ABCB1 3435C>T and 2677G>T/A polymorphisms in Polish and Bosnian patients with Crohn’s disease – A preliminary report

  • Krzysztof Borecki Department of Gerontobiology, Pomeranian Medical University, Szczecin, Poland
  • Iwona Zawada Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland
  • Anna Pawinska-Matecka Central Laboratory, Regional Hospital, Szczecin, Poland
  • Nermin Nusret Salkic Department of Gastroenterology and Hepatology, University Clinical Center Tuzla, Tuzla, Bosnia and Herzegovina
  • Beata Karakiewicz Public Health Department, Pomeranian Medical University, Szczecin, Poland
  • Grażyna Adler Department of Gerontobiology, Pomeranian Medical University, Szczecin, Poland
Keywords: ABCB1, Crohn’s disease, allele frequency, Poland, Bosnia and Herzegovina, 3435C>T, 2677G>T/A, single nucleotide polymorphism, SNP

Abstract

The role of ABCB1 single nucleotide polymorphisms (SNPs) in the development of Crohn’s disease (CD) remains unclear. Due to inconsistent results of several European population-based studies and limited information on populations from Poland and Bosnia and Herzegovina (BH), we conducted a preliminary association study of two main ABCB1 SNPs and CD. ABCB1 3435C>T and 2677G>T/A SNPs were analyzed in Polish and Bosnian patients with CD (n = 85 and n = 30, respectively) and controls (n = 82 and n = 30, respectively) using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for 3435C>T and allele-specific PCR for 2677G>A/T SNP. A deviation from Hardy-Weinberg equilibrium was found for both SNPs in Polish patients with CD, and for 2677G>A/T in Polish control group. The allele and genotype frequencies of the two ABCB1 SNPs were not significantly different between the CD patients and controls in both populations (p > 0.05). Similarly, the genotype distribution of 3435C>T and 2677G>T/A SNPs was not significantly different between Polish and Bosnian patients with CD (p > 0.05). At least one mutated ABCB1 allele was carried by 97.7% of Polish and 90.0% of Bosnian patients with CD. No association was found between the ABCB1 SNPs and CD in the two populations. In conclusion, the two ABCB1 SNPs may not contribute to CD susceptibility in the populations of Poland and BH. Further studies with larger samples in both populations are warranted.

Downloads

Download data is not yet available.

Author Biographies

Krzysztof Borecki, Department of Gerontobiology, Pomeranian Medical University, Szczecin, Poland

Department of Gerontobiology

Iwona Zawada, Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland
Department of Gastroenterology
Nermin Nusret Salkic, Department of Gastroenterology and Hepatology, University Clinical Center Tuzla, Tuzla, Bosnia and Herzegovina
Department of Gastroenterology and Hepatology
Beata Karakiewicz, Public Health Department, Pomeranian Medical University, Szczecin, Poland
Public Health Department
Grażyna Adler, Department of Gerontobiology, Pomeranian Medical University, Szczecin, Poland
Department of Gerontobiology

References

Baumgart DC, Sandborn WJ. Crohn's disease. Lancet 2012;380(9853):1590-605. https://doi.org/10.1016/S0140-6736(12)60026-9.

de Lange KM, Barrett JC. Understanding inflammatory bowel disease via immunogenetics. J Autoimmun 2015;64:91-100. https://doi.org/10.1016/j.jaut.2015.07.013.

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(7422):119-24. https://doi.org/10.1038/nature11582.

Yadav V, Varum F, Bravo R, Furrer E, Bojic D, Basit AW. Inflammatory bowel disease: Exploring gut pathophysiology for novel therapeutic targets. Transl Res 2016;176:38-68. https://doi.org/10.1016/j.trsl.2016.04.009.

Dudarewicz M, Baranska M, Rychlik-Sych M, Trzcinski R, Dziki A, Skretkowicz J. C3435T polymorphism of the ABCB1/MDR1 gene encoding P-glycoprotein in patients with inflammatory bowel disease in a Polish population. Pharmacol Rep 2012;64(2):343-50. https://doi.org/10.1016/S1734-1140(12)70774-0.

Brinar M, Cukovic-Cavka S, Bozina N, Ravic KG, Markos P, Ladic A, et al. MDR1 polymorphisms are associated with inflammatory bowel disease in a cohort of Croatian IBD patients. BMC Gastroenterol 2013;13:57. https://doi.org/10.1186/1471-230X-13-57.

Van Assche G, Dignass A, Panes J, Beaugerie L, Karagiannis J, Allez M, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Definitions and diagnosis. J Crohns Colitis 2010;4(1):7-27. https://doi.org/10.1016/j.crohns.2009.12.003.

Farnood A, Naderi N, Moghaddam SJ, Noorinayer B, Firouzi F, Aghazadeh R, et al. The frequency of C3435T MDR1 gene polymorphism in Iranian patients with ulcerative colitis. Int J Colorectal Dis 2007;22(9):999-1003. https://doi.org/10.1007/s00384-007-0270-6.

Kurzawski M, Pawlik A, Górnik W, Drozdzik M. Frequency of common MDR1 gene variants in a Polish population. Pharmacol Rep 2006;58(1):35-40.

Fiedler T, Büning C, Reuter W, Pitre G, Gentz E, Schmidt HH, et al. Possible role of MDR1 two-locus genotypes for young-age onset ulcerative colitis but not Crohn's disease. Eur J Clin Pharmacol 2007;63(10):917-25. https://doi.org/10.1007/s00228-007-0334-0.

Schwab M, Schaeffeler E, Marx C, Fromm MF, Kaskas B, Metzler J, et al. Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis. Gastroenterology 2003;124(1):26-33. https://doi.org/10.1053/gast.2003.50010.

Ho GT, Nimmo ER, Tenesa A, Fennell J, Drummond H, Mowat C, et al. Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis. Gastroenterology 2005;128(2):288-96. https://doi.org/10.1053/j.gastro.2004.11.019.

Onnie CM, Fisher SA, Pattni R, Sanderson J, Forbes A, Lewis CM, et al. 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 2006;12(4):263-71. https://doi.org/10.1097/01.MIB.0000209791.98866.ba.

Huebner C, Browning BL, Petermann I, Han DY, Philpott M, Barclay M, et al. Genetic analysis of MDR1 and inflammatory bowel disease reveals protective effect of heterozygous variants for ulcerative colitis. Inflamm Bowel Dis 2009;15(12):1784-93. https://doi.org/10.1002/ibd.21019.

Jazwinska-Tarnawska E, Jeskowiak I, Waszczuk E, Mulak A, Glowacka K, Hurkacz M, et al. Genetic polymorphism of ABCB1 gene (C3435T) in patients with inflammatory bowel diseases. Is there any gender dependency? Pharmacol Rep 2015;67(2):294-8. https://doi.org/10.1016/j.pharep.2014.09.014.

Oostenbrug LE, Dijkstra G, Nolte IM, van Dullemen HM, Oosterom E, Faber KN, et al. Absence of association between the multidrug resistance (MDR1) gene and inflammatory bowel disease. Scand J Gastroenterol 2006;41(10):1174-82. https://doi.org/10.1080/00365520600575746.

Ardizzone S, Maconi G, Bianchi V, Russo A, Colombo E, Cassinotti A, et al. Multidrug resistance 1 gene polymorphism and susceptibility to inflammatory bowel disease. Inflamm Bowel Dis 2007;13(5):516-23. https://doi.org/10.1002/ibd.20108.

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(7):530-9. https://doi.org/10.1038/sj.gene.6364123.

Gazouli M, Zacharatos P, Gorgoulis V, Mantzaris G, Papalambros E, Ikonomopoulos J. The C3435T MDR1 gene polymorphism is not associated with susceptibility for ulcerative colitis in Greek population. Gastroenterology 2004;126(1):367-9. https://doi.org/10.1053/j.gastro.2003.08.044.

Fischer S, Lakatos PL; Hungarian IBD Study Group, Lakatos L, Kovacs A, Molnar T, et al. ATP-binding cassette transporter ABCG2 (BCRP) and ABCB1 (MDR1) variants are not associated with disease susceptibility, disease phenotype response to medical therapy or need for surgery in Hungarian patients with inflammatory bowel diseases. Scand J Gastroenterol 2007;42(6):726-33. https://doi.org/10.1080/00365520601101559.

Urcelay E, Mendoza JL, Martín MC, Mas A, Martínez A, Taxonera C, et al. MDR1 gene: Susceptibility in Spanish Crohn's disease and ulcerative colitis patients. Inflamm Bowel Dis 2006;12(1):33-7. https://doi.org/10.1097/01.MIB.0000194184.92671.78.

Lal S, Stempak JM, Law C, Elkadri AA, Steinhart AH, Silverberg MS. Association between the C3435T polymorphism of the MDR1 gene and Crohn's disease. Inflamm Bowel Dis 2006;12(10):1006-7. https://doi.org/10.1097/01.mib.0000228999.37090.e1.

Glas J, Török HP, Schiemann U, Folwaczny C. MDR1 gene polymorphism in ulcerative colitis. Gastroenterology 2004;126(1):367.

Croucher PJ, Mascheretti S, Foelsch UR, Hampe J, Schreiber S. Lack of association between the C3435T MDR1 gene polymorphism and inflammatory bowel disease in two independent Northern European populations. Gastroenterology 2003;125(6):1919-20. https://doi.org/10.1053/j.gastro.2003.05.016.

Brant SR, Panhuysen CI, Nicolae D, Reddy DM, Bonen DK, Karaliukas R, et al. MDR1 Ala893 polymorphism is associated with inflammatory bowel disease. Am J Hum Genet 2003;73(6):1282-92. https://doi.org/10.1086/379927.

Wang J, Guo X, Yu S, Zhang J, Song J, Ji M, et al. MDR1 C3435T polymorphism and inflammatory bowel disease risk: A meta-analysis. Mol Biol Rep 2014;41(4):2679-85. https://doi.org/10.1007/s11033-014-3127-4.

ABCB1 3435C>T and 2677G>T/A polymorphisms in Polish and Bosnian patients with Crohn’s disease – A preliminary report
Published
2017-11-20
How to Cite
1.
Borecki K, Zawada I, Pawinska-Matecka A, Salkic NN, Karakiewicz B, Adler G. ABCB1 3435C>T and 2677G>T/A polymorphisms in Polish and Bosnian patients with Crohn’s disease – A preliminary report. Bosn J of Basic Med Sci [Internet]. 2017Nov.20 [cited 2020Sep.25];17(4):323-7. Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/2172
Section
Molecular Biology

INTRODUCTION

Crohn’s disease (CD) is a heritable complex disease characterized by chronic inflammation of the gastrointestinal tract. Together with ulcerative colitis, CD belongs to a group of intestinal disorders called inflammatory bowel disease (IBD) [1]. The common symptoms of CD include abdominal pain, fever, and other clinical signs of bowel obstruction, as well as diarrhea with blood and/or mucus in stool [1].

The etiopathogenesis of CD still remains unclear. However, familial aggregation as well as a higher concordance rate in monozygotic than in dizygotic twins, suggest the contribution of genetic factors to the development of CD [2]. Recent genome-wide association studies (GWAS) have successfully detected more than 160 IBD susceptibility loci, whereas 30 loci were unique to CD [3]. One of the key genes that might be involved in the pathogenesis of CD is ATP-binding cassette subfamily B member 1 (ABCB1); the protein is also known as multidrug resistance protein 1 or permeability glycoprotein 1 (P-gp) [4].

P-gp is an ABC transporter that regulates the passage of endogenous and exogenous substances through the cell membrane. P-gp is expressed in intestinal epithelial cells (IECs) and acts as a protective barrier against bacterial toxins, drugs and other xenobiotics in the gastrointestinal tract [4,5]. The ABCB1 gene is located within 7q21.1, a chromosomal region suggested to be linked to IBD [5]. Moreover, among the most important polymorphisms linked to CD are 2677G>A/T (rs2032582) and 3435C>T (rs1045642) single-nucleotide polymorphisms (SNPs) located in the exons 21 and 26 of the ABCB1 gene, respectively [5,6]. To date, contradictory results have been reported on the effect of 2677G>A/T SNP on P-gp expression [6]. Nevertheless, the presence of the variant allele might alter the P-gp affinity or stability for the substrate [6]. Moreover, the altered function of P-gp has also been associated with 3435C>T SNP of the ABCB1 gene [5]. Although 3435C>T is a synonymous SNP, and the risk allele does not directly affect the P-gp amino acid sequence, it moderately alters mRNA stability of the ABCB1 gene [6].

The aim of our study was to investigate the association of ABCB1 2677G>A/T and 3435C>T SNPs with CD in patients and controls from Poland and Bosnia and Herzegovina (B&H).

MATERIALS AND METHODS

Participants

The Local Bioethical Committees approved the protocol of this study (decision reference numbers 29-BS-4329/11 and KB-0012/183/13 from B&H and Poland, respectively). All participants provided written informed consent prior to the study enrollment. In this preliminary study, we collected blood samples from 227 participants (combined from both countries) for genotyping the two ABCB1 SNPs. The samples from patients and controls from both populations are still being collected for the future research purposes. The characteristics of the Polish and Bosnian patients with CD and controls are shown in Table 1. A total of 85 Polish patients with CD and 82 controls and 30 Bosnian patients with CD and 30 controls were selected consecutively from a pool of patients undergoing diagnostic evaluation or treatment at the participating institutions, between January and July 2013. CD diagnosis was determined according to the clinical, radiological, endoscopic, and histological criteria [7]. The patients enrolled as controls had undergone diagnostic testing for reasons other than IBD and had a colonoscopy performed during their diagnostic evaluation, which excluded the possibility of undiagnosed CD. Age at the time of diagnosis of CD was obtained from a direct interview with patients or from their medical records.

TABLE 1: Characteristics of cohorts from Poland and Bosnia and Herzegovina

DNA extraction and genotyping

Genomic DNA was isolated from peripheral blood leukocytes using the Qiagen extraction kit (Qiagen, Hilden, Germany), according to the manufacturer’s instructions. The genotyping of ABCB1 3435C>T (rs1045642) was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, according to the previously described protocols [8]. ABCB1 2677G>A/T (rs2032582) was genotyped using allele-specific PCR (ASPCR), according to the method described by Kurzawski et al. [9]. The forward and reverse primers, as well as restriction enzymes and restriction recognition sites are shown in Table 2. DNA amplification was performed using a LabCycler device (SensoQuest GmbH, Göttingen, Germany). Genotypes were determined by electrophoresis of the restricted DNA fragments and allele-specific amplicons, in 2% agarose gel (Sigma-Aldrich Chemie Gmbh, Munich, Germany) stained with DNA-star dye (Lonza Inc., Rockland, ME, USA).

TABLE 2: Forward and reverse primers, restriction enzymes and restriction recognition sites for ABCB1 polymorphisms

Statistical analysis

Data were analyzed using the GraphPad Prism v5.03 software (GraphPad Software Inc., San Diego, CA, USA). Genotype and allele frequencies were determined by direct counting. The SNPs were tested for the Hardy–Weinberg equilibrium (HWE) by comparing the observed genotype distributions with the expected values, using a χ2 test. The differences in the genotype and allele distribution between CD patients and controls, in both populations, were tested using a χ2 test with Yates’ correction, where appropriate, or Fisher’s exact test. All p values were two-sided and the statistical significance was set at p < 0.05.

RESULTS

Deviation from the HWE was found in the group of Polish patients with CD for both ABCB1 SNPs, and in the Polish control group for 2677G>A/T SNP. The distribution of ABCB1 genotypes and alleles in the two populations is shown in Table 3. In the Polish group, at least one mutated allele of ABCB1 SNPs was found in 97.7% (n = 83) of CD patients and in 84.2% (n = 69) of controls. Comparably, in the Bosnian group, at least one mutated ABCB1 allele was found in 90.0% (n = 27) of CD patients and in 90.0% (n = 27) of controls (p > 0.05). The allele and genotype frequencies of the two ABCB1 SNPs were not significantly different between the CD patients and controls in both populations (p > 0.05). Similarly, the genotype distribution of 3435C>T and 2677G>T/A SNPs was not significantly different between Polish and Bosnian patients with CD (p > 0.05).

TABLE 3: Genotype and allele distribution of ABCB1 polymorphisms in patients with CD and controls

DISCUSSION

Recently, an increasing incidence of IBD has been reported, including CD and UC. It has been suggested that the susceptibility to IBD as well as individual response to therapy may be linked to genetic factors, such as ABCB1 gene mutations. Here we investigated the association of two ABCB1 SNPs with CD in populations from Poland and B&H. At least one mutated allele of 3435C>T or 2677G>T/A SNPs was carried by 97.7% of Polish and 90.0% of Bosnian patients with CD. The frequency of mutated alleles reported in our study is higher compared to the frequency described for a German cohort of patients with CD (85.2%) [10]. In our study, the frequency of 3435C>T mutated allele was 55.9% in the group of Polish patients with CD. This result for the 3435T allele is comparable to the results reported by the following studies: 57.4% in another group of Polish patients with CD [5]; 53.2% [10] and 54.9% [11] in German cohorts of CD patients; 53.0% in a Scottish [12]; 51.9% in British [13]; and 56.6% in New Zeland population [14]. Lower frequencies of the 3435T allele compared to our Polish group of CD patients were revealed in the next studies: 48.9% in another group of Polish patients with CD [15]; 40.9% in a Dutch group [16]; and 39% in an Italian group [17]. The frequency of 2677G>T/A mutated alleles (T or A allele, 52.4%) in our group of Polish patients with CD was higher than reported for the Scottish, 47.2% for 2677T [12]; British, 42.2% [13]; German, 45.6% [10] and New Zeland population, 46.4% [14]; while it was nearly identical to the 2677G>T/A frequency observed in the Italian population, 52% [17]. In our group of CD patients from B&H, the frequencies of 3435C>T and 2677G>T/A mutated alleles were 63.3% and 56.7% (T or A allele), respectively. These frequencies are higher than those described for CD patients from southeastern and central European countries, including Slovenia (51.9% and 40.5%, respectively), Croatia (47.5% and 38.4% for 2677T, respectively), Greece (51.9% for 3435T), and Hungary (50.2% and 41.3%, respectively) [6,18-20].

To date, contradictory results have been reported on the association between ABCB1 3435C>T and 2677G>T/A variants and CD in European populations. According to Urcelay et al. [21], the ABCB1 3435CC genotype was significantly more frequent in Spanish patients with CD than in controls, and the carriage of the 3435C allele was significantly associated with CD [21]. Lal et al. [22] observed that the 3435T allele was significantly more frequent in Canadian patients with CD than in controls [22]. Although Huebner et al. [14] did not show any association of ABCB1 2677G>A/T or 3435C>T with CD in New Zealand patients with self-reported European ancestry, they indicated a significant association of ABCB1 3435T with an increased probability of ileal/stricturing phenotypes of CD [14]. Brinar et al. [6] showed no significant differences in the allele frequencies of both SNPs and the genotype frequencies of 2677G>T/A between Croatian patients with CD and controls, however, they suggested the protective role of heterozygous 3435CT genotype, as it was significantly less frequent in their CD patients [6]. In the other Polish population, Jazwinska-Tarnawska et al. [15] found a statistically significant correlation between gender and the 3435C>T genotype in CD and IBD patients, with a higher frequency of the 3435CT genotype among the males with CD and IBD compared to the females [15]. Similar to our results, other studies that reported no association between CD and the two ABCB1 SNPs are as follows: in the other group from Poland [5]; in several groups from Germany for 3435C>T alleles and genotypes [10,11,23]; in German and British groups for 3435C>T allele [24]; and in a Greek population [19].

In a large, multicenter North American cohort Brant et al. [25] showed no association of ABCB1 2677G>A/T and 3435C>T with CD, however, the authors found an association between the 2677G allele and IBD [25]. In the Scottish and British populations there was also no association between the ABCB1 SNPs and CD [12,13], but the frequency of 2677TT genotype was significantly increased in the British patients without the ileal CD phenotype [13]. Comparably, no association between the two ABCB1 SNPs and CD was reported for the populations from the Netherlands, Hungary, and Italy [16,17,20], although there was a tendency for the 2677G allele to be associated with the disease susceptibility among Hungarian patients with CD [20]. Finally, two meta-analyses, the first including 9 [13] and the second including 13 case-control studies [26], revealed no association between the 3435T and 2677T [13] and 3435C>T [26] alleles, respectively, with CD. Despite the fact that most of the above-mentioned studies were carried out on rather small groups of participants, it is supposed that ABCB1 2677G>A/T and 3435C>T SNPs are not associated with CD in the European populations.

CONCLUSION

The current study is the first report on ABCB1 2677G>A/T SNP frequency in Polish patients with CD and ABCB1 3435C>T and 2677G>A/T SNP frequencies in Bosnian patients with CD. Our results indicate that the ABCB1 SNPs do not contribute to CD risk in the populations from Poland and B&H. Overall, these data confirm the genetic complexity of CD. Nevertheless, due to the small sample size of the investigated cohorts, we plan to re-evaluate these results in subsequent studies with larger cohorts of CD patients from both populations.

DECLARATION OF INTERESTS

The authors declare no conflict of interests.

REFERENCES

  1. , (). Crohn’s disease. Lancet. https://doi.org/10.1016/S0140-6736(12)60026-9
  2. , (). Understanding inflammatory bowel disease via immunogenetics. J Autoimmun. https://doi.org/10.1016/j.jaut.2015.07.013
  3. , , , , , (). Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. https://doi.org/10.1038/nature11582
  4. , , , , , (). Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets. Transl Res. https://doi.org/10.1016/j.trsl.2016.04.009
  5. , , , , , (). C3435T polymorphism of the ABCB1/MDR1 gene encoding P-glycoprotein in patients with inflammatory bowel disease in a Polish population. Pharmacol Rep. https://doi.org/10.1016/S1734-1140(12)70774-0
  6. , , , , , (). MDR1 polymorphisms are associated with inflammatory bowel disease in a cohort of Croatian IBD patients. BMC Gastroenterol. https://doi.org/10.1186/1471-230X-13-57
  7. , , , , , (). The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: Definitions and diagnosis. J Crohns Colitis. https://doi.org/10.1016/j.crohns.2009.12.003
  8. , , , , , (). The frequency of C3435T MDR1 gene polymorphism in Iranian patients with ulcerative colitis. Int J Colorectal Dis. https://doi.org/10.1007/s00384-007-0270-6
  9. , , , (). Frequency of common MDR1 gene variants in a Polish population. Pharmacol Rep.
  10. , , , , , (). Possible role of MDR1 two-locus genotypes for young-age onset ulcerative colitis but not Crohn’s disease. Eur J Clin Pharmacol. https://doi.org/10.1007/s00228-007-0334-0
  11. , , , , , (). Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis. Gastroenterology. https://doi.org/10.1053/gast.2003.50010
  12. , , , , , (). Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis. Gastroenterology. https://doi.org/10.1053/j.gastro.2004.11.019
  13. , , , , , (). 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. https://doi.org/10.1097/01.MIB.0000209791.98866.ba
  14. , , , , , (). Genetic analysis of MDR1 and inflammatory bowel disease reveals protective effect of heterozygous variants for ulcerative colitis. Inflamm Bowel Dis. https://doi.org/10.1002/ibd.21019
  15. , , , , , (). Genetic polymorphism of ABCB1 gene (C3435T) in patients with inflammatory bowel diseases. Is there any gender dependency?. Pharmacol Rep. https://doi.org/10.1016/j.pharep.2014.09.014
  16. , , , , , (). Absence of association between the multidrug resistance (MDR1) gene and inflammatory bowel disease. Scand J Gastroenterol. https://doi.org/10.1080/00365520600575746
  17. , , , , , (). Multidrug resistance 1 gene polymorphism and susceptibility to inflammatory bowel disease. Inflamm Bowel Dis. https://doi.org/10.1002/ibd.20108
  18. , , , (). Polymorphisms in multidrug resistance 1 (MDR1) gene are associated with refractory Crohn disease and ulcerative colitis. Genes Immun. https://doi.org/10.1038/sj.gene.6364123
  19. , , , , , (). The C3435T MDR1 gene polymorphism is not associated with susceptibility for ulcerative colitis in Greek population. Gastroenterology. https://doi.org/10.1053/j.gastro.2003.08.044
  20. , (). ATP-binding cassette transporter ABCG2 (BCRP) and ABCB1 (MDR1) variants are not associated with disease susceptibility, disease phenotype response to medical therapy or need for surgery in Hungarian patients with inflammatory bowel diseases. Scand J Gastroenterol. https://doi.org/10.1080/00365520601101559
  21. , , , , , (). MDR1 gene: susceptibility in Spanish Crohn’s disease and ulcerative colitis patients. Inflamm Bowel Dis. https://doi.org/10.1097/01.MIB.0000194184.92671.78
  22. , , , , , (). Association between the C3435T polymorphism of the MDR1 gene and Crohn’s disease. Inflamm Bowel Dis. https://doi.org/10.1097/01.mib.0000228999.37090.e1
  23. , , , (). MDR1 gene polymorphism in ulcerative colitis. Gastroenterology.
  24. , , , , (). Lack of association between the C3435T MDR1 gene polymorphism and inflammatory bowel disease in two independent Northern European populations. Gastroenterology. https://doi.org/10.1053/j.gastro.2003.05.016
  25. , , , , , (). MDR1 Ala893 polymorphism is associated with inflammatory bowel disease. Am J Hum Genet. https://doi.org/10.1086/379927
  26. , , , , , (). MDR1 C3435T polymorphism and inflammatory bowel disease risk: A meta-analysis. Mol Biol Rep. https://doi.org/10.1007/s11033-014-3127-4