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letter
. 2003 Aug;52(8):1227–1228. doi: 10.1136/gut.52.8.1227-b

Association between K469E allele of intercellular adhesion molecule 1 gene and inflammatory bowel disease in different populations

A Papa 1, S Danese 1, A Armuzzi 1, E Gaetani 2, A Flex 2, P Pola 2, A Gasbarrini 2
PMCID: PMC1773734  PMID: 12865290

We read with interest the article by Matsuzawa et al showing an association between the K469E allele of intercellular adhesion molecule (ICAM)-1 gene and inflammatory bowel disease (IBD) in a Japanese population (Gut 2003;52:75–8). The ICAM-1 gene lies on chromosome 19p13, previously implicated in determining susceptibility to IBD,1 and codifies for a surface glycoprotein that belongs to the immunoglobulin superfamily. ICAM-1 plays an important role in the trafficking and activation of leucocytes and is upregulated in the inflamed mucosa of IBD patients. Matsuzawa et al found that the allelic frequency of K469 was significantly higher in both Crohn’s disease (CD) and ulcerative colitis (UC) patients than controls (Gut 2003;52:75–8). These data are in contrast with the results of two previous studies from the USA2 and Germany3 which showed no significant difference in K469 allele frequency between IBD patients and healthy controls. The G241R polymorphism of the ICAM-1 gene was also investigated in these studies, and IBD patients were stratified by antineutrophil cytoplasmic antibody (ANCA) status. In particular, Yang et al found a significantly increased frequency of the G241R polymorphism both in ANCA negative UC and ANCA positive CD patients2 while Braun et al showed an association between R241 allele and UC, independently of ANCA status.3

We also searched for the K469E mutation in 42 consecutive Italian IBD patients (31 males, mean age 36 (14) years), 17 with CD and 25 with UC, and 227 ethnically matched controls. Our preliminary results (see table 1), although obtained in a limited number of patients, are in contrast with the findings of Matsuzawa et al (Gut 2003;52:75–8) and confirm those obtained in Caucasians patients.2,3 The possible explanation for such a discrepancy in results is the influence of the different geographic distribution of the genetic mutation. Japanese patients with IBD have a genetic background that differs from Western patients, as also demonstrated recently for the NOD2/CARD15 gene polymorphisms. Indeed, several studies have reported an association between CD and NOD2/CARD15 mutations in Caucasians4–6 but not in Japanese cohorts.7,8 These data indicate that there may be significant genetic heterogeneity between different ethnic and racial IBD populations and environmental factors may play a leading role in the pathogenesis of IBD. Thus gene-environment interactions represent a crucial event in the pathogenesis of IBD and they cannot be considered as distinct entities.

Table 1 .

Allelic frequencies of the E/K469 ICAM-1 polymorphism in Italian patients affected by IBD, and in controls

Controls (n=227) IBD
(n=42)
UC
(n=25)
CD
(n=17)
Allelic frequency (%)
    E469 45 45 46 44
    K469 55 55 54 56

IBD, inflammatory bowel disease; UC, ulcerative colitis; CD, Crohn’s disease; ICAM, intercellular adhesion molecule.

References

  • 1.Rioux JD, Silverberg MS, Daly MJ, et al. Genome wide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. Am J Hum Gen 2000;66:1863–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Yang H, Vora DK, Targan SR, et al. Intercellular adhesion molecule 1 gene associations with immunologic subsets of inflammatory bowel disease. Gastroenterology 1995;109:440–8. [DOI] [PubMed] [Google Scholar]
  • 3.Braun C, Zahn R, Martin K, et al. Polymorphisms of the ICAM-1 gene are associated with inflammatory bowel disease, regardless of the p-ANCA status. Clin Immunol 2001;101:357–60. [DOI] [PubMed] [Google Scholar]
  • 4.Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001;411:599–603. [DOI] [PubMed] [Google Scholar]
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Gut. 2003 Aug;52(8):1227–1228.

Authors’ reply

K Sugimura 3, J Matsuzawa 4

We would like to address the possible cause of the inconsistency of the ICAM1 alleles, which associated with inflammatory bowel disease (IBD), between Japanese (K469) (Gut 2003;52:75–8) and German White populations (R241).1

Inconsistency of the associated alleles with a certain complex genetic disease among ethnic groups has been repeatedly described in the long term history of the association studies between inflammatory bowel disease (IBD) and HLA alleles. For example, the positive association between ulcerative colitis and DRB1*0103 in a Caucasian population but with DRB1*1502 in the Japanese has been reported in many studies. Such allelic inconsistencies were also observed in the HLA-B, HLA-DQA, and DQB genes.2

Three explanations have been considered for these inconsistencies.3 Firstly, the marker genes (HLA genes) themselves may not be the primary disease predisposing genes in this region but are in linkage disequilibrium with one or more primary responsible genes located in this region. Also, in different populations there may be different linkage disequilibria. This explanation seems to fit with the inconsistencies of ICAM1 allele association.

The second explanation is that there may be genetic heterogeneity in the allele associations in a certain gene. Recently, the existence of a population specific disease predisposing mutation (DPM) in NOD2 to Crohn’s disease (CD) has been proposed,4–7 suggesting the genetic heterogeneity of CD in the NOD2 region. However, if a certain DPM allele of NOD2 exists in a certain population, the increasing frequency of that DPM allele in CD should be observed consistently in all ethnic groups.7 In contrast, ICAM1 K469 frequency, which is increased in Japanese patients with IBD, is not increased in German patients. This observation could argue that the ICAM1 K469 polymorphism does not have a pathological effect directly but more likely occurs in strong linkage disequilibrium with a causative factor in both populations—that is, the time is not ripe enough to discuss the existence of genetic heterogeneity in this region (chromosome 19p13).

The third explanation is that these inconsistencies may be due to sample size and/or inappropriate control populations. As the ICAM1 polymorphism consists of only two SNPs and these polymorphisms are less informative, a considerable volume of sample size and simple composition of haplotype in the ethnic group would be required to detect the increase in the predisposing haplotype.

In conclusion, this inconsistency of the associated ICAM1 allele is most likely due to the difference in linkage disequilibria of the ICAM1 allele to the DPM in 19p13 among ethnic groups. However, the positive associations between the ICAM1 polymorphism and IBD in these ethnic groups highlights the potential importance of this region in the search for the predisposing gene(s) to IBD.1,8

References

  • 1.Braun C, Zahn R, Martin K, et al. Polymorphisms of the ICAM-1 gene are associated with inflammatory bowel disease, regardless of the p-ANCA status. Clin Immunol 2001;101:357–60. [DOI] [PubMed] [Google Scholar]
  • 2.Yang H, Taylor KD, Rotter JI. Inflammatory bowel disease. In: King RA, Rotter JI, Motulsky AG, eds. The Genetic Basis of Common Disease, 2nd edn. New York: Oxford University Press, 2002:266–97.
  • 3.Yang H, Rotter JI. The genetics of ulcerative colitis and Crohn’s disease. In: Kirsner JB, ed. Inflammatory Bowel Diseases, 5th edn. Philadelphia: WB Saunders, 2000:250–79.
  • 4.Yamazaki K, Takazoe M, Tanaka T, et al Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn’s disease. J Hum Genet 2002;47:469–72. [DOI] [PubMed] [Google Scholar]
  • 5.Inoue N, Tamura K, Kinouchi Y, et al. Lack of common NOD2 variants in Japanese patients with Crohn’s disease. Gastroenterology 2002;123:86–91. [DOI] [PubMed] [Google Scholar]
  • 6.Hampe J, Frenzel H, Mirza MM, et al. Evidence for a NOD2-independent susceptibility locus for inflammatory bowel disease on chromosome 16p. Proc Natl Acad Sci U S A 2002;99:321–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Sugimura K, Taylor KD, Lin Y, et al. A novel NOD2/CARD15 haplotype conferring risk for Crohn’s disease in Ashkenazi Jews. Am J Hum Genet 2003;72:509–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Yang H, Vora DK, Targan SR, et al. Intercellular adhesion molecule 1 gene associations with immunologic subsets of inflammatory bowel disease. Gastroenterology 1995;109:440–8. [DOI] [PubMed] [Google Scholar]

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