Article Text

Human CAZyme genes polymorphism and risk of IBS: a population-based study
  1. Leire Torices1,
  2. Andreea Zamfir-Taranu1,
  3. Cristina Esteban-Blanco1,
  4. Isotta Bozzarelli1,
  5. Ferdinando Bonfiglio2,3,
  6. Mauro D'Amato1,4,5
  1. 1Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain
  2. 2Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy
  3. 3CEINGE Biotecnologie Avanzate scarl, Naples, Italy
  4. 4Ikerbasque, Basque Foundation for Science, Bilbao, Spain
  5. 5Department of Medicine and Surgery, LUM University, Casamassima, Italy
  1. Correspondence to Professor Mauro D'Amato, Department of Medicine & Surgery, LUM University, Casamassima, Italy; damato{at}

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A series of papers in Gut recently highlighted genetic variation in the sucrase-isomaltase gene (SI; coding for a brush-border disaccharidase) as a likely causative factor in a subset of patients with irritable bowel syndrome (IBS).1–4 Hypomorphic (dysfunctional) SI variants may thus underlie gastrointestinal symptoms in rare recessive forms of congenital SI deficiency (CSID)5 as well as milder complex (IBS) manifestations,6 across a broad spectrum of genetic SI deficiencies (GSID) that vary in severity and onset of presentation.7 Moreover, SI carrier status has been shown to also affect the response to specific carbohydrate-focused diets, thus providing a rationale for personalising (dietary) therapeutic strategies in IBS.1 8

Together with SI, a number of human Carbohydrate-Active enZymes (hCAZymes, are involved in the breakdown of polysaccharides during the process of carbohydrate digestion, which is initiated by salivary amylases (AMYs) and finalised in the small intestine by pancreatic AMYs and brush-border disaccharidases SI, lactase (LCT), maltase-glucoamylase (MGAM) and trehalase (TREH) (figure 1).5 Of note, similar to SI in GSIDs, mutations in other hCAZymes cause rare genetic forms of carbohydrate maldigestion, while regulatory DNA variations (persistent genotype) influence lactose intolerance in adults.5 This suggests hCAZyme genes other than SI may contribute to IBS predisposition via similar mechanisms (reduced hCAZyme activity increasing IBS risk): we sought to test this hypothesis through the analysis of genetic and health-related data in 366,432 individuals of European ancestry from the large population-based cohort UK Biobank (UKBB) detailed methods’ description is provided in online supplemental material).

Supplemental material

Figure 1

Schematic representation of the process of carbohydrate digestion. Reported are the types of carbohydrates, the hCAZymes involved and the corresponding genes studied here.

Patients with IBS were identified across four definitions, based on alternative diagnoses from hospital admissions, general practitioner’s notes, Digestive Health Questionnaires including Rome III Criteria and as self-reported condition from health-related questionnaires (online supplemental table S1). Rare (allele frequency<1%) hCAZyme functional (missense, nonsense, read-through and splice-site) DNA variants were extracted from UKBB whole-exome sequencing data for nine genes of interest (AMY1A, AMY1B, AMY1C, AMY2A, AMY2B, LCT, MGAM, SI and TREH), and hypomorphic variants computationally predicted using stringent criteria from Ensembl Variant Effect Predictor and the pathogenicity classifier AlphaMissense. UKBB participants were stratified into carrier and non-carrier groups for each gene, and hCAZyme-IBS associations were tested via adjusted logistic regression. Additionally, cumulative analyses were carried out for selected genes, in which carrier status was considered collapsing hypomorphic variants from multiple genes into a single group.

In total, 1714 hypomorphic variants were identified across hCAZyme genes (online supplemental table S2). As reported in table 1, when individually tested for association with IBS (based on different definitions), three hCAZyme genes showed significant effects on disease risk after correction for multiple comparisons, namely SI (as previously shown), AMY1B (a salivary AMY) and AMY2A (a pancreatic AMY). Carriers of a hypomorphic variant in any of these genes were also exposed to increased risk of IBS (table 1), while the strongest association was detected in relation to the number of genes affected by hypomorphic variation (table 1). No other significant associations were detected (not shown).

Table 1

Significant associations between hCAZymes genes and risk of IBS

These results confirm and extend previous findings on the importance of hCAZyme genotype in relation to IBS risk.6 7 AMY1B and AMY2A code for AMYs that break down starch into smaller sugars and disaccharides, hence their reduced activity may ultimately lead to excess carbohydrates in the lower bowel where they induce IBS symptoms via osmotic diarrhoea and bacterial fermentation. Of note, AMY1 and AMY2 copy numbers (a type of genetic variation not studied here) have been shown to affect AMY activity and starch intake, as well as oral and gut microbiota composition.9 10

In summary, we provide additional evidence that hCAZyme genotype is relevant to IBS risk. This warrants replication of current findings, as it holds potential implications for personalising (dietary) therapeutic approaches in IBS.

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Patient consent for publication

Ethics approval

UKBB received ethical approval from the competent research ethics committee (REC reference 11/NW/0382), and this research has been conducted under application number 17435 (principal investigator MD’A). This work is part of a large study on the genetics of gastrointestinal diseases (GenGIScan project), approved by the local Basque Ethics Committee (Comité de Ética de la Investigación con medicamentos de Euskadi, code: PI2021041). Participants gave informed consent to participate in the study before taking part.


Supplementary materials

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  • LT and AZ-T are joint first authors.

  • X @LeireTorices, @ZamfirTaranu, @damato_mauro

  • FB and MD contributed equally.

  • Contributors MD’A and FB study design, conceptualization and supervision; LT, AZT, CEB and FB statistical and computational analysis; LT, AZT, CEB, FB, IB and MD’A data analysis and interpretation; MD’A obtained funding; MD’A, FB, LT and AZT drafted the manuscript with input and critical revision of all other authors. All authors approved the final draft of the manuscript.

  • Funding This work was supported by funding from the Spanish Government MCIN/AEI/10.13039/501100011033 (PCI2021-122064-2A to MD’A) under the umbrella of the European Joint Programming Initiative 'A Healthy Diet for a Healthy Life' (JPI HDHL) and of the ERA-NET Cofund ERA-HDHL (GA No. 696295 of the EU Horizon 2020 Research and Innovation Programme) and the Spanish Government MCIN/AEI/10.13039/501100011033 (PID2020-113625RB-I00 to MD’A).

  • Competing interests MD’A received unrestricted research grants and consulting fees from QOL Medical LLC. The sponsor had no role in the study design or in the collection, analysis and interpretation of data.

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.