Journal of Gastroenterology

, 46:1081 | Cite as

Haplotype in the IBD5 region is associated with refractory Crohn’s disease in Slovenian patients and modulates expression of the SLC22A5 gene

Original Article—Alimentary Tract

Abstract

Background

The IBD5 locus (OMIM ID 606348) on chromosome 5 was suggested to be one of the most important genetic factors involved in the pathogenesis of inflammatory bowel diseases (IBDs). However the main contributor from this region is still unknown.

Methods

We investigated the possible association of the IBD5 locus with IBD in Slovenian patients and correlation between disease-associated single nucleotide polymorphisms (SNPs) and quantitative gene expression (eQTL) of candidate genes from the IBD5 locus in peripheral blood lymphocytes and colon tissue biopsies from IBD patients. We genotyped SNPs from the IBD5 locus in 312 healthy controls and 632 IBD patients.

Results

We found statistically significant association of polymorphisms rs1050152 in gene SLC22A4 (p = 0.005, OR = 2.177, 95% CI = 1.270–3.526) and rs2631372 in gene SLC22A5 (p = 0.001, OR = 0.473, 95% CI = 0.307–0.731) and TC haplotype of both polymorphisms (p = 0.006, OR = 1,541, 95% CI = 1.130–2.100) with refractory Crohn’s disease (CD) in Slovenian patients who do not respond to standard therapy, including patients who develop fistulas. We found decreased expression of SLC22A4 and SLC22A5 genes in peripheral blood lymphocytes from IBD patients compared to control group and decreased expression of SLC22A5 gene in inflamed tissue biopsies compared to noninflamed colon (p = 0.009). We found lower expression of SLC22A5 gene in IBD patients with disease-susceptible genotypes for both disease-associated SNPs.

Conclusions

Our data suggest that SNPs and haplotype in the IBD5 SLC22A4/SLC22A5 region contribute to the development of particularly refractory Crohn’s disease in the Slovenian population, and expression studies in blood lymphocytes and colon tissue biopsies and eQTL analysis suggest that SLC22A5 is the main gene in the IBD5 region contributing to the IBD pathogenesis.

Keywords

Inflammatory bowel disease IBD5 Expression quantitative trait locus (eQTL) 

References

  1. 1.
    Weersma RK, van Dullemen HM, van der SG, Nolte IM, Kleibeuker JH, Dijkstra G. Review article: inflammatory bowel disease and genetics. Aliment Pharmacol Ther. 2007;26(Suppl 2):57–65.Google Scholar
  2. 2.
    Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347:417–29.PubMedCrossRefGoogle Scholar
  3. 3.
    Mathew CG. New links to the pathogenesis of Crohn disease provided by genome-wide association scans. Nat Rev Genet. 2008;9:9–14.PubMedCrossRefGoogle Scholar
  4. 4.
    Arnott ID, Nimmo ER, Drummond HE, Fennell J, Smith BR, MacKinlay E, et al. NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn’s disease patients: evidence for genetic heterogeneity within Europe? Genes Immun. 2004;5:417–25.PubMedCrossRefGoogle Scholar
  5. 5.
    Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;411:599–603.PubMedCrossRefGoogle Scholar
  6. 6.
    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;411:603–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Bairead E, Harmon DL, Curtis AM, Kelly Y, O’Leary C, Gardner M, et al. Association of NOD2 with Crohn’s disease in a homogenous Irish population. Eur J Hum Genet. 2003;11:237–44.PubMedCrossRefGoogle Scholar
  8. 8.
    Economou M, Trikalinos TA, Loizou KT, Tsianos EV, Ioannidis JP. Differential effects of NOD2 variants on Crohn’s disease risk and phenotype in diverse populations: a metaanalysis. Am J Gastroenterol. 2004;99:2393–404.PubMedCrossRefGoogle Scholar
  9. 9.
    Zhang H, Massey D, Tremelling M, Parkes M. Genetics of inflammatory bowel disease: clues to pathogenesis. Br Med Bull. 2008;87:17–30.PubMedCrossRefGoogle Scholar
  10. 10.
    Rioux JD, Daly MJ, Silverberg MS, Lindblad K, Steinhart H, Cohen Z, et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet. 2001;29:223–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, McLeod RS, Griffiths AM, et al. Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. Am J Hum Genet. 2000;66:1863–70.PubMedCrossRefGoogle Scholar
  12. 12.
    Rebouche CJ, Seim H. Carnitine metabolism and its regulation in microorganisms and mammals. Annu Rev Nutr. 1998;18:39–61.PubMedCrossRefGoogle Scholar
  13. 13.
    Wu X, Huang W, Prasad PD, Seth P, Rajan DP, Leibach FH, et al. Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter. J Pharmacol Exp Ther. 1999;290:1482–92.PubMedGoogle Scholar
  14. 14.
    Peltekova VD, Wintle RF, Rubin LA, Amos CI, Huang Q, Gu X, et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet. 2004;36:471–5.PubMedCrossRefGoogle Scholar
  15. 15.
    Noble CL, Nimmo ER, Drummond H, Ho GT, Tenesa A, Smith L, et al. The contribution of OCTN1/2 variants within the IBD5 locus to disease susceptibility and severity in Crohn’s disease. Gastroenterology. 2005;129:1854–64.PubMedCrossRefGoogle Scholar
  16. 16.
    Torok HP, Glas J, Tonenchi L, Lohse P, Muller-Myhsok B, Limbersky O, et al. Polymorphisms in the DLG5 and OCTN cation transporter genes in Crohn’s disease. Gut. 2005;54:1421–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Palmieri O, Latiano A, Valvano R, D’Inca R, Vecchi M, Sturniolo GC, et al. Variants of OCTN1–2 cation transporter genes are associated with both Crohn’s disease and ulcerative colitis. Aliment Pharmacol Ther. 2006;23:497–506.PubMedCrossRefGoogle Scholar
  18. 18.
    Tosa M, Negoro K, Kinouchi Y, Abe H, Nomura E, Takagi S, et al. Lack of association between IBD5 and Crohn’s disease in Japanese patients demonstrates population-specific differences in inflammatory bowel disease. Scand J Gastroenterol. 2006;41:48–53.PubMedCrossRefGoogle Scholar
  19. 19.
    Bene J, Magyari L, Talian G, Komlosi K, Gasztonyi B, Tari B, et al. Prevalence of SLC22A4, SLC22A5 and CARD15 gene mutations in Hungarian pediatric patients with Crohn’s disease. World J Gastroenterol. 2006;12:5550–3.PubMedGoogle Scholar
  20. 20.
    Giallourakis C, Stoll M, Miller K, Hampe J, Lander ES, Daly MJ, et al. IBD5 is a general risk factor for inflammatory bowel disease: replication of association with Crohn disease and identification of a novel association with ulcerative colitis. Am J Hum Genet. 2003;73:205–11.PubMedCrossRefGoogle Scholar
  21. 21.
    Noble CL, Abbas AR, Cornelius J, Lees CW, Ho GT, Toy K, et al. Regional variation in gene expression in the healthy colon is dysregulated in ulcerative colitis. Gut. 2008;57:1398–405.PubMedCrossRefGoogle Scholar
  22. 22.
    Reinhard C, Rioux JD. Role of the IBD5 susceptibility locus in the inflammatory bowel diseases. Inflamm Bowel Dis. 2006;12:227–38.PubMedCrossRefGoogle Scholar
  23. 23.
    Weersma RK, Zhou L, Nolte IM, van der Steege G, van Dullemen HM, Oosterom E, et al. Runt-related transcription factor 3 is associated with ulcerative colitis and shows epistasis with solute carrier family 22, members 4 and 5. Inflamm Bowel Dis. 2008;14:1615–22.PubMedCrossRefGoogle Scholar
  24. 24.
    Huang Y, Zheng J, Przytycka TM. Discovery of regulatory mechanisms from gene expression variation by eQTL analysis. In: Chen JY, Lonardi S, editors. Biological data mining. Boco Raton: Chapman & Hall/CRC; 2009. p. 205–28.Google Scholar
  25. 25.
    Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40:955–62.PubMedCrossRefGoogle Scholar
  26. 26.
    Potocnik U, Ferkolj I, Glavac D, Dean M. Polymorphisms in multidrug resistance 1 (MDR1) gene are associated with refractory Crohn disease and ulcerative colitis. Genes Immun. 2004;5:530–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: controversies, consensus and implications. Gut. 2006;55:749–53.PubMedCrossRefGoogle Scholar
  28. 28.
    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Gazouli M, Mantzaris G, Archimandritis AJ, Nasioulas G, Anagnou NP. Single nucleotide polymorphisms of OCTN1, OCTN2, and DLG5 genes in Greek patients with Crohn’s disease. World J Gastroenterol. 2005;11:7525–30.PubMedGoogle Scholar
  30. 30.
    Lakner L, Csongei V, Sarlos P, Jaromi L, Safrany E, Varga M, et al. IGR2096a_1 T and IGR2198a_1 C alleles on IBD5 locus of chromosome 5q31 region confer risk for Crohn’s disease in Hungarian patients. Int J Colorectal Dis. 2009;24:503–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Magyari L, Melegh B. Susceptibility genetic variants in Hungarian morbus Crohn and ulcerative colitis patients. Orv Hetil. 2009;150:81–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Li M, Gao X, Guo CC, Wu KC, Zhang X, Hu PJ. OCTN and CARD15 gene polymorphism in Chinese patients with inflammatory bowel disease. World J Gastroenterol. 2008;14:4923–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Nakahara S, Arimura Y, Saito K, Goto A, Motoya S, Shinomura Y, et al. Association of SLC22A4/5 polymorphisms with steroid responsiveness of inflammatory bowel disease in Japan. Dis Colon Rectum. 2008;51:598–603.PubMedCrossRefGoogle Scholar
  34. 34.
    Franke A, Hampe J, Rosenstiel P, Becker C, Wagner F, Hasler R, et al. Systematic association mapping identifies NELL1 as a novel IBD disease gene. PLoS One. 2007;2:e691.Google Scholar
  35. 35.
    Armuzzi A, Ahmad T, Ling KL, de Silva A, Cullen S, van Heel D, et al. Genotype-phenotype analysis of the Crohn’s disease susceptibility haplotype on chromosome 5q31. Gut. 2003;52:1133–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Urcelay E, Mendoza JL, Martinez A, Fernandez L, Taxonera C, az-Rubio M, et al. IBD5 polymorphisms in inflammatory bowel disease: association with response to infliximab. World J Gastroenterol. 2005;11:1187–92.PubMedGoogle Scholar
  37. 37.
    Gasche C, Scholmerich J, Brynskov J, D’Haens G, Hanauer SB, Irvine EJ, et al. A simple classification of Crohn’s disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis. 2000;6:8–15.PubMedCrossRefGoogle Scholar
  38. 38.
    Gilad Y, Rifkin SA, Pritchard JK. Revealing the architecture of gene regulation: the promise of eQTL studies. Trends Genet. 2008;24:408–15.PubMedCrossRefGoogle Scholar
  39. 39.
    Dixon AL, Liang L, Moffatt MF, Chen W, Heath S, Wong KC, et al. A genome-wide association study of global gene expression 3. Nat Genet. 2007;39:1202–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Heap GA, Trynka G, Jansen RC, Bruinenberg M, Swertz MA, Dinesen LC, et al. Complex nature of SNP genotype effects on gene expression in primary human leucocytes. BMC Med Genomics. 2009;2:1.Google Scholar
  41. 41.
    Palacios R, Comas D, Elorza J, Villoslada P. Genomic regulation of CTLA4 and multiple sclerosis. J Neuroimmunol. 2008;203:108–15.PubMedCrossRefGoogle Scholar
  42. 42.
    Hunt KA, Zhernakova A, Turner G, Heap GA, Franke L, Bruinenberg M, et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet. 2008;40:395–402.PubMedCrossRefGoogle Scholar
  43. 43.
    Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S, et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature. 2007;448:470–3.PubMedCrossRefGoogle Scholar
  44. 44.
    Rebouche CJ. Carnitine function and requirements during the life cycle. FASEB J. 1992;6:3379–86.PubMedGoogle Scholar

Copyright information

© Springer 2011

Authors and Affiliations

  1. 1.Center for Human Molecular Genetics and Pharmacogenomics, Faculty of MedicineUniversity of MariborMariborSlovenia
  2. 2.Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty for Chemistry and Chemical EngineeringUniversity of MariborMariborSlovenia

Personalised recommendations