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Lack of genetic markers in Asian crohn's disease.


NOD2/CARD15 gene polymorphisms and Crohn's disease in the Chinese population.
Leong RW, Armuzzi A, Ahmad T, Wong ML, Tse P, Jewell DP, Sung JJ.

Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China. rupertleong@hotmail.com

Crohn's disease affects people world-wide, but the incidence in Asia is lower than in Western countries. This difference may be due to genetic and/or environmental factors. Three single nucleotide polymorphisms (SNPs) of the NOD2/CARD15 gene have been identified to be independently associated with the development of Crohn's disease in Caucasians. Whether these SNPs are involved in the pathogenesis of Crohn's disease in the Chinese population is unknown.

To determine if NOD2/CARD15 gene polymorphisms are found in Chinese patients with Crohn's disease.

Sixty-five consecutive Chinese Crohn's disease patients had genotyping performed using sequence-specific PCR directed against the wild-type and the Arg702Trp, Gly908Arg and 3020insC variants of the NOD2/CARD15 gene. Controls consisted of 63 patients with ulcerative colitis and 70 patients with dyspepsia.

None of the patients with Crohn's disease had heterozygous or homozygous SNP variants. Similarly none of the ulcerative colitis or dyspeptic controls had these SNPs.

The three previously described SNPs associated with the development of Crohn's disease in Caucasians are not found in Chinese patients with Crohn's disease.


Pediatric Crohn disease: clinical and genetic characteristics in Taiwan.
Hsiao CH, Wei SC, Wong JM, Lai HS, Chang MH, Ni YH.

Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.


Crohn disease (CD) is a heterogeneous disorder. The nucleotide oligomerization domain 2/caspase activating recruitment domain 15 (NOD2/CARD15) gene located at 16q12 is strongly associated with susceptibility to CD in white people but is absent in adult Asian patients, whereas the role of Toll-like receptor 4 (TLR4) polymorphisms has also been reported. Because clinical and genetic data in Asian children with CD are lacking, the aim of this study was to elucidate the clinical and genetic characteristics of Taiwanese children with CD.


All of the children hospitalized at the National Taiwan University Hospital between January 2000 and July 2005 who fulfilled the diagnostic criteria for CD were enrolled. Their clinical characteristics were recorded, and genomic DNA was extracted from their white blood cells. After polymerase chain reaction was performed, direct sequencing was done to detect the 4 NOD2 hotspot mutations (P268S, R702W, G908R, 1007fs) and TLR4 polymorphisms (Asp299Gly, Thr399Ile).


CD was diagnosed in 10 children (6 boys and 4 girls; age range at diagnosis, 14 months to 13 years; median age, 11.1 years). There were 5 children with ileocolonic region involvement, 3 with colonic region involvement, 2 with ileal region involvement, 4 with additional upper gastrointestinal tract involvement, and 2 with additional perianal fistula. Half of the children had growth retardation at diagnosis. Neither NOD2/CARD15 mutations nor TLR4 polymorphisms were found in the 10 patients.


Ileocolonic location and inflammatory behavior constitute the most frequent phenotype of CD in Taiwan. Mutations in the NOD2/CARD15 and TLR4 genes that are common in the West are not associated with CD in Taiwanese children.



Several studies from Western populations have recently shown that three mutations in NOD2 gene (C2104T, G2722C, and 3020insC) are associated with susceptibility to Crohn's disease (CD). However, three mutations were shown not to be associated with CD in Japanese and Chinese population. Here, we have analyzed the frequency of three NOD2 mutations in Korean patients to determine whether the NOD2 mutations are associated with susceptibility to CD in Korean population.

Blood samples were obtained from 128 patients with CD, 47 patients with ulcerative colitis, 19 Behcet's colitis, and 200 healthy controls. DNA in the region of three NOD2 mutations was sequenced by single base extension method, and the frequency of mutations were analyzed.

Among the subjects in our study groups, including patients with CD, ulcerative colitis, Behcet's colitis, and healthy controls, none had NOD2 mutations.

Our results indicate that although three NOD2 mutations are associated with susceptibility to CD in Western populations, these might be rare and may not be associated with susceptibility to CD in Korean patients.


Lack of common NOD2 variants in Japanese patients with Crohn's disease.
Inoue N, Tamura K, Kinouchi Y, Fukuda Y, Takahashi S, Ogura Y, Inohara N, Núñez G, Kishi Y, Koike Y, Shimosegawa T, Shimoyama T, Hibi T.

Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.

Previous studies have linked Crohn's disease (CD) to the pericentromeric region of chromosome 16 (IBD1). Three independent studies of Western populations have recently shown that 3 variants of NOD2, a gene located at 16q12, are associated with susceptibility to CD. Here, we have evaluated the 3 NOD2 variants in Japanese patients to determine whether the gene is also associated with susceptibility to CD in a non-Western population.


Blood samples were obtained from 350 patients with CD, 272 patients with ulcerative colitis, and 292 healthy controls at 3 hospitals in Japan. DNA was sequenced in the region of the 3 NOD2 variants (C2104T in exon 4, G2722C in exon 8, and 3020insC in exon 11) by genomic polymerase chain reaction followed by direct sequencing.


Among the subjects in our 3 study groups, including patients with CD, patients with ulcerative colitis, and healthy controls, none had common NOD2 variants that have been associated with CD in white patients.

These results indicate that genetic variation, which may predispose some human populations to CD, may not be present in other populations and specifically that common variants in NOD2 found in white patients with CD are not associated with CD in the Japanese population.


Common variants in NOD2 and IL23R are not associated with inflammatory bowel disease in Indians.
Mahurkar S, Banerjee R, Rani VS, Thakur N, Rao GV, Reddy DN, Chandak GR.

Centre for Cellular and Molecular Biology, Hyderabad, India.

Ulcerative colitis (UC) and Crohn's disease (CD) are two major phenotypes of inflammatory bowel disease (IBD) that present with inflammation of the colon or the entire gastrointestinal tract, respectively. Genome-wide association studies have confirmed the role of nucleotide-binding oligomerization domain protein-2 (NOD2) variants and identified several other genes associated with IBD. We investigated whether variants in NOD2 and interleukin-23 receptor (IL23R) are associated with IBD in a well-characterized case-control cohort from southern India.

We recruited 652 patients (411 UC and 241 CD) using established diagnostic criteria and 442 age-, sex-, and ethnically-matched, normal individuals. By direct sequencing, we screened the complete NOD2 gene and genotyped the R381Q variant in IL23R, and performed an association analysis and genotype-phenotype correlation analysis.

The clinical presentation of UC and CD patients did not differ significantly from the Europeans. We observed a monomorphic status for three common disease-susceptible variants, R702W, G908R, and 1007fs in NOD2; three other single nucleotide polymorphisms, P268S, R459R, and R587R, had a comparable minor allele frequency in patients and controls. Compared to Europeans, we found a low frequency (∼1%) of the protective allele at R381Q in IL23R and no statistically-significant association with IBD (odds ratio = 0.87; 95% confidence interval = 0.26-2.86; P>0.05).

Our study suggests that variants in the NOD2 gene and the protective variant R381Q in IL23R are not associated with IBD in Indians. Additional variants in these or other candidate genes might play a major role in the pathophysiology of IBD in Indians.


The more I read about studies like these, the more I think we are dealing with numerous diseases with different causes, with CD being used as an umbrella term. Super interesting stuff -- thanks for the share!
Hi Jesse. I have thought this for many years, but couldn't find any medical literature (or medicos) that supported the idea. There just seems so much variation in symptoms, successful/unsuccessful treatments, and even in what foods Crohn's sufferers can and cannot tolerate.
Not sure if genetic studies for crohn's disease should be that prioritised, they are interesting but they don't seem to result in any direct benefits, they knew long before these genetic studies that patients with crohn's disease were immune deficient. Reactions to harmless pathogens showed that patients with cd reached bacterial clearance much slower than controls.

First, they don't know who with crohn's disease has these mutations, finding out costs too much.

Second, what are you going to do if you do know. How would this influence treatment in any way, are you going to warn everyone with a NOD2 mutation that they might develop crohn's disease, make some airtight room for them and never let them out?

These studies cost so much money, and I do not see the immediate benefit.

That autophagy was compromised was also known before genetic studies, and even if you know, what are you going to do about it, develop some dangerous drugs influencing autophagy with side effects?

Instead why isn't bacterial susceptibility testing done more, so you don't mess up resistance in crohn's disease patients.

Why not look at non-HIV immonodeficiencies like chronic granulomatous disease.

Why not do genetic studies on the pathogens which people can control instead of human genetic studies which is out of anyone's hands.

Why not spend money on getting GI to check vitamin D to correct immune deficiencies instead of talking about it.

I really don't think the billions they spend on genetic susceptibility to pinpoint 400 more genes with a 0,03% extra chance of developing CD is going to end up helping treat crohn's disease.

Genes don't explain the explosive rate at which crohn's disease is increasing worldwide. 600+ patients in India with IBD in that study and not a single relationship to NOD2.
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