Download Genetic Statement 1 - Asia Pacific Working Group in Inflammatory

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
(data from NTUH, Wei et al)
Genetics-statement 1
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)
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. 2008 Dec;103(12):3167-82.
Chua 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. 2009 May;10(2):124-30.
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. 2005
Oct;83(5):498-503.
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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
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. 2007 Sep;13(9):1069-76
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.
2008 Oct;103(10):2519-26. Epub 2008 Jul 30.
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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.
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 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. 2009 Sep;15(9):1385-90.
Yang SK, Lee SG, Cho YK, Lim J, Lee I, Song K. Association of TNF-alpha/LTA polymorphisms with
Crohn's disease in Koreans. Cytokine. 2006 Jul;35(1-2):13-20. Epub 2006 Aug 22.
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. 2010 Oct;105(10):2209-17. Epub 2010 Apr
20.
• But there is lots on
ANZ caucasians these are becoming
Asian guidelines not
Asia Pacific
guidelines
• Need to specify date
and year
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.
Takatsu N, Matsui T, Murakami Y, Ishihara H, Hisabe T, Nagahama T, Maki S, Beppu T, Takaki Y,
Hirai F, Yao K. Adverse reactions to azathioprine cannot be predicted by thiopurine S
methyltransferase genotype in Japanese patients with inflammatory bowel disease. J Gastroenterol
Hepatol. 2009 Jul;24(7):1258-64.
Kim JH, Cheon JH, Hong SS, Eun CS, Byeon JS, Hong SY, Kim BY, Kwon SH, Kim SW, Han DS,
Yang SK, Kim WH. Influences of thiopurine methyltransferase genotype and activity on thiopurine
induced leukopenia in Korean patients with inflammatory bowel disease: a retrospective cohort study.
J Clin Gastroenterol. 2010 Nov-Dec;44(10):e242-8.
Cao Q, Zhu Q, Shang Y, Gao M, Si J. Thiopurine methyltransferase gene polymorphisms in Chinese
patients with inflammatory bowel disease. Digestion. 2009;79(1):58-63. Epub 2009 Feb 28.
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. 2009 Feb;39(2):121-6.
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. 2010 Oct;45(10):1014-21.
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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. 2010 Oct;45(10):1014-21.)
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