Functional Variation in Human CAZyme Genes in Relation to the Efficacy of a Carbohydrate-Restricted Diet in IBS...

Limiting the dietary intake of certain carbohydrates 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 relationship to the response to a FODMAP-lowering diet in the DOMINO study.

hCAZy polymorphism was studied in patients with IBS 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.

In the dietary arm, the number of hypomorphic hCAZyme genes positively correlated with treatment response rate (P = .03; odds ratio = 1.51; confidence interval = 0.99-2.32). In the IBS-D group (n = 55), hCAZyme carriers were 6 times more likely to respond to the diet than non-carriers (P = .002; odds ratio = 6.33; confidence interval = 1.83-24.77). These trends were not observed in the medication arm.

hCAZYme 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.