TRPM8 polymorphisms associated with increased risk of IBS-C and IBS-M

Recently in Gut, genetic variation affecting ion channels activity has been highlighted in relation to bowel function and the biology of stool frequency. It is also known that 2% of patients with IBS carry functional missense mutations in the voltage-gated channel NaV1.5 (SCN5A gene). Hence, channelopathies represent potential abnormalities underlying GI dysfunction and IBS. We inspected data from our previous genome-wide association study (GWAS) of IBS, in relation to 27 genes whose ion channel products contribute to GI sensorimotor development and function, visceral sensation and GI motility (see online supplementary table S1). Significant (uncorrected) results were detected for four genes (calcium voltagegated channels CACNA1A and CACNA1E, and transient receptor potential channels TRPV3 and TRPM8; see online supplementary figure S1), which were selected for replication analyses in an independent set of IBS cases (N=386) and controls (N=357) (see online supplementary material methods). A sexadjusted logistic regression analysis of genotype data from this cohort (see online supplementary material methods) detected significant associations for TRPM8, and a meta-analysis of GWAS and replication yielded (i) strongest evidence of association at this locus, (ii) no statistical heterogeneity (Cochran’s Q test p>0.05) and (iii) same direction of genetic risk effects in the two studies (table 1). Rome III IBS-subtype information available for the replication cohort revealed TRPM8 single nucleotide polymorphisms (SNP) to impact IBS risk exclusively in the IBS-C and IBS-M types, with strongest evidence obtained from their