Abstract
Objective
Ulcerative colitis (UC) and Crohn’s disease (CD) result from an interaction between genetic and environmental factors. Though several polymorphisms have been identified in PTPN2, their roles in the incidence of UC and CD are conflicting. This meta-analysis was aimed to clarify the impact of these polymorphisms on UC and CD risk.
Method
PubMed, EMBASE, Cochrane Library and CBM were searched until 23 July 2013 for eligible studies on three PTPN2 polymorphisms: rs2542151, rs1893217 and rs7234029. Data were extracted, and pooled odd ratios (ORs) as well as 95 % confidence intervals (95 % CIs) were calculated.
Conclusion
The meta-analysis indicated that rs2542151, rs1893217 and rs1893217 were associated with increased CD risk, while the former was associated with increased UC risk. The differences in age of onset and ethnic groups may influence the associations. Gene–gene and gene–environment interactions should be investigated in the future.
Results
Seventeen studies with 18,308 cases and 20,406 controls were included. Significant associations were found between rs2542151 polymorphism and CD susceptibility (OR = 1.22, 95 % CI, 1.15–1.30, I 2 = 32 %), as well as between rs2542151 and UC susceptibility (OR = 1.16, 95 % CI, 1.07–1.25, I 2 = 39 %). A similar result was found in Caucasians, but not in Asians. Moreover, a significant increase in CD risk for all carriers of the minor allele of rs1893217 (OR = 1.45, 95 % CI, 1.23–1.70, I 2 = 0 %) and rs7234029 (OR = 1.36, 95 % CI, 1.16–1.59, I 2 = 0 %) were found. For children, the rs1893217 polymorphism appeared to confer susceptibility to CD (OR = 1.56, 95 % CI, 1.28–1.89, I 2 = 0 %).
Similar content being viewed by others
References
Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347(6):417–29.
Leone V, Chang EB, Devkota S. Diet, microbes, and host genetics: the perfect storm in inflammatory bowel diseases. J Gastroenterol. 2013;48(3):315–21.
Maeda S, Hsu LC, Liu H, Bankston LA, Iimura M, Kagnoff MF, et al. Nod2 mutation in Crohn’s disease potentiates NF-kappaB activity and IL-1beta processing. Science. 2005;307(5710):734–8.
Hammer HF. Gut microbiota and inflammatory bowel disease. Dig Dis. 2011;29(6):550–3.
Simmons A. Crohn’s disease: Genes, viruses and microbes. Nature. 2010;466(7307):699–700.
Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42(12):1118–25.
Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, Taylor KD, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011;43(3):246–52.
Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474(7351):307–17.
Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411(6837):603–6.
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(5804):1461–3.
Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39(2):207–11.
Libioulle C, Louis E, Hansoul S, Sandor C, Farnir F, Franchimont D, et al. Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet. 2007;3(4):e58.
Silverberg MS, Duerr RH, Brant SR, Bromfield G, Datta LW, Jani N, et al. Refined genomic localization and ethnic differences observed for the IBD5 association with Crohn’s disease. Eur J Hum Genet. 2007;15(3):328–35.
Yamazaki K, McGovern D, Ragoussis J, Paolucci M, Butler H, Jewell D, et al. Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn’s disease. Hum Mol Genet. 2005;14(22):3499–506.
Lees CW, Barrett JC, Parkes M, Satsangi J. New IBD genetics: common pathways with other diseases. Gut. 2011;60(12):1739–53.
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447(7145):661–78.
Tonks NK, Neel BG. Combinatorial control of the specificity of protein tyrosine phosphatases. Curr Opin Cell Biol. 2001;13(2):182–95.
Scharl M, Paul G, Weber A, Jung BC, Docherty MJ, Hausmann M, et al. Protection of epithelial barrier function by the Crohn’s disease associated gene protein tyrosine phosphatase n2. Gastroenterology. 2009;137(6):2030–40.
Scharl M, Wojtal KA, Becker HM, Fischbeck A, Frei P, Arikkat J, et al. Protein tyrosine phosphatase nonreceptor type 2 regulates autophagosome formation in human intestinal cells. Inflamm Bowel Dis. 2012;18(7):1287–302.
Scharl M, McCole DF, Weber A, Vavricka SR, Frei P, Kellermeier S, et al. Protein tyrosine phosphatase N2 regulates TNFα-induced signalling and cytokine secretion in human intestinal epithelial cells. Gut. 2011;60(2):189–97.
Scharl M, Hruz P, McCole DF. Protein tyrosine phosphatase non-receptor Type 2 regulates IFN-γ-induced cytokine signaling in THP-1 monocytes. Inflamm Bowel Dis. 2010;16(12):2055–64.
You-Ten KE, Muise ES, Itié A, Michaliszyn E, Wagner J, Jothy S, et al. Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice. J Exp Med. 1997;186(5):683–93.
Heinonen KM, Nestel FP, Newell EW, Charette G, Seemayer TA, Tremblay ML, et al. T-cell protein tyrosine phosphatase deletion results in progressive systemic inflammatory disease. Blood. 2004;103(9):3457–64.
Fisher SA, Tremelling M, Anderson CA, Gwilliam R, Bumpstead S, Prescott NJ, et al. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn’s disease. Nat Genet. 2008;40(6):710–2.
Jung C, Colombel JF, Lemann M, Beaugerie L, Allez M, Cosnes J, et al. Genotype/phenotype analyses for 53 Crohn’s disease associated genetic polymorphisms. PLoS ONE. 2012;7(12):e52223.
Lv C, Yang X, Zhang Y, Zhao X, Chen Z, Long J, et al. Confirmation of three inflammatory bowel disease susceptibility loci in a Chinese cohort. Int J Colorectal Dis. 2012;27(11):1465–72.
Waterman M, Xu W, Stempak JM, Milgrom R, Bernstein CN, Griffiths AM, et al. Distinct and overlapping genetic loci in Crohn’s disease and ulcerative colitis: correlations with pathogenesis. Inflamm Bowel Dis. 2011;17(9):1936–42.
Yu W, Hegarty JP, Berg A, Kelly AA, Wang Y, Poritz LS, et al. PTPN2 is associated with Crohn’s disease and its expression is regulated by NKX2-3. Dis Markers. 2012;32(2):83–91.
Morgan AR, Han DY, Huebner C, Lam WJ, Fraser AG, Ferguson LR, et al. PTPN2 but not PTPN22 is associated with Crohn’s disease in a New Zealand population. Tissue Antigens. 2010;76(2):119–25.
Glas J, Wagner J, Seiderer J, Olszak T, Wetzke M, Beigel F, et al. PTPN2 gene variants are associated with susceptibility to both Crohn’s disease and ulcerative colitis supporting a common genetic disease background. PLoS ONE. 2012;7(3):e33682.
Franke A, Balschun T, Karlsen TH, Hedderich J, May S, Lu T, Schuldt D, et al. Replication of signals from recent studies of Crohn’s disease identifies previously unknown disease loci for ulcerative colitis. Nat Genet. 2008;40(6):713–5.
Peter I, Mitchell AA, Ozelius L, Erazo M, Hu J, Doheny D, et al. Evaluation of 22 genetic variants with Crohn’s disease risk in the Ashkenazi Jewish population: a case-control study. BMC Med Genet. 2011;12:63.
Latiano A, Palmieri O, Latiano T, Corritore G, Bossa F, Martino G, et al. Investigation of multiple susceptibility loci for inflammatory bowel disease in an Italian cohort of patients. PLoS ONE. 2011;6(7):e22688.
Yamazaki K, Takahashi A, Takazoe M, Kubo M, Onouchi Y, Fujino A, et al. Positive association of genetic variants in the upstream region of NKX2-3 with Crohn’s disease in Japanese patients. Gut. 2009;58(2):228–32.
Weersma RK, Stokkers PC, Cleynen I, Wolfkamp SC, Henckaerts L, Schreiber S, et al. Confirmation of multiple Crohn’s disease susceptibility loci in a large Dutch-Belgian cohort. Am J Gastroenterol. 2009;104(3):630–8.
Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet. 2007;39(7):830–2.
Chen ZY. Correlation between gene polymorphism of IL23R, PTPN2, 10q and inflammatory bowel disease. Guangzhou: Southern Medical University; 2008.
Amre DK, Mack DR, Morgan K, Israel D, Deslandres C, Seidman EG, et al. Susceptibility loci reported in genome-wide association studies are associated with Crohn’s disease in Canadian children. Aliment Pharmacol Ther. 2010;31(11):1186–91.
Marcil V, Mack DR, Kumar V, Faure C, Carlson CS, Beaulieu P, et al. Association between the PTPN2 gene and Crohn’s disease: dissection of potential causal variants. Inflamm Bowel Dis. 2013;19(6):1149–55.
Scharl M, Mwinyi J, Fischbeck A, Leucht K, Eloranta JJ, Arikkat J, et al. Crohn’s disease-associated polymorphism within the PTPN2 gene affects muramyl-dipeptide-induced cytokine secretion and autophagy. Inflamm Bowel Dis. 2012;18(5):900–12.
Burchard EG, Ziv E, Coyle N, Gomez SL, Tang H, Karter AJ, et al. The importance of race and ethnic background in biomedical research and clinical practice. N Engl J Med. 2003;348:1170–5.
Marcil V, Seidman E, Sinnett D, Boudreau F, Gendron FP, Beaulieu JF, et al. Modification in oxidative stress, inflammation, and lipoprotein assembly in response to hepatocyte nuclear factor 4alpha knockdown in intestinal epithelial cells. J Biol Chem. 2010;285(52):40448–60.
UK IBD Genetics Consortium, Barrett JC, Lee JC, Lees CW, Prescott NJ, Anderson CA, et al. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet. 2009;41(12):1330–4.
Author information
Authors and Affiliations
Corresponding author
Additional information
Responsible Editor: Ian Ahnfelt-Rønne.
J. X. Zhang and J. H. He contributed equally to this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Zhang, JX., He, JH., Wang, J. et al. Associations between PTPN2 polymorphisms and susceptibility to ulcerative colitis and Crohn’s disease: a meta-analysis. Inflamm. Res. 63, 71–79 (2014). https://doi.org/10.1007/s00011-013-0673-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00011-013-0673-5