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


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


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 (chi(2) = 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 (chi(2) = 16.054, df = 8, p = 0.034 for age at diagnosis >or=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 (chi(2) = 16.101, df = 6, p = 0.017 for age at diagnosis >or=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.
Fiedler
T
T
Department of Gastroenterology, Hepatology & Endocrinology, Charité - Universitätsmedizin Berlin, CCM, Charitéplatz 1, Berlin, 10117, Germany. thomas.fiedler@charite.de
Büning
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Reuter
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Pitre
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Gentz
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Schmidt
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Büttner
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Ockenga
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Gerloff
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Meisel
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Lochs
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Roots
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Köpke
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Johne
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D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D003424:Crohn Disease / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005858:Germany / Q000453:epidemiology; D005938:Glucocorticoids / Q000627:therapeutic use; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D016896:Treatment Outcome
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids