Nod2 not linked to indian Crohn’s disease

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Nod2 not linked to indian Crohn’s disease

Same conclusion as the previous study.

Also interesting, Indians who come to the West have much higher prevalence of crohn's disease.


NOD2 gene mutations associate weakly with ulcerative colitis but not with Crohn's disease in Indian patients with inflammatory bowel disease

Wellcome Trust Research Laboratory, Christian Medical College, Vellore 632004, India

January 2013

Pugazhendhi S, Santhanam S, Venkataraman J, Creveaux I, Ramakrishna BS.

BACKGROUND:

Three mutations (two missense and one frameshift) in the NOD2 gene are associated with Crohn's disease (CD) in a proportion of patients with Crohn's disease in North America, Europe and Australia. These three mutations are not found in Indian patients with CD. We undertook new studies to identify polymorphisms in the NOD2 gene in the Indian population and to detect whether any of these were associated with inflammatory bowel disease (IBD) in this population.

METHODS:

Individual exons of the NOD2 gene were amplified by PCR and subjected to denaturing high performance liquid chromatography (DHPLC) to detect heteroduplex formation. All 12 exons of the NOD2 gene were amplified and Sanger-sequenced to detect polymorphisms in the NOD2 gene. 310 patients with CD, 318 patients with ulcerative colitis (UC) and 442 healthy controls (HC) were recruited for association studies. DNA from these participants was evaluated for the identified eight polymorphisms by Sequenom analysis.

RESULTS:

Heteroduplex formation was noted by DHPLC in exons 2 and 4 of the NOD2 gene. Sequencing of the entire NOD2 gene data revealed eight polymorphisms - rs2067085, rs2066842, rs2066843, rs1861759, rs2111235, rs5743266, rs2076753, and rs5743291 - of which the latter four were described for the first time in Indians. None of these polymorphisms was associated with CD. The SNPs rs2066842 and rs2066843 were in significant linkage disequilibrium. Both SNPs showed a significant association with UC (P=0.03 and 0.04 respectively; odds ratio 1.44 and 1.41 respectively).

CONCLUSION:

Four NOD2 polymorphisms were identified for the first time in the Indian population. Of 8 NOD2 polymorphisms, none were associated with CD but two were weakly associated with UC. NOD2 polymorphisms do not play a major role in CD genesis in India.

 

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Environmental factors associated with Crohn’s disease in India—there’s more to it than meets the eye

County Durham & Darlington NHS Foundation Trust and Durham University, Durham, UK

Anjan Dhar

Inflammatory bowel disease (IBD) has traditionally been considered a Western disease. However, the last 2 decades have seen an increase in the reports of both ulcerative colitis (UC) and Crohn’s disease (CD) from Asian countries [1]. Most of these reported series have been hospital-based with only one population-based survey by Sood et al. [2]. Time-trend data from Japan and China indicate a dramatic increase in the incidence of UC and a more gradual increase in that of CD [1]. In addition, a higher incidence of UC has been noted amongst second-generation Asian migrants in the United Kingdom [3]. This increase in the incidence and prevalence of IBD in Asia mirrors the epidemiological trend in the Western world that occurred 50 years ago Though increased awareness of IBD, better diagnostic facilities, and the growth of the specialty appear to have played a major factor for this increase in reported incidence, there is probably also a genuine increase in the incidence of both UC and CD [1].
The role of the changing environment in the pathogenesis of IBD is likely to be a major contributory factor for the increase in this condition in Asian countries. Improvement in sanitation and public health, while inevitably leading to a decrease in the burden of infectious diseases, have been shown to be associated with an increase in autoimmune and chronic inflammatory diseases [4]. The environmental factors which are well-recognised as associated with IBD include smoking, diet, stress, microbial agents, appendicectomy, social status and intestinal permeability to fermentable oligo-, di- and mono-saccharides and polyols (FODMAPs).
In this issue of the Journal, Pugazhendhi et al. [5] from a tertiary referral hospital in southern India report a case–control study that looked at the association of surrogate markers of environmental hygiene in patients with CD compared to age-linked healthy controls. They found that urban residence, safe drinking water and availability of piped water (all indicators of better hygiene) were positively associated with CD whereas consumption of fish (a source of ω-3 polyunsaturated fatty acids) and exposure to cattle (an indicator of poor hygiene) were negatively associated with CD. The message of the study is clear—improved hygiene was associated with a higher prevalence of CD in this area.
The ‘hygiene hypothesis’ [6] of IBD is based on the observation that incidence of IBD has increased in both developing and developed countries with improvements in hygiene during the 20th century. It claims that raising children in extremely hygienic environments negatively affects immune development and tolerance to a variety of antigenic challenges, which in later life predisposes them to develop chronic inflammatory diseases such as IBD. However, the evidence for the contribution of several factors included in this hypothesis has never been analyzed in a systematic manner. In the present study too, except for diet (fish oil), all the other factors found to be correlated with the development of CD, can be linked to gut microbiota and immune tolerance.
The mucosal surface of the human gastrointestinal tract is approximately 200–300 m2 in area and is colonised by 1014 bacteria of more than 1,000 different species and subspecies [7, 8]. The phylogenetic diversity of the human gut microbiome allows an individual microbial fingerprint to be created. This adult profile is usually well established by the age of 2 years [9, 10]. Though it remains unclear whether the overall microbial fingerprint of the gut flora in patients with CD is different from controls, the relative numbers of at least certain bacterial strains have been shown to differ in this disease [11–13]. Though a single pathogenic organism has never been found in patients with CD, adherent invasive Escherichia coli, AIEC, have been detected in some patients [14]. In addition to E. coli, an increase in anaerobic bacteria such as Bacteroides spp. has been shown in patients with CD.
Furthermore, an imbalance in the normal gut microbiota without actual acquisition of a particular infectious organism may be responsible for the development of IBD. In fact, metagenomic studies have shown that entire classes of bacteria are lost or over-represented in patients with IBD [15]. In animal models of colitis, the exposure of germ-free animals to bacteria has been clearly shown to induce intestinal inflammation. In addition, timing of exposure of an individual to various bacteria may also be important. For instance, exposure to a pathogen in a small dose during early childhood may be associated with induction of immune tolerance, since regulatory dendritic cells may fail to induce a proliferation of the regulatory T cells in the terminal ileum. In addition, there is a complex interplay between mucosa-associated bacteria, mucosal immunology and mucosal barrier permeability, whereby an increase in mucosal permeability (well known in patients with CD and their relatives) often leads to a continuous, persistent antigenic challenge resulting in an exaggerated and prolonged/persistent inflammatory response in the mucosa.
So what do the results of the present study add to the knowledge that is already available? Being an observational study, it does not achieve much, except that it supports the previous studies that have looked at various aspects of the hygiene hypothesis. Further, the impact of environmental deprivation in the developing world on CD may be difficult to compare with that in the western world. A definitive answer is likely to come from bacterial fingerprinting studies on the gut flora from patients with CD and age-matched controls, both of whom have been exposed to similar environmental conditions, and by linking these data to genetic susceptibility, disease phenotype, smoking etc. Some initial data using pulsed-field gel electrophoresis profiles of E. coli strains from patients with CD, UC and controls show a well-defined clustering, supporting the idea of a disease-associated gut microenvironment [16]. With the recent developments in sequencing techniques for gut microflora, and microRNA arrays the next few years should be quite exciting, and lead to newer clues to the role of environmental factors in the etiopathogenesis of IBD.