The *1244 A>G polymorphism of MyD88 (rs7744) is closely associated with susceptibility to ulcerative colitis

Matsunaga,Kazuhiro; Tahara,Tomomitsu; Shiroeda,Hisakazu; Otsuka,Toshimi; Nakamura,Masakatsu; Shimasaki,Takeo; Toshikuni,Nobuyuki; Kawada,Natsuko; Shibata,Tomoyuki; Arisawa,Tomiyasu

doi:10.3892/mmr.2013.1769

The *1244 A>G polymorphism of MyD88 (rs7744) is closely associated with susceptibility to ulcerative colitis

Authors:
- Kazuhiro Matsunaga
- Tomomitsu Tahara
- Hisakazu Shiroeda
- Toshimi Otsuka
- Masakatsu Nakamura
- Takeo Shimasaki
- Nobuyuki Toshikuni
- Natsuko Kawada
- Tomoyuki Shibata
- Tomiyasu Arisawa
View Affiliations

Affiliations: Department of Gastroenterology, Kanazawa Medical University, Uchinada‑machi, Ishikawa 920‑0293, Japan, Department of Gatroenterology, Fujita Health University, Kutsukake‑cho, Toyoake 470‑1192, Japan
Published online on: November 1, 2013 https://doi.org/10.3892/mmr.2013.1769
Pages: 28-32

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Toll‑like receptor activation intitially recruits the myeloid differentiation primary response gene (88) (MyD88) protein. A polymorphism *1244 A>G (rs7744) in the 3'‑untranslated region of MyD88 has been identified. In the present study, the association of this polymorphism with ulcerative colitis (UC) was investigated. The population studied comprised 922 individuals, including patients with UC (UC cases) and without (controls). Genotyping of rs7744 was performed by PCR single-strand conformation polymorphism and the rs7744 G allele frequencies in the controls and UC cases were 32.8 and 43.5%, respectively (P<0.0001). The results showed that the genotype frequency of the AA homozygote was significantly lower and that of the GG homozygote was significantly higher in the UC cases compared with those in the controls (P=0.0012 for both groups). The rs7744 minor allele variants were significantly associated with susceptibility to UC as indicated by dominant and recessive genetic models. The minor allele variants were associated with an increased risk for UC in the male individuals but not the female individuals. The rs7744 was also associated with a non‑continuous phenotype of UC and steroid unused/independent UC. This minor allele homozygote was associated with the disease severity of UC, hospitalization and response to steroid treatment. The results of the present study provided evidence that MyD88 polymorphism rs7744 was significantly associated with the development of UC and that this polymorphism may be associated with the response to treatment therapies for UC.

View Figures

View References

1	Podolsky DK: Inflammatory bowel disease. N Engl J Med. 347:417–429. 2002. View Article : Google Scholar
2	Chamaillard M, Philpott D, Girardin SE, et al: Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases. Proc Natl Acad Sci USA. 100:3455–3460. 2003. View Article : Google Scholar : PubMed/NCBI
3	Sakamoto N, Kono S, Wakai K, et al; Epidemiology Group of the Research Committee on Inflammatory Bowel Disease in Japan. Dietary risk factors for inflammatory bowel disease: a multicenter case-control study in Japan. Inflamm Bowel Dis. 11:154–163. 2005. View Article : Google Scholar : PubMed/NCBI
4	Head KA and Jurenka JS: Inflammatory bowel disease part 1. Ulcerative colitis - pathophysiology and conventional and alternative treatment options. Altern Med Rev. 8:247–283. 2003.PubMed/NCBI
5	Lakatos PL, Fischer S, Lakatos L, Gal I and Papp J: Current concept on the pathogenesis of inflammatory bowel disease-crosstalk between genetic and microbial factors: pathogenic bacteria and altered bacterial sensing or changes in mucosal integrity take ‘toll’? World J Gastroenterol. 12:1829–1841. 2006.
6	Gersemann M, Wehkamp J and Stange EF: Innate immune dysfunction in inflammatory bowel disease. J Intern Med. 271:421–428. 2012. View Article : Google Scholar : PubMed/NCBI
7	UK IBD Genetics Consortium. Barrett JC, Lee JC, Lees CW, et al: Genomewide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet. 41:1330–1334. 2009. View Article : Google Scholar : PubMed/NCBI
8	Silverberg MS, Cho JH, Rioux JD, et al: Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet. 41:216–220. 2009. View Article : Google Scholar : PubMed/NCBI
9	McGovern DP, Gardet A, Törkvist L, et al: Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet. 42:332–337. 2010. View Article : Google Scholar : PubMed/NCBI
10	Franke A, Balschun T, Sina C, et al: Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL). Nat Genet. 42:292–294. 2010. View Article : Google Scholar : PubMed/NCBI
11	Fukata M and Abreu MT: TLR4 signaling in the intestine in health and disease. Biochem Soc Trans. 35:1473–1478. 2007. View Article : Google Scholar : PubMed/NCBI
12	Arancibia SA, Béltran CJ, Aguirre IM, et al: Toll-like receptors are key participants in innate immune responses. Biol Res. 40:97–112. 2007. View Article : Google Scholar : PubMed/NCBI
13	Chen Z, Nakajima T, Inoue Y, et al: A single nucleotide polymorphism in the 3′-untranslated region of MyD88 gene is associated with Buerger disease but not with Takayasu arteritis in Japanese. J Hum Genet. 56:545–547. 2011.
14	Mishra PJ and Bertino JR: MicroRNA polymorphisms: the future of pharmacogenomics, molecular epidemiology and individualized medicine. Pharmacogenomics. 10:399–416. 2009. View Article : Google Scholar : PubMed/NCBI
15	Siddique I and Khan I: Mechanism of regulation of Na-H Exchanger in inflammatory bowel disease: role of TLR-4 signaling mechanism. Dig Dis Sci. 56:1656–1662. 2011. View Article : Google Scholar : PubMed/NCBI
16	Podolsky DK: Inflammatory bowel disease (2). N Engl J Med. 325:1008–1016. 1991. View Article : Google Scholar : PubMed/NCBI
17	Arisawa T, Tahara T, Shibata T, et al: A polymorphism of microRNA 27a genome region is associated with the development of gastric mucosal atrophy in Japanese male subjects. Dig Dis Sci. 52:1691–1697. 2007. View Article : Google Scholar : PubMed/NCBI
18	Arisawa T, Tahara T, Shiroeda H, et al: NFKB1 polymorphism is associated with age-related gene methylation in Helicobacter pylori-infected subjects. Int J Mol Med. 30:255–262. 2012.PubMed/NCBI
19	Ruemmele FM, Beaulieu JF, Dionne S, et al: Lipopolysaccharide modulation of normal enterocyte turnover by toll-like receptors is mediated by endogenously produced tumour necrosis factor alpha. Gut. 51:842–848. 2002. View Article : Google Scholar
20	Boone DL and Ma A: Connecting the dots from Toll-like receptors to innate immune cells and inflammatory bowel disease. J Clin Invest. 111:1284–1286. 2003. View Article : Google Scholar : PubMed/NCBI
21	Pierik M, Joossens S, Van Steen K, et al: Toll-like receptor-1, -2, and -6 polymorphisms influence disease extension in inflammatory bowel diseases. Inflamm Bowel Dis. 12:1–8. 2006. View Article : Google Scholar : PubMed/NCBI
22	Lubbad A, Oriowo MA and Khan I: Curcumin attenuates inflammation through inhibition of TLR-4 receptor in experimental colitis. Mol Cell Biochem. 322:127–135. 2009. View Article : Google Scholar : PubMed/NCBI
23	Sepúlveda SE, Beltrán CJ, Peralta A, et al: Inflammatory bowel diseases: an immunological approach. Rev Med Chil. 136:367–375. 2008.(In Spanish).
24	Cantó E, Ricart E, Monfort D, et al: TNF alpha production to TLR2 ligands in active IBD patients. Clin Immunol. 119:156–165. 2006.PubMed/NCBI
25	Tomita T, Kanai T, Fujii T, et al: MyD88-dependent pathway in T cells directly modulates the expansion of colitogenic CD4⁺ T cells in chronic colitis. J Immunol. 180:5291–5299. 2008. View Article : Google Scholar : PubMed/NCBI
26	Aoyagi Y, Nagata S, Kudo T, et al: Peroxisome proliferator- activated receptor γ 2 mutation may cause a subset of ulcerative colitis. Pediatr Int. 52:729–734. 2010.
27	Hugot JP and Thomas G: Genome-wide scanning in inflammatory bowel diseases. Dig Dis. 16:364–369. 1998. View Article : Google Scholar : PubMed/NCBI
28	Scott GK, Goga A, Bhaumik D, Berger CE, Sullivan CS and Benz CC: Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA miR-125a or miR-125b. J Biol Chem. 282:1479–1486. 2007. View Article : Google Scholar : PubMed/NCBI
29	Potter C, Cordell HJ, Barton A, et al; Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS). Association between anti-tumour necrosis factor treatment response and genetic variants within the TLR and NF{kappa}B signalling pathways. Ann Rheum Dis. 69:1315–1320. 2010.PubMed/NCBI
30	Cho JH and Brant SR: Genetics and genetic markers in inflammatory bowel disease. Curr Opin Gastroenterol. 14:283–288. 1998. View Article : Google Scholar
31	Fisher SA, Hampe J, Macpherson AJ, et al: Sex stratification of an inflammatory bowel disease genome search shows male-specific linkage to the HLA region of chromosome 6. Eur J Hum Genet. 10:259–265. 2002. View Article : Google Scholar : PubMed/NCBI