Introduction C3435TPolymorphismofthe ABCB1/MDR1 geneencodingP-glycoproteininpatientswithinflammatoryboweldiseaseinaPolishpopulation , AdamDziki , JadwigaSkrêtkowicz Micha³Dudarewicz , Ma³gorzataBarañska ,MariolaRychlik-Sych ,Radzis³awTrzciñski

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C3435T Polymorphism of the ABCB1/MDR1 gene encoding P-glycoprotein in patients with

inflammatory bowel disease in a Polish population

Micha³ Dudarewicz¹, Ma³gorzata Barañska¹, Mariola Rychlik-Sych¹, Radzis³aw Trzciñski², Adam Dziki², Jadwiga Skrêtkowicz¹

1Department of Pharmacogenetics, Medical University of Lodz, Muszyñskiego 1, PL 90-151 £ód, Poland

2Department of General and Colorectal Surgery, Medical University of Lodz, Plac Hallera 1, PL 90-647 £ód, Poland

Correspondence:Ma³gorzata Barañska, e-mail: malgorzata.baranska@umed.lodz.pl

Abstract:

Background: Inflammatory bowel disease (IBD) belongs to the group of chronic diseases of the gastrointestinal tract, prevalence of which is increasing in the Polish population. The two main clinical types of IBD are ulcerative colitis (UC) and Crohn’s disease (CD). The expression level of the ABCB1/MDR1 gene which encodes P-glycoprotein seems to be of great prognostic relevance while evaluating patients’ susceptibility to UC or CD. One of the most significant ABCB1/MDR1 gene mutations is the C3435T polymorphism. A decreased expression of the ABCB1/MDR1 gene and lower P-glycoprotein activity has been associated with the 3435T variant. The aim of the study was to evaluate the C3435T polymorphism in the IBD patients and to investigate a possible correlation with disease susceptibility.

Methods: The study was performed on 108 patients with IBD and on 137 healthy individuals. All the participants were of Caucasian origin and came from central Poland. The C3435T polymorphism was analyzed by using the PCR-RFLP method.

Results: Our results showed that ORs for IBD development (including UC and CD) were elevated in individuals both with the 3435CC genotype and the 3435C allele. The differences in genotype and allele frequencies were not significant.

Conclusions: The C3435T polymorphism of the ABCB1/MDR1 gene is not a risk factor for IBD, including UC and CD, in the popu- lation coming from central Poland.

Key words:

inflammatory bowel disease, P-glycoprotein, genetic polymorphisms, ABCB1/MDR1 gene

Introduction

The etiology of inflammatory bowel disease (IBD), i.e., ulcerative colitis (UC) and Crohn’s disease (CD), has not been completely elucidated to date. UC is characterized by inflammatory lesions that mostly develop in the mucosa and spread proximally from the anus, while in CD, inflammatory lesions may occur in

any area of the gastrointestinal tract and involve the entire thickness of the intestinal wall, having focal characteristics, i.e., appearing in a place surrounded by the healthy mucosa [7].

Environmental as well as genetic factors play an important role in IBD induction and progression. The former, such as cigarette smoke, dietary components, urban environment, hygienic conditions or contact

Pharmacological Reports 2012, 64, 343350 ISSN 1734-1140

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The involvement of genetic factors in the IBD pathogenesis has been confirmed by the observations performed on mono- and dizygotic twins as well as by the familial aggregation of the disease [9, 21, 25, 29].

The first identified gene associated with Crohn’s dis- ease was NOD2/CARD15 gene (nucleotide-binding oligomerization domain; caspase recruitment domain), which was localized on chromosome 16 [10, 19].

Identification of the gene associated with CD enabled the determination of alleles responsible for the elevated susceptibility to the disease [16]. Three mutations, Arg702Trp, Gly908Arg, and Leu1007fsinsC, in the sequence of the NOD2/CARD15 gene appeared to be the factors strongly related to CD [2, 28]. Patients with CD, and being the carriers of at least one of the three NOD2/CARD15 gene mutations are at higher risk for developing stenosis and the small intestine involvement [2].

The IL-23 receptor gene and ATG16L1 (autophagy related 16-like protein), and NKX2-3 (NK2 transcrip- tion factor related, locus 3) genes seem to play an important role in the pathogenesis of IBD [5]. Experi- ments carried out on mice with the inactive equivalent of the human ABCB1/MDR1 gene (ATP-binding cassette subfamily B member 1; multidrug resistance 1), which encodes multidrug resistance protein (P-glycoprotein), have been shown to develop spontaneous colitis [2, 12]. Moreover, the results of the studies on human genome (a meta-analysis of 2004) also demonstrate that the ABCB1/MDR1 gene is located on the long arm of chromosome 7 (region 7q21.12), and is the most likely locus of susceptibility to IBD [25, 30].

The mucosa of the gastrointestinal tract forms one of the largest surface areas of the human organism that is in contact with the external environment.

Membrane transporters regulate the flow of both ex- ogenous and endogenous substances between the cell and its environment. Proteins of the ABC superfamily including P-glycoprotein encoded by the ABCB1/

MDR1 gene are by far the most important and the best defined group of transporters [22].

P-glycoprotein (P-gp) in the cells of the intestinal epithelium acts as a protective barrier against xenobiot- ics, bacterial toxins and drugs. Polymorphic ABCB1/

MDR1 gene is located on the chromosome 7; its tran- scription rate affects the level of P-gp expression in

of the greatest clinical importance. C3435T mutation in the exon 26 has been observed to alter the P-gp function. A decreased expression of the ABCB1/MDR1 gene and P-glycoprotein activity has been associated with the 3435T allele [15].

On the basis of the data available in the literature, the ABCB1/MDR1 gene expression in patients with ulcerative colitis has been found to be lower when compared to patients suffering from CD and healthy individuals [31]. It has been suggested that P-gp lower activity related to the 3435T allele results in a higher exposure of the intestinal epithelium to harm- ful action of toxins produced by intestinal bacteria.

The results of studies on the effect of ABCB1/

MDR1 gene polymorphism performed in multiple populations, e.g., German, Scottish or Italian are in- consistent. No similar investigations on this subject have been carried out in Poland to date. Therefore, we have made an attempt to find the answer to the ques- tion whether there is any relationship between the fre- quency of the C3435T mutation in the ABCB1/MDR1 gene and IBD in a Polish population.

Patients and Methods

A total of 245 individuals of Caucasian origin from central Poland (108 patients with inflammatory bowel disease and 137 healthy volunteers) were analyzed.

The patients were treated between 2006 and 2010 in the Department of General and Colorectal Surgery of the Medical University of Lodz.

A total of 61 patients were diagnosed as having ulcerative colitis, and the other 47 patients as having Crohn’s disease. The diagnoses of IBD (ulcerative colitis or Crohn’s disease) were made by established cri- teria of clinical, radiological and endoscopic analyses and from histologic reports. Median duration of either ulcerative colitis or Crohn’s disease in this series was 6.8 years (range, 0.5–24 years). Patients with indeter- minate colitis were excluded from the study.

The patient group involved individuals aged 18–83 years (average 42.1 years, SD = 14.8). There were 59 men (54.6%) and 49 women (45.4%). Eighty-six (79.6%) patients were treated with 5-aminosalicylic

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acid (5-ASA) or sulfasalazine (48/61 patients with UC and 38/47 patients with CD). Moreover, 40 patients (37.0%) were treated with oral or intravenous corticosteroids (28 patients with UC, 12 with CD) and 21 patients (19.4%; 13/61 with UC and 8/47 with CD) were also given immunosuppressant (azathioprine) for more aggressive disease. In three patients with CD, infliximab, which is a biologic agent, was used.

Severe colitis was determined by the need for surgery or for disease refractory to treatment or for acute severe disease. If medical treatment failed, surgery was performed. Six and eleven patients with UC under- went restorative proctocolectomy and colectomy with ileostomy, respectively. In most patients with CD, pathological lesions were located in the ileocolonic region. In the group of patients with CD, the follow- ing procedures were performed: right hemicolectomy with small bowel resection in 21 patients, colectomy with ileostomy in 2 patients, colectomy and subse- quent proctectomy in one patient, and right hemicolectomy and sigmoid resection in one patient.

A control group consisted of 137 healthy unrelated volunteers aged 19–75 years (average 36.5 years, SD

= 11.6). There were 101 men (73.7%) and 36 women (26.3%). The study design was approved by the local ethics committee on human research, and informed consent was obtained from all the patients.

The samples were analyzed for the presence of two alleles of the ABCB1/MDR1 gene by using the PCR- RFLP (polymerase chain reaction-restriction fragment length polymorphism) method according to the proce- dure proposed by Cascorbi et al. [4]. The restriction en-

donuclease Sau3AI (EURx Ltd., Poland) was utilized to detect the presence of the wild-type 3435C allele and the variant 3435T allele in analyzed individuals.

Thus, subjects were assigned to three different classes of genotypes: carriers of the homozygous 3435CC genotype, heterozygotes carrying the 3435CT genotype and carriers of the homozygous 3435TT genotype.

The frequency of particular ABCB1/MDR1 alleles and genotypes in patients with IBD was compared with that in healthy controls and analyzed statistically using the c² test (with Yates modification for small groups). Values p < 0.01 were considered as statisti- cally significant. The c² test was also utilized to evaluate the accordance of the observed genotype frequency distribution with the Hardy-Weinberg equilibrium. The odds ratio (OR) with 95% confidence interval (95% CI) was calculated using STATISTICA ver- sion 8.0 (data analysis software system, StatSoft Inc.).

Results

There was no significant difference in the frequency of ABCB1/MDR1 genotypes between patients with IBD (including UC and CD) and healthy controls.

The percentage of the wild-type 3435CC genotype in the control group was lower than in patients with IBD, including UC and CD. The variant 3435TT genotype was more frequent in the control group than in the IBD, UC and CD group (Tab. 1).

The ABCB1/MDR1 polymorphism in IBD

Micha³ Dudarewicz et al.

Tab. 1.Distribution of the ABCB1/MDR1 genotypes in analyzed groups (IBD, UC, CD patients and healthy individuals)

Genotype Control group n = 137

IBD patients n = 108

UC patients n = 61

CD patients n = 47

n (%)

OR (95% CI)

p n

(%)

OR (95% CI)

p n

(%)

OR (95% CI)

p

3435CC 26

(18.98)

31 (28.70)

1.72 (0.95–3.12)

0.0737 18

(29.51)

1.79 (0.89–3.59)

0.0999 13

(27.66)

1.63 (0.76–3.52)

0.2089

3435CT 67

(48.90)

48 (44.44)

0.84 (0.50–1.39)

0.4873 26

(42.62)

0.78 (0.42–1.43)

0.4135 22

(46.81)

0.92 (0.47–1.79)

0.8040

3435TT 44

(32.12)

29 (26.86)

0.78 (0.44–1.35)

0.3710 17

(27.87)

0.82 (0.42–1.59)

0.5500 12

(25.53)

0.72 (0.34–1.53)

0.3972

IBD inflammatory bowel disease, UC ulcerative colitis, CD Crohns disease, p significance level, OR odds ratio, CI confidence interval

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Tab.2.DistributionoftheABCB1/MDR1genotypeswithrespecttogenderinstudiedgroups(IBD,UC,CDpatientsandhealthyindividuals) GenotypeControlgroup, n=137IBDpatients n=108UCpatients n=61CDpatients n=47 M n(%)F n(%)

MFMFMF n (%)OR (95%CI)pn (%)OR (95%CI)pn (%)OR (95%CI)pn (%)OR (95%CI)pn (%)OR (95%CI)pn (%)OR (95% 3435CC18 (13.14)8 (5.84)19 (17.59)2.19 (1.04–4.62)0.037412 (11.11)1.14 (0.41–3.15)0.807613 (21.31)2.31 (1.00–5.33)0.04755 (8.20)1.03 (0.29–3.66)0.77976 (12.77)1.98 (0.67–5.84)0.21217 (14.89)1.23 (0.38–3.93) 3435CT50 (36.50)17 (12.40)24 (22.22)0.70 (0.37–1.34)0.280024 (22.22)1.07 (0.45–2.54)0.872714 (22.95)0.57 (0.27–1.22)0.147412 (19.67)1.34 (0.46–3.89)0.588310 (21.28)1.02 (0.39–2.66)0.967712 (25.53)0.89 (0.33–2.44) 3435TT33 (24.09)11 (8.03)16 (14.82)0.77 (0.38–1.56)0.462113 (12.04)0.82 (0.32–2.13)0.683812 (19.67)0.92 (0.41–2.03)0.82885 (8.20)0.67 (0.20–2.27)0.73054 (8.51)0.52 (0.16–1.66)0.39078 (17.02)0.96 (0.32–2.84) IBDinflammatoryboweldisease,UCulcerativecolitis,CDCrohnsdisease,Mmales,Ffemales,psignificancelevel,ORoddsratio,CIconfidenceinterval Tab.3.DistributionoftheABCB1/MDR1alleleswithrespecttogenderinstudiedgroups(IBD,UC,CDpatientsandhealthyindividuals) AlleleControlgroup, n=137 (274alleles) IBDpatients, n=108 (216alleles) UCpatients, n=61 (122alleles)

CDpatients, n=47 (94alleles) M n(%)F n(%)

MFMFM n (%)OR (95%CI)pn (%)OR (95%CI)pn (%)OR (95%CI)pn (%)OR (95%CI)pn (%)OR (95%CI)pn (%)OR (95% 3435C86 (31.39)33 (12.04)62 (28.70)1.49 (0.95–2.36)0.084448 (22.22)1.13 (0.62–2.09)0.684940 (32.79)1.42 (0.84–2.40)0.189222 (18.03)1.18 (0.56–2.50)0.662822 (23.40)1.65 (0.83–3.26)0.148626 (27.66)1.10 (0.54–2.23) 3435T116 (42.34)39 (14.23)56 (25.93)0.67 (0.42–1.06)0.084450 (23.15)0.88 (0.48–1.62)0.684938 (31.15)0.70 (0.42–1.19)0.189222 (18.03)0.85 (0.40–1.79)0.662818 (19.15)0.61 (0.31–1.20)0.148628 (29.79)0.91 (0.45–1.85) IBDinflammatoryboweldisease,UCulcerativecolitis,CDCrohnsdisease,Mmales,Ffemales,psignificancelevel,ORoddsratio,CIconfidenceinterval

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A comparison has been performed between male patients and male controls, and between female patients and female controls. The analysis considering genotype and gender distribution did not show any significant difference (Tab. 2). The 3435CC genotype was present more frequently in men suffering from IBD and UC as compared with male controls. The 3435CC genotype also occurred more frequently in female patients in comparison with female healthy volunteers. The variant 3435TT genotype was more frequently observed in male controls than in male patients with IBD, UC and CD.

The observed genotype frequency distribution did not show a significant deviation from the Hardy- Weinberg equilibrium both in the control and the IBD group (including the UC and CD group; data not shown). Accordance with the Hardy-Weinberg equilibrium confirms the fact that the studied groups are representatives of respective populations (healthy volunteers and individuals suffering from IBD, as well as UC and CD).

Carriers of the wild-type 3435CC genotype possess increased ORs for IBD development, including ulcerative colitis and Crohn’s disease (ORs: 1.72, 1.79, and 1.63, respectively; p > 0.01, Tab. 1). Genotype distribution analysis performed in men and women showed that respective ORs for males with the 3435CC genotype reach higher values (ORs: 2.19, 2.31, 1.98, respectively; p > 0.01, Tab. 2). The variant 3435T allele was present more frequently in healthy volunteers than in patients suffering from IBD, including UC and CD. However, the wild-type 3435C allele occurred more frequently among patients with IBD than the controls. The 3435C allele frequency was also higher in both UC patients and in CD patients than in the

healthy volunteers (Tab. 4). The differences in allele distribution in men and women were not significant (Tab. 3).

Discussion

IBD belongs to the group of chronic diseases occur- ring especially among inhabitants of the developed countries of North America and Europe. However, higher IBD prevalence has also been observed in the developing regions of the world together with the progression of urbanization. There has been a consider- able increase in the IBD prevalence in Eastern Europe including Poland, however, current reliable epidemi- ological studies are not available in this region [23].

Pathogenesis of IBD has not been completely under- stood to date.

Since P-glycoprotein is regarded as a protective barrier, altered P-gp expression and function in the gastrointestinal tract due to mutations of the ABCB1/

MDR1 gene could affect the uptake of xenobiotics.

Thus, analyzing mutations of the gene encoding P-gp appears to be of great prognostic importance while evaluating individual susceptibility to IBD [11]. The single nucleotide polymorphism at position 3435 is considered to be one of the most significant ABCB1/MDR1 gene mutations. It depends on ex- change of cytosine into thymine (C3435T) and does not affect the protein sequence [13]. The previously reported relationship between the C3435T polymorphism and decreased P-gp expression and activity may have resulted from linkage of C3435T mutation

Tab. 4.Distribution of the ABCB1/MDR1 alleles in analyzed groups (IBD, UC, CD patients and healthy individuals)

Allele Control group n = 137 (274 alleles)

IBD patients n = 108 (216 alleles)

UC patients n = 61 (122 alleles)

CD patients n = 47 (94 alleles) n

(%)

n (%)

OR (95% CI)

p n

(%)

OR (95% CI)

p n

(%)

OR (95% CI)

p

3435C 119

(43.43)

110 (50.93)

1.35 (0.94–1.93)

0.0987 62

(50.82)

1.35 (0.88–2.06)

0.1729 48

(51.06)

1.36 (0.85–2.17)

0.1996

3435T 155

(56.57)

106 (49.07)

0.74 (0.52–1.06)

0.0987 60

(49.18)

0.74 (0.48–1.14)

0.1729 46

(48.94)

0.74 (0.46–1.18)

0.1996

IBD inflammatory bowel disease, UC ulcerative colitis, CD Crohns disease, p significance level, OR odds ratio, CI confidence interval

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ABCB1/MDR1 expression by impact on mRNA splic- ing, its stability or translation efficiency [3, 22]. Nev- ertheless, the mechanism of possible functional effect of the C3435T polymorphism remains not known.

Hoffmeyer et al. observed lower P-gp expression level and activity in carriers of the variant 3435TT genotype in comparison to individuals with the wild- type 3435CC genotype [13]. Consecutive impairment of barrier function attributed to presence of the 3435T allele may lead to higher exposure of the gastrointestinal tract to xenobiotics. Ho et al. were the first to put forward a hypothesis that decreased level of P-gp in colon epithelium increases susceptibility to ulcerative colitis [12].

A study performed in German population demon- strated that the 3435TT genotype was associated with the twofold increase in the risk of UC development, whereas for carriers of the single 3435T allele the risk was 1.4 [26]. In another study performed in German population, a higher frequency of the 3435CC genotype was observed in patients with UC than in healthy individuals (29.2% vs. 22.2%), however, the difference did not appear to be statistically significant [9].

Ho et al. reported a statistically significant association between UC and a higher frequency of the variant T allele (p = 0.02, OR = 1.28), and the TT genotype as well (p = 0.04, OR = 1.60). It is worth to note that the risk of UC with the proximally spreading lesions (i.e., extensive colitis) was estimated in this study as 1.70 (p = 0.009) for the 3435T allele carriers and as high as 2.64 (p = 0.003) for the 3435TT homozygotes [12].

Farnood et al. observed in Iranian population a higher risk of UC development for the 3435T allele carriers (p < 0.001, OR = 1.52) and the 3435TT homozygotes (p = 0.044, OR = 1.62). Furthermore, these authors postulate a protective role of the 3435CC genotype against the UC development in Iranian population [8].

In 2006, the results of a meta-analysis study in- volving nearly 7000 individuals were published. The authors stated that the UC risk was significantly associated with the 3435T allele (p = 0.013). The estimated risk (OR) of UC for the variant allele carriers was 1.12 [20].

The results of studies relating the C3435T polymorphism to CD are not consistent. Ardizzone et al.

[2] analyzed 520 individuals of Italian origin and

of the ABCB1/MDR1 gene also possess a threefold in- creased risk (OR = 3.34) for developing CD with ileocolonic localization as compared to individuals with the wild-type allele [2]. However, Urcelay et al. [29]

detected the association between the 3435C allele and the 3435CC genotype with higher prevalence of CD in Spanish population. Moreover, these authors postu- late specific duplicity of the ABCB1/MDR1 gene polymorphism regarding the 3435T allele as a risk factor for UC, and the 3435C allele as a risk factor for CD development [29].

This study was performed in a population coming from central Poland. To the best of our knowledge, this is the first investigation on clinical relevance of the C3435T polymorphism in Polish patients with IBD. We found that the frequency of particular geno- types and alleles of the ABCB1/MDR1 gene in pa- tients with IBD, including UC and CD, did not differ significantly from the frequency observed in healthy individuals (Tab. 1). The frequency of the 3435CC, 3435CT and 3435TT genotype in our control group was: 18.98, 48.90 and 32.12%, respectively. These results were comparable to those obtained in German (20.8, 50.5 and 28,6%, respectively) [4], in Portu- guese (22.0, 42.0 and 36.0%, respectively) [1] and in another sample of Polish population (originating from Western Pomerania: 23.3, 56.3 and 20.4%, respectively) [6]. Jamroziak et al. analyzed subjects of Polish origin from £ódŸ region and found that respective genotype frequencies equalled 42.0, 41.0 and 17.0% [14].

The allele frequency in our control group was 43.43% for 3435C and 56.57% for 3435T (Tab. 4).

The allele distribution was comparable to the data reported for German (46.1 and 53.9%, respectively) [4], for Portuguese (43.0 and 57.0%, respectively) [1], as well as for Polish population from Western Pomerania (47.5 and 52.5%, respectively) [6]. The allele frequency in Polish population was also evaluated in the study by Jamroziak et al. The 3435C allele occurred in 62.0% subjects from £ódŸ region and the 3435T allele in 38.0% [14].

Results of our investigation showed that both 3435CC genotype and 3435C allele carriers were present more frequently among Polish patients with IBD, including UC and CD, than the controls (Tabs.

1, 4). The estimated risk of IBD development (OR) for carriers of the 3435CC genotype was 1.72 (ORs

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for UC and CD were 1.79, 1.63, respectively), and for carriers of the 3435C allele was 1.35 (ORs for UC and CD were 1.35, 1.36, respectively). The risk associated with the presence of both CC genotype and C allele was not statistically significant though. Further analysis considering genotype and gender distribution showed that ORs were higher for men with the CC genotype. ORs for IBD, UC, and CD reached respective values: 2.19, 2.31 and 1.98 (Tab. 2). Results of allele and gender distribution analysis are presented in Table 3.

In conclusion, for the first time it has been investi- gated distribution of the ABCB1/MDR1 genotypes and alleles in Polish patients with IBD. The results of our study indicated that the C3435T polymorphism of the ABCB1/MDR1 gene is not a risk factor for IBD, including UC and CD, in the population coming from central Poland. In order to more precisely determine the relevance of the ABCB1/MDR1 gene polymor- phism and P-glycoprotein in pathogenesis of IBD, further studies should not only involve more individuals but also evaluate the P-gp gene expression and the activity of protein product in the tissues of the gastrointestinal tract.

Acknowledgments:

The study was financed from the European Social Fund and the National Budget within the Action 2.6: The Integrated Operational Program for Regional Development in connection with the Project

Scholarships Supporting Innovative Research of Doctoral Students and by grant No. 503/8-011-01/503-01 and by grant No.

502-03/8-011-01/502-64-031 from the Medical University of Lodz, Poland.

References:

1.Ameyaw MM, Regateiro F, Li T, Liu X, Tariq M, Mobarek A, Thornton N et al.: MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics, 2001, 11, 217–221.

2.Ardizzone S, Maconi G, Bianchi V, Russo A, Colombo E, Cassinotti A, Penati C et al.: Multidrug resistance 1 gene polymorphism and susceptibility to inflammatory bowel disease. Inflamm Bowel Dis, 2007, 13, 516–523.

3.Ca³ka K, Balcerczak E, Sa³agacka A, Mirowski M:

Multidrug resistant proteins in multiple myeloma (Polish). Acta Haematol Pol, 2008, 39, 417–428.

4.Cascorbi I, Gerloff T, Johne A, Meisel C, Hoffmeyer S, Schwab M, Schaeffeler E et al.: Frequency of single nucleotide polymorphisms in the P-glycoprotein drug trans-

porter MDR1 gene in white subjects. Clin Pharmacol Ther, 2001, 69, 169–174.

5.Cho JH: The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol, 2008, 8, 458–466.

6.DroŸdzik M, Bia³ecka M, Myœliwiec K, Honczarenko K, Stankiewicz J, Sych Z: Polymorphism in the P-glycoprotein drug transporter MDR1 gene: a possible link between environmental and genetic factors in Parkinson’s disease.

Pharmacogenetics, 2003, 13, 259–263.

7.Eder P, Stawczyk K, Krela-KaŸmierczak I, Linke K:

Chosen markers of inflammatory bowel diseases (Polish). Gastroenterol Pol 2007, 14, 429–431.

8.Farnood A, Naderi N, Moghaddam SJM, Noorinayer B, Firouzi F, Aghazadeh R, Daryani NE, Zali MR: The frequency of C3435T MDR1 gene polymorphism in Iranian patients with ulcerative colitis. Int J Colorectal Dis, 2007, 22, 999–1003.

9.Fiedler T, Büning C, Reuter W, Pitre G, Gentz E, Schmidt HH, Büttner J 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, 917–925.

10.Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Masch- eretti S, Fisher S, Frenzel H et al.: Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet, 2001, 357, 1925–1928.

11.Ho G-T, Moodie FM, Satsangi J: Multidrug resistance 1 gene (P-glycoprotein 170): an important determinant in gastrointestinal disease? Gut, 2003, 52, 759–766.

12.Ho G-T, Nimmo ER, Tenesa A, Fennell J, Drummond H, Mowat C, Arnott ID, Satsangi J: Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis. Gastroenterol- ogy, 2005, 128, 288–296.

13.Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brock- möller J, Johne A, Cascorbi I et al.: Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P- glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA, 2000, 97, 3473–3478.

14.Jamroziak K, Balcerczak E, M³ynarski W, Mirowski M, Robak T: Distribution of allelic variants of functional C3435T polymorphism of drug transporter MDR1 gene in a sample of Polish population. Pol J Pharmacol, 2002, 54, 495–500.

15.Kerb R: Implications of genetic polymorphisms in drug transporters for pharmacotherapy. Cancer Lett, 2006, 234, 4–33.

16.Kurzawski M, DroŸdzik M, Suchy J, Kurzawski G, Bia³ecka M, Górnik W, Lubiñski J: Polymorphism in the P-glycoprotein drug transporter MDR1 gene in colon cancer patients. Eur J Clin Pharmacol, 2005, 61, 389–394.

17.Maresca M, Fantini J: Some food-associated mycotoxins as potential risk factors in humans predisposed to chronic intestinal inflammatory diseases. Toxicon, 2010, 56, 282–294.

18.Molodecky NA, Kaplan GG: Environmental risk factors for inflammatory bowel disease. Gastroenterol Hepatol, 2010, 6, 339–346.

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20.Onnie CM, Fisher SA, Pattni R, Sanderson J, Forbes A, Lewis CM, Mathew CG: 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. In- flamm Bowel Dis, 2006, 12, 263–271.

21.Oostenbrug LE, van Dullemen HM, te Meerman GJ, Jan- sen PL. IBD and genetics: new developments. Scand J Gastroenterol Suppl. 2003, 239, 63–68.

22.Pañczyk M, Sa³agacka A, Mirowski M: MDR1 (ABCB1) gene encoding glycoprotein P (P-gp), a member of ABC transporter superfamily: consequences for therapy and progression of neoplastic diseases (Polish).

Postêpy Biochem, 2007, 53, 361–373.

23.Petryszyn P, Semianów-Wejchert J, Annabhani A, Paradowski L: Quality of life, education, occupational and social status of patients with inflammatory bowel disease – literature review (Polish). Gastroenterol Pol, 2008, 15, 421–424.

24.Pithadia AB, Jain S: Treatment of inflammatory bowel disease (IBD). Pharmacol Rep, 2011, 63, 629–642.

25.Potoènik U, Ferkolj I, Glavaè D, Dean M: Polymor- phisms in multidrug resistance 1 (MDR1) gene are asso- ciated with refractory Crohn disease and ulcerative colitis. Genes Immun, 2004, 5, 530–539.

26.Schwab M, Schaeffeler E, Marx C, Fromm MF, Kaskas B, Metzler J, Stange E et al.: Association between the

view. J Physiol Pharmacol, 2009, 60, Suppl 6, 61–71.

28.Szeliga J, Soñdka Z, Jackowski M, Jarkiewicz-Tretyn J, Tretyn A: The outline of immunopathogenesis of Crohn’s disease with special consideration of NOD2/CARD15 gene polymorphism (Polish). Gastroenterol Pol, 2007, 14, 129–133.

29.Urcelay E, Mendoza JL, Martín MC, Mas A, Martínez A, Taxonera C, Fernandez-Arquero M et al.: MDR1 gene: susceptibility in Spanish Crohn’s disease and ulcerative colitis patients. Inflamm Bowel Dis, 2006, 12, 33–37.

30.van Heel DA, Fisher SA, Kirby A, Daly MJ, Rioux JD, Lewis CM; Genome Scan Meta-Analysis Group of the IBD International Genetics Consortium: Inflammatory bowel disease susceptibility loci defined by genome scan meta-analysis of 1952 affected relative pairs. Hum Mol Genet, 2004, 13, 763–770.

31.Yacyshyn B, Maksymowych W, Bowen-Yacyshyn MB:

Differences in P-glycoprotein-170 expression and activity between Crohn’s disease and ulcerative colitis. Hum Immunol, 1999, 60, 677–687.

Received:March 23, 2011; in the revised form: December 6, 2011;

accepted:December 13, 2011.