Pharmacogenetics was used to evaluate the effect of polymorphisms in select candidate genes on the response of patients with
chronic constipation to tegaserod (ZelmacĀ® / ZelnormĀ®). The analysis identified twelve single
nucleotide polymorphisms (SNPs) in six genes (HTR4, HTR3B, MLN, AQP3, SLC12A2, SCNN1A) that were associated with at least a 60% response rate to tegaserod and an
odds ratios of 5 or greater (compared to
placebo) after 4 weeks of treatment. The identified genes display a wide range of different functions, including
serotonin signaling,
secretion and
motility, all of which are important in maintaining the normal function of the
gastrointestinal tract. Thus, these data imply that
chronic constipation may result from a variety of pathophysiological mechanisms related to variants in the above identified genes, all of which respond well to treatment with tegaserod. Patients without these variants do not respond to treatment significantly more than they do to
placebo, which could indicate that their
chronic constipation is not due to pathophysiological mechanisms but rather to environmental or possibly psychological factors. Patients with these variants are also less likely to respond to
placebo, again implying that these variants are associated with a true
pathophysiology.