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Possible role of MDR1 two-locus genotypes for young-age onset ulcerative colitis but not Crohn’s disease

  • Pharmacogenetics
  • Published:
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Abstract

Background

The role of the single nucleotide polymorphisms (SNPs) on positions 2677G>T/A and 3435C>T of the multi-drug-resistance gene 1 (MDR1) in inflammatory bowel disease (IBD) remains unclear.

Aims

To further elucidate the potential impact of MDR1 two-locus genotypes on susceptibility to IBD and disease behaviour.

Patients and methods

Three hundred eighty-eight German IBD patients [244 with Crohn’s disease (CD), 144 with ulcerative colitis (UC)] and 1,005 German healthy controls were genotyped for the two MDR1 SNPs on positions 2677G>T/A and 3435C>T. Genotype–phenotype analysis was performed with respect to disease susceptibility stratified by age at diagnosis as well as disease localisation and behaviour.

Results

Genotype distribution did not differ between all UC or CD patients and controls. Between UC and CD patients, however, we observed a trend of different distribution of the combined genotypes derived from SNPs 2677 and 3435 (χ2 = 15.997, df = 8, p = 0.054). In subgroup analysis, genotype frequencies between UC patients with early onset of disease and controls showed significant difference for combined positions 2677 and 3435 (χ2 = 16.054, df = 8, p = 0.034 for age at diagnosis ≥25, lower quartile). Herein the rare genotype 2677GG/3435TT was more frequently observed (odds ratio = 7.0, 95% confidence interval 2.5 – 19.7). In this group severe course of disease behaviour depended on the combined MDR1 SNPs (χ2 = 16.101, df = 6, p = 0.017 for age at diagnosis ≥25). No association of MDR1 genotypes with disease subgroups in CD was observed.

Conclusions

While overall genotype distribution did not differ, combined MDR1 genotypes derived from positions 2677 and 3435 are possibly associated with young age onset of UC and severe course of disease in this patient group.

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References

  1. Podolsky DK (2002) Inflammatory bowel disease. N Engl J Med 347(6):417–429

    Article  PubMed  CAS  Google Scholar 

  2. Ahmad T, Tamboli CP, Jewell D et al (2004) Clinical relevance of advances in genetics and pharmacogenetics of IBD. Gastroenterology 126(6):1533–1549

    Article  PubMed  CAS  Google Scholar 

  3. Vermeire S, Rutgeerts P (2005) Current status of genetics research in inflammatory bowel disease. Genes Immun 6(8):637–645

    PubMed  CAS  Google Scholar 

  4. Panwala CM, Jones JC, Viney JL (1998) A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis. J Immunol 161(10):5733–5744

    PubMed  CAS  Google Scholar 

  5. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE et al (2003) P-glycoprotein: from genomics to mechanism. Oncogene 22(47):7468–7485

    Article  PubMed  CAS  Google Scholar 

  6. Fojo AT, Ueda K, Slamon DJ et al (1987) Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci USA 84(1):265–269

    Article  PubMed  CAS  Google Scholar 

  7. Mouly S, Paine MF (2003) P-glycoprotein increases from proximal to distal regions of human small intestine. Pharm Res 20(10):1595–1599

    Article  PubMed  CAS  Google Scholar 

  8. Lown KS, Mayo RR, Leichtman AB et al (1997) Role of intestinal P-glycoprotein (MDR1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther 62(3):248–260

    Article  PubMed  CAS  Google Scholar 

  9. Schwab M, Schaeffeler E, Marx C et al (2003) Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis. Gastroenterology 124(1):26–33

    Article  PubMed  CAS  Google Scholar 

  10. Ho GT, Nimmo ER, Tenesa A et al (2005) Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis. Gastroenterology 128(2):288–296

    Article  PubMed  CAS  Google Scholar 

  11. Croucher PJ, Mascheretti S, Foelsch UR et al (2003) Lack of association between the C3435T MDR1 gene polymorphism and inflammatory bowel disease in two independent Northern European populations. Gastroenterology 125(6):1919–1920

    Article  PubMed  Google Scholar 

  12. Gazouli M, Zacharatos P, Gorgoulis V et al (2004) The C3435T MDR1 gene polymorphism is not associated with susceptibility for ulcerative colitis in Greek population. Gastroenterology 126(1):367–369

    Article  PubMed  CAS  Google Scholar 

  13. Glas J, Torok HP, Schiemann U et al (2004) MDR1 gene polymorphism in ulcerative colitis. Gastroenterology 126(1):367

    Article  PubMed  Google Scholar 

  14. Oostenbrug LE, Dijkstra G, Nolte IM, van Dullemen HM, Oosterom E, Faber N, de Jong DJ, van der Linde K, te Meerman GJ, van der Steege G, Kleibeuker JH, Jansen PL (2006) Absence of association between the multidrug resistance (MDR1) gene and inflammatory bowel disease. Scand J Gastroenterol 41(10):1174–1182

    Article  PubMed  CAS  Google Scholar 

  15. Onnie CM, Fisher SA, Pattni R, Sanderson J, Forbes A, Lewis CM, Mathew G (2006) Associations of allelic variants of the multidrug resistance gene (ABCB1 or MDR1) and inflammatory bowel disease and their effects on disease behavior: a case-control and meta-analysis study. Inflamm Bowel Dis 12(4):263–271

    Article  PubMed  Google Scholar 

  16. Annese V, Valvano MR, Palmieri O, Latiano A,Bossa F, Andriulli A (2006) Multidrug resistance 1 gene in inflammatory bowel disease: a meta-analysis. World J Gastroenterol 12(23):3636–3644

    PubMed  CAS  Google Scholar 

  17. Brant SR, Panhuysen CI, Nicolae D et al (2003) MDR1 Ala893 polymorphism is associated with inflammatory bowel disease. Am J Hum Genet 73(6):1282–1292

    Article  PubMed  CAS  Google Scholar 

  18. Johne A, Kopke K, Gerloff T et al (2002) Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin Pharmacol Ther 72(5):584–594

    Article  PubMed  CAS  Google Scholar 

  19. Kim RB, Leake BF, Choo EF et al (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70(2):189–199

    Article  PubMed  CAS  Google Scholar 

  20. Potocnik U, Ferkolj I, Glavac D et al (2004) Polymorphisms in multidrug resistance 1 (MDR1) gene are associated with refractory Crohn disease and ulcerative colitis. Genes Immun 5(7):530–539

    Article  PubMed  CAS  Google Scholar 

  21. Malchow H, Ewe K, Brandes JW et al (1984) European Cooperative Crohn’s Disease Study (ECCDS): results of drug treatment. Gastroenterology 86(2):249–266

    PubMed  CAS  Google Scholar 

  22. Cascorbi I, Gerloff T, Johne A et al (2001) Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther 69(3):169–174

    Article  PubMed  CAS  Google Scholar 

  23. Gasche C, Scholmerich J, Brynskov J et al (2000) A simple classification of Crohn’s disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis 6(1):8–15

    Article  PubMed  CAS  Google Scholar 

  24. Buning C, Genschel J, Buhner S et al (2004) Mutations in the NOD2/CARD15 gene in Crohn’s disease are associated with ileocecal resection and are a risk factor for reoperation. Aliment Pharmacol Ther 19(10):1073–1078

    Article  PubMed  CAS  Google Scholar 

  25. Oselin K, Gerloff T, Mrozikiewicz PM et al (2003) MDR1 polymorphisms G2677T in exon 21 and C3435T in exon 26 fail to affect rhodamine 123 efflux in peripheral blood lymphocytes. Fundam Clin Pharmacol 17(4):463–469

    Article  PubMed  CAS  Google Scholar 

  26. Chen CJ, Clark D, Ueda K et al (1990) Genomic organization of the human multidrug resistance (MDR1) gene and origin of P-glycoproteins. J Biol Chem 265(1):506–514

    PubMed  CAS  Google Scholar 

  27. Bernstein CN, Blanchard JF, Rawsthorne P, Wajda A (1999) Epidemiology of Crohn’s disease and ulcerative colitis in a central Canadian province: a population-based study. Am J Epidemiol 149(10):916–924

    PubMed  CAS  Google Scholar 

  28. Yacyshyn B, Maksymowych W, Bowen-Yacyshyn MB (1999) Differences in P-glycoprotein-170 expression and activity between Crohn’s disease and ulcerative colitis. Hum Immunol 60(8):677–687

    Article  PubMed  CAS  Google Scholar 

  29. Langmann T, Moehle C, Mauerer R et al (2004) Loss of detoxification in inflammatory bowel disease: dysregulation of pregnane X receptor target genes. Gastroenterology 127(1):26–40

    Article  PubMed  CAS  Google Scholar 

  30. Ho GT, Soranzo N, Nimmo ER, Tenesa A, Goldstein DB, Satsangi J (2005) ABCB1/MDR1 gene determines susceptibility and phenotype in ulcerative colitis: discrimination of critical variants using a gene-wide haplotype tagging approach. Hum Mol Genet 15(5)797–805

    Article  CAS  Google Scholar 

  31. Russell RK, Wilson DC, Satsangi J (2004) Unravelling the complex genetics of inflammatory bowel disease. Arch Dis Child 89:598–603

    Article  PubMed  CAS  Google Scholar 

  32. Osuga T, Sakaeda T, Nakamura T, Yamada T, Koyama T, Tamura T, Aoyama N, Okamura N, Kasuga M, Okumura K (2006) MDR1 C3435T polymorphism is predictive of later onset of ulcerative colitis in Japanese. Biol Pharm Bull 29(2):324–329

    Article  PubMed  CAS  Google Scholar 

  33. Marzolini C, Paus E, Buclin T, Kim RB (2004) Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 75(1):13–33

    Article  PubMed  CAS  Google Scholar 

  34. Dilger K, Schwab M, Fromm MF (2004) Identification of budesonide and prednisone as substrates of the intestinal drug efflux pump P-glycoprotein. Inflamm Bowel Dis 10(5):578–583

    Article  PubMed  Google Scholar 

  35. Wang D, Johnson AD, Papp AC, Kroetz DL, Sadee W (2005) Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics 10:693–704

    Article  Google Scholar 

  36. Schaefer M, Roots I, Gerloff T (2006) In-vitro transport characteristics discriminate wild-type ABCB1 (MDR1) from ALA893SER and ALA893THR polymorphisms. Pharmacogenet Genomics 12:855–861

    Article  CAS  Google Scholar 

  37. Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM (2007) A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 315(5811):525–528

    Article  PubMed  CAS  Google Scholar 

  38. Resta-Lenert S, Smitham J, Barrett KE (2005) Epithelial dysfunction associated with the development of colitis in conventionally housed mdr1a -/- mice. Am J Physiol Gastrointest Liver Physiol 289:G153–G162

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

The authors are indebted to the patients with IBD who made this study possible. We thank very much Mrs. Bettina Bochow and Mrs. Anja Alfandega for excellent technical support. This study was supported by grants of the German Federal Ministry of Education and Research (Berlin Center for Genome Based Bioinformatics grant No. 031U209B).

Competing Interest Statement

There is no competing interest of any of the authors concerning this article.

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Authors and Affiliations

  1. Department of Gastroenterology, Hepatology & Endocrinology, Charité – Universitätsmedizin Berlin, CCM, Charitéplatz 1, Berlin, 10117, Germany

    T. Fiedler, C. Büning, W. Reuter, G. Pitre, E. Gentz, HH. Schmidt, J. Büttner, J. Ockenga & H. Lochs

  2. Institute of Clinical Pharmacology, Charité – Universitätsmedizin Berlin, CCM, Charitéplatz 1, Berlin, 10117, Germany

    T. Gerloff, C. Meisel, I. Roots, K. Köpke & A. Johne

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  1. T. Fiedler
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  2. C. Büning
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  3. W. Reuter
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  14. A. Johne
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Correspondence to T. Fiedler.

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Fiedler, T., Büning, C., Reuter, W. et al. Possible role of MDR1 two-locus genotypes for young-age onset ulcerative colitis but not Crohn’s disease. Eur J Clin Pharmacol 63, 917–925 (2007). https://doi.org/10.1007/s00228-007-0334-0

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  • DOI: https://doi.org/10.1007/s00228-007-0334-0

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