Association between the C3435T polymorphism of the MDR1 gene and Crohnʼs disease

To the Editor: We read with interest the recent case-case control study by Urcelay et al,1 in which they found an increased incidence of the C3435 allele and the homozygous CC genotype of the multidrug resistance gene (MDR)1 in Crohn's disease (CD). The MDR1 gene encodes P-glycoprotein 170, which acts as an intestinal epithelial efflux transporter pump and may play a role in protecting the epithelium against xenobiotics and bacterial products.2 The finding that MDR1 knockout mice develop colitis, which is reversed with antibiotics,3 provides support to the role of this gene in the pathogenesis of IBD through altered host-bacterial interplay. We recently genotyped the C3435T MDR1 polymorphism (rs 1045642) in 247 CD (43.7% female; 27.9% Jewish; 95.1% white) and 112 ulcerative colitis (UC; 54.5% female; 21.4% Jewish; 89.3% white) affected individuals and 512 unaffected family members (49.4% female; 22.5% Jewish; 93.9% white) from trio and tetrad families. Genotyping was performed using the Sequenom Mass Array 7K system (San Diego, CA) and matrix-assisted laser desorption-time of flight mass spectometry analysis. Phenotypic information was obtained from medical case notes for disease type, behavior, and location according to the Montreal classification.4 Associations with disease susceptibility and genotype-phenotype relationships were analyzed using the family-based association test. We found no association between the C3435T polymorphism and UC (z = 0.92; P = 0.36). However, over-transmission of the 3435T allele was significantly associated with CD (z = 2.26; P = 0.02), with the strongest association arising in Jewish patients (Z = 2.50; P = 0.01). Thus far, more studies have implicated MDR1 variation in UC rather than CD, leading to the suggestion that MDR1 may be a “UC-specific” gene.5 Our data and those of Urcelay and colleagues suggest that this is not the case. Indeed, although the mdr1 knockout mouse mentioned earlier displays a histologic picture similar to UC with superficial epithelial inflammation, it also displays some features consistent with CD, such as transmural B- and T-cell infiltrates.5 It is noteworthy, however, that our data suggest that over-transmission of the 3435T allele is associated with CD, whereas those of Urcelay and colleagues suggest that the same allele may in fact protect against the disease. Carriage of the TT genotype has been associated with reduced P-glycoprotein function in whites,6 but the mechanism by which this may confer susceptibility to, or protect against, CD remains unclear. As Ho et al5 pointed out in a recent review paper in this journal, the role that P-glycoprotein plays in the innate and adaptive immunity framework of the gastrointestinal tract remains a crucial area of future research. There has certainly been considerable heterogeneity in the reported associations between the MDR1 C3435T polymorphism and UC or CD; carriage of the 3435T allele, for example, was shown to confer susceptibility to UC but not CD in Scottish7 and German8 populations. Our data add to this heterogeneity and, as Urcelay and colleagues point out, these reported differences in MDR1 genotype associations are likely to be explained by ethnic diversity. The varied association of the MDR1 gene with IBD susceptibility certainly reinforces the importance of stratifying for differences in ethnic composition of study populations when carrying out such genetic association studies for potential disease susceptibility or protective genes.

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