Functional variation in human Carbohydrate-Active enZYmes (hCAZymes) in relation to the efficacy of a FODMAP-reducing diet in IBS patients

ObjectiveLimiting the dietary intake of carbohydrates poorly absorbed in the small intestine (FODMAPs) has therapeutic effects in some but not all irritable bowel syndrome (IBS) patients. We investigated genetic variation in human Carbohydrate-Active enZYmes (hCAZymes) genes in relation to the response to a FODMAP-lowering diet in the DOMINO study. DesignhCAZy polymorphism was studied in IBS patients from the dietary (FODMAP-lowering; N=196) and medication (otilonium bromide; N=54) arms of the DOMINO trial via targeted sequencing of 6 genes of interest (AMY2B, LCT, MGAM, MGAM2, SI and TREH). hCAZyme defective (hypomorphic) variants were identified via computational annotation using clinical pathogenicity classifiers. Age-and sex-adjusted logistic regression was used to test hCAZyme polymorphisms in cumulative analyses where IBS patients were stratified into carrier and non-carrier groups (collapsing all hCAZyme hypomorphic variants into a single bin). Quantitative analysis of hCAZyme variation was also performed, in which the number of hCAZyme genes affected by a hypomorphic variant was taken into account. ResultsIn the dietary arm, the number of hypomorphic hCAZyme genes positively correlated with treatment response rate (P=0.03, OR=1.51 [CI=0.99-2.32]). In the IBS-D group (N=55), hCAZyme carriers were six times more likely to respond to the diet than non-carriers (P=0.002, OR=6.33 [CI=1.83-24.77]). These trends were not observed in the medication arm. ConclusionshCAZYme genetic variation may be relevant to the efficacy of a carbohydrate-lowering diet. This warrants additional testing and replication of findings, including mechanistic investigations of this phenomenon. WHAT IS KNOWNO_LICarbohydrates are known triggers of IBS symptoms, and limiting their dietary consumption appears to have therapeutic effects C_LIO_LIThe lowFODMAP diet improves symptoms in some but not all IBS patients C_LI WHAT IS NEW HEREO_LICarrying hypomorphic hCAZyme gene variants associates with increased efficacy of a FODMAP-lowering diet in IBS, especially in patients with diarrhoea (IBS-D) C_LIO_LIhCAZyme genotype information may be relevant to increase therapeutic precision in IBS, contributing to personalising carbohydrate-focused dietary interventions C_LI