Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis.
OBJECTIVE
The human multidrug resistance 1 (MDR1) gene product P-glycoprotein is highly expressed in intestinal epithelial cells, where it constitutes a barrier against xenobiotics. The finding that mdr1a knockout mice develop a form of colitis that is similar to ulcerative colitis, which can be prevented by antibiotics, indicates a barrier function for P-glycoprotein against the invasion of bacteria or toxins. Because the MDR1 single nucleotide polymorphism C3435T is associated with lower intestinal P-glycoprotein expression, we tested whether this polymorphism predisposes to development of ulcerative colitis.


METHODS
Allele frequencies and genotype distributions of the C3435T single nucleotide polymorphism were investigated in 149 patients with ulcerative colitis, 126 patients with Crohn's disease, and sex-matched healthy controls.


RESULTS
Significantly increased frequencies of the 3435T allele and the 3435TT genotype were observed in patients with ulcerative colitis compared with controls (3435T: P = 0.049; odds ratio, 1.4; 95% confidence interval, 1.02-1.94; 3435TT: P = 0.045; odds ratio, 2.03; 95% confidence interval, 1.04-3.95). In contrast, frequencies of the T allele and the TT genotype were the same in patients with Crohn's disease as in controls (P = 0.66 and P = 0.59, respectively). In comparison to 998 non-sex-matched controls, the effect for the TT genotype in ulcerative colitis patients was more pronounced (P = 0.0055; odds ratio, 2.1).


CONCLUSIONS
The higher frequency of the 3435TT genotype in patients with ulcerative colitis corroborates the findings from the mdr1a knockout mice. The results support the notion that P-glycoprotein plays a major role in the defense against intestinal bacteria or toxins. Impairment of barrier function in 3435TT subjects could render this genotype more susceptible to the development of ulcerative colitis.
Schwab
Matthias
M
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376 Stuttgart, Germany. matthias.schwab@kp-stuttgart.de
Schaeffeler
Elke
E
Marx
Claudia
C
Fromm
Martin F
MF
Kaskas
Bernd
B
Metzler
Joerg
J
Stange
Eduard
E
Herfarth
Hans
H
Schoelmerich
Juergen
J
Gregor
Michael
M
Walker
Siegfried
S
Cascorbi
Ingolf
I
Roots
Ivar
I
Brinkmann
Ulrich
U
Zanger
Ulrich M
UM
Eichelbaum
Michel
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000235:genetics*; D035061:Control Groups; D003424:Crohn Disease / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D019450:Genes, MDR / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic