  Google Scholar 

  33. Lu XC, Tao Y, Wu C, Zhao PL, Li K, Zheng JY et al. Association between variants of the autophagy related gene—IRGM and susceptibility to Crohn's disease and ulcerative colitis: a meta-analysis. PLoS One 2013; 8: e80602.

    Article  Google Scholar 

  34. Na SY, Park SS, Seo JK . Genetic polymorphisms in autophagy-associated genes in Korean children with early-onset Crohn disease. J Pediatr Gastroenterol Nutr 2015; 61: 285–291.

    Article  CAS  Google Scholar 

  35. Laukens D, Peeters H, Marichal D, Vander Cruyssen B, Mielants H, Elewaut D et al. CARD15 gene polymorphisms in patients with spondyloarthropathies identify a specific phenotype previously related to Crohn's disease. Ann Rheum Dis 2005; 64: 930–935.

    Article  CAS  Google Scholar 

  36. van der Linden S, Valkenburg HA, Cats A . Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 1984; 27: 361–368.

    Article  CAS  Google Scholar 

  37. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B et al. The structure of haplotype blocks in the human genome. Science 2002; 296: 2225–2229.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The study was supported by grants from the National Natural Science Foundation of China (30972530, 81273169, 81573218 and 81571572). We thank all patients and healthy subjects who provided the DNA and information necessary for our study. We also thank Shanghai Genesky Bio-Tech Co., Ltd. (http://biotech.geneskies.com/index.html), for valuable help with the test of SNPs.

Author information

Author notes

  1. Q Xia and M Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China

    Q Xia, M Wang, X Yang, X Li, X Zhang & F Pan

  2. Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China

    S Xu, Z Shuai, J Xu & C Ding

  3. Department of Obstetrics, South Medical University Affiliated Maternal & Child Health Hospital of Foshan, Foshan, Guangdong, China

    D Fan

  4. Menzies Research Institute Tasmania, University of Tasmania, Hobart, TAS, Australia

    C Ding & F Pan

Authors
  1. Q Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. X Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. X Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. X Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Z Shuai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. F Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F Pan.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on Genes and Immunity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xia, Q., Wang, M., Yang, X. et al. Autophagy-related IRGM genes confer susceptibility to ankylosing spondylitis in a Chinese female population: a case–control study. Genes Immun 18, 42–47 (2017). https://doi.org/10.1038/gene.2016.48

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2016.48

This article is cited by

Search

Advanced search

Quick links