In this issue of Gut, Yeo and colleagues¹ report on the association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome (D-IBS) in women (see page 1452). In a study of 194 North American female participants with D-IBS in a clinical trial programme and 448 female controls, there was an association between the homozygous short genotype of SERT-P (serotonin reuptake transporter gene) and the D-IBS phenotype, with an odds ratio of 2.25 (95% confidence interval 1.51–3.31). The fact that the confidence interval does not cross the value of 1 suggests that the association is statistically significant, and the authors suggest that the SERT-P may be a candidate gene for D-IBS in women.

To place these interesting observations in perspective, the reader may wish to address the following. What is SERT? What is the theoretical consequence of a polymorphism of the SERT-P gene? What happens to animals when the SERT gene is knocked out? Have other studies addressed the association of this polymorphism and IBS? Are there any pitfalls in the interpretation of such association studies?

WHAT IS SERT?

Serotonin (5-hydroxtryptamine, 5-HT) is secreted in copious amounts from gut enteroendocrine cells and serves as a critical messenger for gastrointestinal fluid secretion and gut motility.^2,3 There are seven subclasses of serotonergic receptors, differentiated on the basis of structure, molecular mechanism, and function.⁴ In contrast with the remarkable diversity of 5-HT receptors, only a single protein, the 5-HT transporter (or SERT), mediates reuptake of 5-HT from the synaptic cleft and thus termination of its action. The approved gene symbol for SERT is SLC6A4 (solute carrier family 6 member 4); this abbreviation is used in …