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Susceptibility to Crohn’s disease may lurk in enzyme mutation

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A preliminary study of genetic polymorphisms affecting transforming enzymes in the gut has singled out for the first time microsomal epoxide hydrolase as a likely candididate for susceptibility to Crohn’s disease (CD).

Homozygous Tyr 113 substitution for His 113 in exon 3 of the microsomal epoxide hydrolase (EPXH) gene was the only one of seven variants in a series of genes coding for detoxifying enzymes with a significantly higher frequency in patients with CD than controls (47% v 21%, respectively). Tyr/Tyr genotype was also more common within the patient group than in the control group (allele frequency 0.67 v 0.61, respectively), and the odds of having the Tyr 113 allele were almost three times higher. This variant and another, in exon 4 of the same gene, were not associated with disease site, disease onset, fistulas, or history of bowel resection.

The variants were identified by PCR-RFLP (restriction fragment length polymorphism). They included those in cytochrome P-450 1A1C (CYP1A1 3′ flanking region, CYP1A1 exon 7); glutathione S-transferases mu-1, pi-1, and theta-1 (GSTM1, GSTP1, GSTT1); and epoxide hydrolases (EPXH) in exons 3 and 4. Screening was performed on 151 consecutive outpatients at a hospital clinic in the Netherlands and age and sex matched healthy controls; all were Caucasian.

Reactive oxygen species and their toxic metabolites have been implicated in inflammation of the gut in CD. Detoxifying enzymes, such as glutathione S-transferases and epoxide hydrolases, may also have a role, so polymorphisms affecting their activity may affect risk of developing CD.

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