Lactase persistence, NOD2 status and Mycobacterium avium subsp. paratuberculosis infection associations to Inflammatory Bowel Disease

Ander Izeta,Elena Molina,Luis Rodrigo,Joseba M Garrido,Natalia Elguezabal,Ramón A Juste,Susana Chamorro

doi:10.1186/1757-4749-4-6

Abstract

BackgroundInflammatory Bowel Disease (IBD), which includes both Crohn’s disease (CD) and ulcerative colitis (UC), is caused by a complex interplay involving genetic predisposition, environmental factors and an infectious agent. Mycobacterium avium subsp. paratuberculosis (MAP) is a promising pathogen candidate since it produces a chronic intestinal inflammatory disease in ruminants that resembles CD in humans. MAP is a ubiquitous microorganism, although its presence in the food chain, especially in milk from infected animals, is what made us think that there could be an association between lactase persistence (LP) and IBD. The LCT mutation has brought adaptation to dairy farming which in turn would have increased exposure of the population to infection by MAP. NOD2 gene mutations are highly associated to CD.MethodsIn our study, CD and UC patients and controls from the North of Spain were genotyped for the lactase gene (LCT) and for three NOD-2 variants, R702W, G908R and Cins1007fs. MAP PCR was carried out in order to assess MAP infection status and these results were correlated with LCT and NOD2 genotypes.ResultsAs for LP, no association was found with IBD, although UC patients were less likely to present the T/T−13910 variant compared to controls, showing a higher C-allele frequency and a tendency to lactase non-persistence (LNP). NOD2 mutations were associated to CD being the per-allele risk higher for the Cins1007fs variant. MAP infection was more extended among the healthy controls (45.2%) compared to CD patients (21.38%) and UC patients (19.04%) and this was attributed to therapy. The Asturian CD cohort presented higher levels of MAP prevalence (38.6%) compared to the Basque CD cohort (15.5%), differences also attributed to therapy. No interaction was found between MAP infection and LCT or NOD2 status.ConclusionsWe conclude that LP is not significantly associated with IBD, but that MAP infection and NOD2 do show not mutually interacting associations with IBD.

Highlights

Inflammatory Bowel Disease (IBD), which includes both Crohn’s disease (CD) and ulcerative colitis (UC), is caused by a complex interplay involving genetic predisposition, environmental factors and an infectious agent
Complete data for Mycobacterium avium subsp. paratuberculosis (MAP) DNA presence in blood and both lactase gene (LCT) and NOD-2 genotyping was accomplished for 278 subjects with IBD (173 with CD and 105 with UC) and 188 healthy controls
Conclusions previous studies have suggested an association between lactase non-persistence (LNP) and IBD at a population level, our study failed to find an association between the C/C−13910 genotype and IBD at an individual level

Summary

Introduction

Inflammatory Bowel Disease (IBD), which includes both Crohn’s disease (CD) and ulcerative colitis (UC), is caused by a complex interplay involving genetic predisposition, environmental factors and an infectious agent. Paratuberculosis (MAP) is a probable pathogen candidate for at least one subtype of IBD, CD, since it is responsible for a disease in ruminants of similar clinical and histological conditions named Johne’s disease (JD) or paratuberculosis [3,4,5] The connection between both intestinal inflammatory bowel diseases, human and ruminant, was first described in the early 1900s [6,7]. Mutations in the NOD2 locus are highly associated with CD in Europeans [17] and a recent genome-wide study from China [18,19] has shown that a high proportion of leprosy patients have many of the same genetic mutations found in patients with CD including NOD2/ CARD15 mutation All these findings lend support to the mycobacterial etiological hypothesis in CD

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