Polymorphisms in the DLG5 and OCTN Cation Transporter Genes in Crohn's Disease

Overview

Journal Gut

Specialty Gastroenterology

Date 2005 Jun 16

PMID 15955786

Citations 42

Authors

H-P Torok

J Glas

L Tonenchi

P Lohse

B Muller-Myhsok

O Limbersky

C Neugebauer

F Schnitzler

J Seiderer

C Tillack

S Brand

G Brunnler

P Jagiello

J T Epplen

T Griga

W Klein

U Schiemann

M Folwaczny

T Ochsenkuhn

C Folwaczny

Affiliations

Soon will be listed here.

Abstract

Background And Aims: Recent data suggest identification of causal genetic variants for inflammatory bowel disease in the DLG5 gene and in the organic cation transporter (OCTN) cluster, both situated in previously described linkage regions.

Patients And Methods: The polymorphisms in DLG5 (113 G-->A, 4136 C-->A, and DLG5_e26), SLC22A4 (1672 C-->T), and SLC22A5 (-207 G-->C) were assessed in 625 patients with Crohn's disease (CD), 363 patients with ulcerative colitis (UC), and 1012 healthy controls. Association with disease susceptibility, clinical phenotypes, and possible genetic interactions of these polymorphisms with disease associated CARD15/NOD2 mutations was analysed.

Results: No significant association of DLG5 polymorphisms with CD or UC was observed. Homozygosity for the OCTN-TC haplotype was associated with an increased CD risk (OR = 1.65), which was even greater in the presence of CARD15 mutations. Genotype-phenotype analysis revealed that this association was particularly strong in patients with colonic disease. The TC haplotype was associated with non-fistulising non-fibrostenotic disease, an earlier age of disease onset, and reduced need for surgery.

Conclusion: Our observations argue against a role of DLG5 polymorphisms in the susceptibility for inflammatory bowel disease, whereas the OCTN polymorphisms are associated with CD. However, due to the comparable weak association observed herein, extended linkage disequilibrium analyses of these variants with the IBD5 haplotype tagged single nucleotide polymorphims might be advisable before definitive conclusions about their causative role in CD can be drawn.

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References

Klein W, Tromm A, Griga T, Folwaczny C, Hocke M, Eitner K . Interaction of polymorphisms in the CARD15 and CD14 genes in patients with Crohn disease. Scand J Gastroenterol. 2003; 38(8):834-6. DOI: 10.1080/00365520310003147. View

Dudbridge F . Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol. 2003; 25(2):115-21. DOI: 10.1002/gepi.10252. View

McGovern D, van Heel D, Negoro K, Ahmad T, Jewell D . Further evidence of IBD5/CARD15 (NOD2) epistasis in the susceptibility to ulcerative colitis. Am J Hum Genet. 2003; 73(6):1465-6. PMC: 1180410. DOI: 10.1086/379745. View

Torok H, Glas J, Lohse P, Folwaczny C . Alterations of the CARD15/NOD2 gene and the impact on management and treatment of Crohn's disease patients. Dig Dis. 2004; 21(4):339-45. DOI: 10.1159/000075357. View

Peltekova V, Wintle R, Rubin L, Amos C, Huang Q, Gu X . Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet. 2004; 36(5):471-5. DOI: 10.1038/ng1339. View

Stoll M, Corneliussen B, Costello C, Waetzig G, Mellgard B, Andreas Koch W . Genetic variation in DLG5 is associated with inflammatory bowel disease. Nat Genet. 2004; 36(5):476-80. DOI: 10.1038/ng1345. View

McLeod R, Steinhart A, Siminovitch K, Greenberg G, Bull S, Blair J . Preliminary report on the Mount Sinai Hospital Inflammatory Bowel Disease Genetics Project. Dis Colon Rectum. 1997; 40(5):553-7. DOI: 10.1007/BF02055377. View

Hampe J, Schreiber S, Shaw S, Lau K, Bridger S, Macpherson A . A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort. Am J Hum Genet. 1999; 64(3):808-16. PMC: 1377799. DOI: 10.1086/302294. View

Yamazaki K, Takazoe M, Tanaka T, Ichimori T, Saito S, Iida A . Association analysis of SLC22A4, SLC22A5 and DLG5 in Japanese patients with Crohn disease. J Hum Genet. 2004; 49(12):664-668. DOI: 10.1007/s10038-004-0204-x. View

10.

Newman B, Gu X, Wintle R, Cescon D, Yazdanpanah M, Liu X . A risk haplotype in the Solute Carrier Family 22A4/22A5 gene cluster influences phenotypic expression of Crohn's disease. Gastroenterology. 2005; 128(2):260-9. DOI: 10.1053/j.gastro.2004.11.056. View

11.

Stephens M, Donnelly P . A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet. 2003; 73(5):1162-9. PMC: 1180495. DOI: 10.1086/379378. View

12.

Stephens M, Smith N, Donnelly P . A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001; 68(4):978-89. PMC: 1275651. DOI: 10.1086/319501. View

13.

Hugot J, Chamaillard M, Zouali H, Lesage S, Cezard J, Belaiche J . Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001; 411(6837):599-603. DOI: 10.1038/35079107. View

14.

Ogura Y, Bonen D, Inohara N, Nicolae D, Chen F, Ramos R . A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature. 2001; 411(6837):603-6. DOI: 10.1038/35079114. View

15.

Hampe J, Cuthbert A, Croucher P, Mirza M, Mascheretti S, Fisher S . Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet. 2001; 357(9272):1925-8. DOI: 10.1016/S0140-6736(00)05063-7. View

16.

Rioux J, Daly M, Silverberg M, Lindblad K, Steinhart H, Cohen Z . Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet. 2001; 29(2):223-8. DOI: 10.1038/ng1001-223. View

17.

Cordell H, Clayton D . A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes. Am J Hum Genet. 2001; 70(1):124-41. PMC: 384883. DOI: 10.1086/338007. View

18.

Radlmayr M, Torok H, Martin K, Folwaczny C . The c-insertion mutation of the NOD2 gene is associated with fistulizing and fibrostenotic phenotypes in Crohn's disease. Gastroenterology. 2002; 122(7):2091-2. DOI: 10.1053/gast.2002.34020. View

19.

Inoue N, Tamura K, Kinouchi Y, Fukuda Y, Takahashi S, Ogura Y . Lack of common NOD2 variants in Japanese patients with Crohn's disease. Gastroenterology. 2002; 123(1):86-91. DOI: 10.1053/gast.2002.34155. View

20.

Yamazaki K, Takazoe M, Tanaka T, Kazumori T, Nakamura Y . Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn's disease. J Hum Genet. 2002; 47(9):469-72. DOI: 10.1007/s100380200067. View