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Limitations: Small case number due to low prevalence rate of CD in this area GWAS, from Japan only so far Summarized the genetic analysis results published.

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Presentation on theme: "Limitations: Small case number due to low prevalence rate of CD in this area GWAS, from Japan only so far Summarized the genetic analysis results published."— Presentation transcript:

1 Limitations: Small case number due to low prevalence rate of CD in this area GWAS, from Japan only so far Summarized the genetic analysis results published from this area Quality of Evidence: II-2, B

2 (data from NTUH, Wei et al)

3 Genetic susceptibility in non-Caucasian Asian Crohn's disease patient differ from Caucasian and Western populations (positive associated with TNFSF15 and negative associated with the three main disease predisposing mutations of NOD2/CARD15) Genetics-statement 1 Summary table in: Thia KT, Loftus EV Jr, Sandborn WJ, Yang SK. An update on the epidemiology of inflammatory bowel disease in Asia. Am J Gastroenterol Dec;103(12): Thia KTLoftus EV JrSandborn WJYang SKAm J Gastroenterol. Chua KHChua KH, Hilmi I, Ng CC, Eng TL, Palaniappan S, Lee WS, Goh KL. Identification of NOD2/CARD15 mutations in Malaysian patients with Crohn's disease. J Dig Dis May;10(2): Hilmi INg CCEng TLPalaniappan SLee WSGoh KLJ Dig Dis. Summary Table 4 in: Wei SC, Ni YH, Yang HI, Su YN, Chang MC, Chang YT, Shieh MJ, Wang CY, Wong JM. A Hospital-based Study of Clinical and Genetic features of Crohn’s disease. J Formos Med Assoc (2011, in press). Leung E, Hong J, Fraser AG, Merriman TR, Vishnu P, Abbott WG, Krissansen GW. Polymorphisms of CARD15/NOD2 and CD14 genes in New Zealand Crohn's disease patients. Immunol Cell Biol Oct;83(5): Immunol Cell Biol.

4 True but remember in asia pacific there are also large communities of caucasians and these guidelines refer to all of Asia Pacific Need more widespread study I am not sure that "Asian" is adequate. The evidence is only showed in a few countries (Japan, China, Korea). The data is still sparse. The present data suggest this, however a firm conclusion cannot be made unless we have more GWAS studies from this region. more data represent the AP region IS NECESSARY Incomplete data

5 Genetics-statement 2 TNFSF15 is the common CD associated genetic change in Asia, but genetic heterogeneity also exists among different Asia-Pacific countries (IL23R associated with CD in Korea; ATG16L1 associated with CD in Australia and Taiwan; DLG5 associated with CD in Malaysia but DLG5 haplotype A is associated with reduced risk of IBD in the New Zealand Caucasian population) Summary Table 4 in: Wei SC, Ni YH, Yang HI, Su YN, Chang MC, Chang YT, Shieh MJ, Wang CY, Wong JM. A Hospital-based Study of Clinical and Genetic features of Crohn’s disease. J Formos Med Assoc (2011, in press). CHUA KH, LIAN LH, KEE BP, THUM CM, LEE WS, HILMI I, GOH LK. Identification of DLG5 and SLC22A5 gene polymorphisms in Malaysian Patients with Crohn’s Disease. JDD (2011, in press) Browning BL, Huebner C, Petermann I, Demmers P, McCulloch A, Gearry RB, Barclay ML, Shelling AN, Ferguson LR. Association of DLG5 variants with inflammatory bowel disease in the New Zealand Caucasian population and meta-analysis of the DLG5 R30Q variant. Inflamm Bowel Dis Sep;13(9): Inflamm Bowel Dis. Fowler EV, Doecke J, Simms LA, Zhao ZZ, Webb PM, Hayward NK, Whiteman DC, Florin TH, Montgomery GW, Cavanaugh JA, Radford-Smith GL. ATG16L1 T300A shows strong associations with disease subgroups in a large Australian IBD population: further support for significant disease heterogeneity. Am J Gastroenterol Oct;103(10): Epub 2008 Jul 30.

6 This is becoming too foussed on Asia. A statement needs to be made about the many D geneti assoitions shown in australin and NZ populations Needs further validation. Reteral centers based study Some IBD genetic studies among Asia population are underpowered due to limited sample size. Several literatures in Japanese IBD patients should be referred, if the word "Asian", is used. (negative correlation in NOD2, IL-23R etc, and possitive association in TNFSF15) Omit this statement as it clashes with 3. There will always be genetic heterogeneity Only 1 Korean study with 380 patients.

7 Genetics-statement 3 So far, there is no known genetic change associated with specific CD phenotype in non-Caucasian Asian, but KCNN4 gene variant is associated with ileal Crohn's Disease in the Australian and New Zealand Caucasian population Wei SC, Ni YH, Yang HI, Su YN, Chang MC, Chang YT, Shieh MJ, Wang CY, Wong JM. A Hospital-based Study of Clinical and Genetic features of Crohn’s disease. J Formos Med Assoc (2011, in press). Yang SKYang SK, Park M, Lim J, Park SH, Ye BD, Lee I, Song K. Contribution of IL23R but not ATG16L1 to Crohn's disease susceptibility in Koreans. Inflamm Bowel Dis Sep;15(9): Park MLim JPark SHYe BDLee ISong KInflamm Bowel Dis. Yang SKYang SK, Lee SG, Cho YK, Lim J, Lee I, Song K. Association of TNF-alpha/LTA polymorphisms with Crohn's disease in Koreans. Cytokine Jul;35(1-2): Epub 2006 Aug 22.Lee SGCho YKLim JLee ISong KCytokine. Simms LA, Doecke JD, Roberts RL, Fowler EV, Zhao ZZ, McGuckin MA, Huang N, Hayward NK, Webb PM, Whiteman DC, Cavanaugh JA, McCallum R, Florin TH, Barclay ML, Gearry RB, Merriman TR, Montgomery GW, Radford-Smith GL. KCNN4 gene variant is associated with ileal Crohn's Disease in the Australian and New Zealand population. Am J Gastroenterol Oct;105(10): Epub 2010 Apr 20.

8 But there is lots on ANZ caucasians - these are becoming Asian guidelines not Asia Pacific guidelines Need to specify date and year

9 Takatsu NTakatsu N, Matsui T, Murakami Y, Ishihara H, Hisabe T, Nagahama T, Maki S, Beppu T, Takaki Y,Matsui TMurakami YIshihara HHisabe TNagahama TMaki SBeppu TTakaki Y Hirai FHirai F, Yao K. Adverse reactions to azathioprine cannot be predicted by thiopurine SYao K methyltransferase genotype in Japanese patients with inflammatory bowel disease. J GastroenterolJ Gastroenterol Hepatol.Hepatol Jul;24(7): Kim JHKim JH, Cheon JH, Hong SS, Eun CS, Byeon JS, Hong SY, Kim BY, Kwon SH, Kim SW, Han DS,Cheon JHHong SSEun CSByeon JSHong SYKim BYKwon SHKim SWHan DS Yang SKYang SK, Kim WH. Influences of thiopurine methyltransferase genotype and activity on thiopurineKim WH induced leukopenia in Korean patients with inflammatory bowel disease: a retrospective cohort study. J Clin Gastroenterol.J Clin Gastroenterol Nov-Dec;44(10):e Cao QCao Q, Zhu Q, Shang Y, Gao M, Si J. Thiopurine methyltransferase gene polymorphisms in ChineseZhu QShang YGao MSi J patients with inflammatory bowel disease. Digestion. 2009;79(1): Epub 2009 Feb 28.Digestion. Leung M, Piatkov I, Rochester C, Boyages SC, Leong RW. Normal thiopurine methyltransferase phenotype testing in a Crohn disease patient with azathioprine induced myelosuppression. Intern Med J Feb;39(2): Ban H, Andoh A, Imaeda H, Kobori A, Bamba S, Tsujikawa T, Sasaki M, Saito Y, Fujiyama Y. The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease.J Gastroenterol Oct;45(10): Genetics-statement 4 TPMT genotype alone may not be useful to predict adverse effects to AZA in Asian IBD patients, MRP4 G2269A might be a new factor accounting for thiopurine sensitivity from Japanese study.

10 It does predict myelotoxicity in those who are deficient. however, all patients can develop myelotoxicity without TPMT mutations. All asian tpmt homozygote deficient ptients will develop bm toxicity if given full dose azathioprine Limited study Basically, TPMT genotyping is uncommon in routine work, but the evidence to deny it is still insufficient. "MRP4 genotyping is useful for AZA tolerability in Asian people. (Ban H, et al. J Gastroenterol Oct;45(10): ) Where is the evidence other factors may be involved; qualifying and clarifying statement useful here. In the West TPMT enzyme levels are measured to predict toxicity. I am not sure about how frequently genotype is done. Kim et al. C Clinic Gastro 2010 thinks otherwise


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