Biochemical Genetics

, Volume 54, Issue 4, pp 476–486 | Cite as

Transferrin Level Before Treatment and Genetic Polymorphism in HFE Gene as Predictive Markers for Response to Adalimumab in Crohn’s Disease Patients

  • Katja Repnik
  • Silvo Koder
  • Pavel Skok
  • Ivan Ferkolj
  • Uroš Potočnik
Original Article


Tumor necrosis factor α inhibitors (anti-TNF) have improved treatment of several complex diseases, including Crohn’s disease (CD). However, the effect varies and approximately one-third of the patients do not respond. Since blood parameters as well as genetic factors have shown a great potential to predict response during treatment, the aim of the study was to evaluate response to anti-TNF treatment with adalimumab (ADA) between genes HFE and TF and haematological parameters in Slovenian refractory CD patients. Single nucleotide polymorphisms (SNPs) rs1799852 in gene TF and rs2071303 in gene HFE were genotyped in 68 refractory CD patients for which response has been measured using inflammatory bowel disease questionnaire (IBDQ) index. Haematological parameters and IBDQ index were determined before therapy and after 4, 12, 20 and 30 weeks. We found novel strong association between SNP rs2071303 in gene HFE and response to ADA treatment, particularly patients with G allele comparing to A allele had better response after 20 weeks (p = 0.008). Further, we found strong association between transferrin level at baseline and treatment response after 12, 20 and 30 weeks, where average transferrin level before therapy was lower in responders (2.38 g/L) compared to non-responders (2.89 g/L, p = 0.005). Association was found between transferrin level in week 30 and SNP rs1799852 (p = 0.023), and between MCHC level before treatment and SNP rs2071303 (p = 0.007). Our results suggest that SNP in gene HFE as well as haematological markers serve as promising prognostic markers of response to anti-TNF treatment in CD patients.


Anti-TNF Adalimumab Transferrin HFE gene TF gene 


  1. Aalto K, Honkanen V, Lahdenne P (2011) Iron status during anti-TNF therapy in children with juvenile idiopathic arthritis. Clin Rheumatol 30:115–119. doi: 10.1007/s10067-010-1571-7 CrossRefPubMedGoogle Scholar
  2. Benyamin B et al (2009) Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels. Am J Hum Genet 84:60–65. doi: 10.1016/j.ajhg.2008.11.011 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Feder JN et al (1998) The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci USA 95:1472–1477CrossRefPubMedPubMedCentralGoogle Scholar
  4. Gasche C, Lomer MC, Cavill I, Weiss G (2004) Iron, anaemia, and inflammatory bowel diseases. Gut 53:1190–1197. doi: 10.1136/gut.2003.035758 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Guyatt G, Mitchell A, Irvine EJ, Singer J, Williams N, Goodacre R, Tompkins C (1989) A new measure of health status for clinical trials in inflammatory bowel disease. Gastroenterology 96:804–810CrossRefPubMedGoogle Scholar
  6. Hetland ML et al (2010) Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO Registry. Arthritis Rheum 62:22–32. doi: 10.1002/art.27227 CrossRefPubMedGoogle Scholar
  7. Hlavaty T, Persoons P, Vermeire S, Ferrante M, Pierik M, van Assche G, Rutgeerts P (2006) Evaluation of short-term responsiveness and cutoff values of inflammatory bowel disease questionnaire in Crohn’s disease. Inflamm Bowel Dis 12:199–204CrossRefPubMedGoogle Scholar
  8. Khusainova RI, Khusnutdinova NN, Litvinov SS, Khusnutdinova EK (2013) Analysis of H63D mutation in hemochromatosis (HFE) gene in populations of central Eurasia. Genetika 49:269–278PubMedGoogle Scholar
  9. Koder S, Repnik K, Ferkolj I, Pernat C, Skok P, Weersma RK, Potočnik U (2015) Genetic polymorphism in ATG16L1 gene influences the response to adalimumab in Crohn’s disease patients. Pharmacogenomics 16:191–204. doi: 10.2217/pgs.14.172 CrossRefPubMedGoogle Scholar
  10. Määttä KM, Nikkari ST, Kunnas TA (2015) Genetic variant coding for iron regulatory protein HFE contributes to hypertension, the TAMRISK study. Medicine (Baltim) 94:e464. doi: 10.1097/MD.0000000000000464 CrossRefGoogle Scholar
  11. Mack DR et al (2007) Laboratory values for children with newly diagnosed inflammatory bowel disease. Pediatrics 119:1113–1119. doi: 10.1542/peds.2006-1865 CrossRefPubMedGoogle Scholar
  12. McLaren CE et al (2011) Genome-wide association study identifies genetic loci associated with iron deficiency. PLoS One 6:e17390. doi: 10.1371/journal.pone.0017390 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Minaur NJ, Jacoby RK, Cosh JA, Taylor G, Rasker JJ (2004) Outcome after 40 years with rheumatoid arthritis: a prospective study of function, disease activity, and mortality. J Rheumatol Suppl 69:3–8PubMedGoogle Scholar
  14. Moczulski DK, Grzeszczak W, Gawlik B (2001) Role of hemochromatosis C282Y and H63D mutations in HFE gene in development of type 2 diabetes and diabetic nephropathy. Diabetes Care 24:1187–1191CrossRefPubMedGoogle Scholar
  15. Papadaki HA, Kritikos HD, Valatas V, Boumpas DT, Eliopoulos GD (2002) Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy. Blood 100:474–482. doi: 10.1182/blood-2002-01-0136 CrossRefPubMedGoogle Scholar
  16. Parkkila S et al (1997) Immunohistochemistry of HLA-H, the protein defective in patients with hereditary hemochromatosis, reveals unique pattern of expression in gastrointestinal tract. Proc Natl Acad Sci USA 94:2534–2539CrossRefPubMedPubMedCentralGoogle Scholar
  17. Rong Y et al (2012) Hemochromatosis gene (HFE) polymorphisms and risk of type 2 diabetes mellitus: a meta-analysis. Am J Epidemiol 176:461–472. doi: 10.1093/aje/kws126 CrossRefPubMedGoogle Scholar
  18. Rosenblum H, Amital H (2011) Anti-TNF therapy: safety aspects of taking the risk. Autoimmun Rev 10:563–568. doi: 10.1016/j.autrev.2011.04.010 CrossRefPubMedGoogle Scholar
  19. Rubin DT, Mulani P, Chao J, Pollack PF, Bensimon AG, Yu AP, Ghosh S (2012) Effect of adalimumab on clinical laboratory parameters in patients with Crohn’s disease: results from the CHARM trial. Inflamm Bowel Dis 18:818–825. doi: 10.1002/ibd.21836 CrossRefPubMedGoogle Scholar
  20. Rusten LS, Jacobsen SE (1995) Tumor necrosis factor (TNF)-alpha directly inhibits human erythropoiesis in vitro: role of p55 and p75 TNF receptors. Blood 85:989–996PubMedGoogle Scholar
  21. Sobolewska A, Włodarczyk M, Stec-Michalska K, Fichna J, Wiśniewska-Jarosińska M (2015) Mean platelet volume in Crohn’s disease patients predicts sustained response to a 52-week infliximab therapy: a pilot study. Dig Dis Sci. doi: 10.1007/s10620-015-3894-3 PubMedPubMedCentralGoogle Scholar
  22. Trinder MW, Lawrance IC (2009) Efficacy of adalimumab for the management of inflammatory bowel disease in the clinical setting. J Gastroenterol Hepatol 24:1252–1257CrossRefPubMedGoogle Scholar
  23. Waheed A et al (1997) Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc Natl Acad Sci USA 94:12384–12389CrossRefPubMedPubMedCentralGoogle Scholar
  24. Zorzi F et al (2012) Efficacy and safety of infliximab and adalimumab in Crohn’s disease: a single centre study. Aliment Pharmacol Ther 35:1397–1407CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Katja Repnik
    • 1
    • 2
  • Silvo Koder
    • 3
  • Pavel Skok
    • 3
  • Ivan Ferkolj
    • 4
  • Uroš Potočnik
    • 1
    • 2
  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
  3. 3.University Medical Centre MariborMariborSlovenia
  4. 4.University Medical Centre LjubljanaLjubljanaSlovenia

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