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Hiroshi IKEGAMI Osaka University Graduate School of Medicine Genetics of type 1 diabetes in Japanese (similarity to and difference from Caucasian populations)

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Presentation on theme: "Hiroshi IKEGAMI Osaka University Graduate School of Medicine Genetics of type 1 diabetes in Japanese (similarity to and difference from Caucasian populations)"— Presentation transcript:

1 Hiroshi IKEGAMI Osaka University Graduate School of Medicine Genetics of type 1 diabetes in Japanese (similarity to and difference from Caucasian populations) IDS8, Awaji Yumebutai （ October 8, 2005 ）

2 General populationSibling Japanese0.01 ～ 0.02% Caucasian0.4 % Caucasian6% ( s = 15) ? Familiar clustering of type 1 diabetes Japanese3.8%( s > 100) Ikegami H et al. Endocrine J 1996

3 Susceptibility genes for type 1 diabetes Major gene ： HLA(IDDM1)  -cell specificity ： INS(IDDM2) negative regulator ： CTLA4(IDDM12) SUMO4(IDDM5) PTPN22

4 Association of DRB1 alleles with type 1 diabetes Type 1 diabetesControlsORP (n=264)(n=314) DRB1 *040533.7%17.2%2.45 <0.00001 *090125.4%13.1%2.26 0.0002 *15021.9%14.6%0.11 <0.0000001 Kawabata Y et al. Diabetes 51:545-551, 2002

5 JapaneseDRB1*0405-DQB1*0401 (DR4) DRB1*0901-DQB1*0303 (DR9) CaucasiansDRB1*0301-DQB1*0201 (DR3) DRB1*0401-DQB1*0302 (DR4) Disease susceptible HLA-haplotypes

6 JapaneseCaucasian DRB1-DQB1 Type 1 diabetes HF 1) Type 1 diabetes HF haplotype susceptibility susceptibility DRB1*0405-DQB1*0401 susceptiblepresent unknown rare DRB1*0901-DQB1*0303 susceptiblepresent unknownrare DRB1*0301-DQB1*0201 unknownraresusceptiblepresent DRB1*0401-DQB1*0302 unknownraresusceptiblepresent DRB1*1501-DQB1*0602 protectivepresentprotectivepresent Different haplotypes are associated with type 1 diabetes in Japanese and Caucasian populations 1)HF: Haplotype frequency, http://square.umin.ac.jp/JSHI/frame.html

7 JapaneseDRB1*0405-DQB1*0401 (DR4) DRB1*0901-DQB1*0303 (DR9) CaucasiansDRB1*0301-DQB1*0201 (DR3) DRB1*0401-DQB1*0302 (DR4) Very high risk genotype DRB1*0301 /0401 (DR3/4) High risk genotypes for type 1 diabetes (Caucasians)

8 Kawabata Y et al. Diabetes 51:545-551, 2002 23.1 1.0 Odds Ratio DRB1*0405 / DRB1*0405 2.1 DRB1*0405 / X 2.8 DRB1*0901 / DRB1*0901 DRB1*0901 / Y Disease-associated genotypes in Japanese （ DRB1*0405 vs. DRB1*0901 haplotype ）

9 JapaneseDRB1*0405-DQB1*0401 (DR4) DRB1*0901-DQB1*0303 (DR9) CaucasiansDRB1*0301-DQB1*0201 (DR3) DRB1*0401-DQB1*0302 (DR4) Very high risk genotype （ Japanese ） DRB1*0901 /0901 (DR9/9) High risk genotypes for type 1 diabetes (Japanese)

10 JapaneseDRB1*0405-DQB1*0401 (DR4) DRB1*0901-DQB1*0303 (DR9) CaucasiansDRB1*0301-DQB1*0201 (DR3) DRB1*0401-DQB1*0302 (DR4) HLA haplotypes associated with type 1 diabetes KoreanDRB1*0301-DQB1*0201 (DR3) DRB1*0405-DQB1*0401 (DR4) DRB1*0901-DQB1*0303 (DR9)

11 DR9 homozygosity confers susceptibility to type 1 diabetes DR4DR9 1 10 20 Odds ratio :homo :hetero JapaneseKorean JapaneseKorean Kawabata Y et al. Diabetes 51:545-551, 2002

12 Susceptibility genes for type 1 diabetes Major gene ： HLA(IDDM1)  -cell specificity ： INS(IDDM2) negative regulator ： CTLA4(IDDM12) SUMO4(IDDM5)

13 Association of INS-VNTR with type 1 diabetes -596 VNTR -23 HphI 4.1 kb region of IDDM2 Class IIIhaplotype Class III  protective Class Ihaplotype Class I ＋ susceptible TH INS IGF2 VNTR Type 1 diabetes susceptibility

14 Frequency of class I INS-VNTR tended to be higher in type 1 diabetes than in controls Controls CasesOdds ratio France 1 55%84%4.2 UK 2 59%76%2.2 Japan 3 94%99% 1 Lucassen et al.Nature Genet 4:305, 1993 2 Bennet et al.Nature Genet 9:284, 1995 3 Kawaguchi et al. BBRC 233:283, 1997

15 Susceptibility genes for type 1 diabetes Major gene ： HLA(IDDM1)  -cell specificity ： INS(IDDM2) negative regulator ： CTLA4(IDDM12) PTPN22 SUMO4(IDDM5)

16 NATURE |VOL 423 | 29 MAY 2003 |www.nature.com/nature

17 Association of CTLA4 with autoimmune diseases (Caucasian populations) Odds ratio(95% CI) Graves’s disease1.51(1.31-1.75) Hashimoto thyroiditis1.45(1.17-1.80) Type 1 diabetes1.14(1.07-1.21) SNP: +6230G>A (rs3087243) Ueda H et al. Nature 2003

18 Arg620Trp (R620W) of PTPN22 was consistently reported to be associated with autoimmune diseases in Caucasian populations Odds ratio (95%CI) Type 1 diabetesN. American 1 1.83 (1.28-2.60) Italian 1 2.31 (0.93-5.82) UK 2 1.78 (1.54-2.06) Caucasian 3 (C/T)1.7(1.3-2.3) (T/T)3.4(1.3-8.9) Graves's disease 2 1.43 (1.17-1.76) RA 4 1.74 (1.27-2.38) SLE 5 (C/T)1.37 (1.07-1.75) (T/T)4.37 (1.98-9.65) 1 Nat Genet 36:337, 2004, 2 Diabetes 53:3020, 2004, 3 Diabetes 54:906, 2005 4 Am J Hum Genet 75:330, 2004, 5 Am J Hum Genet 75:504, 2004

19 estimated by EM algorithm （ Haploview v2.03 ） SUMO4 2176bp M55V MAP3K7IP2 Exon 7 Exon 6 438C>T -504A>GM55V438C>Tfrequency Haplotype AGAC49.6% Haplotype BAGT35.9% Haplotype CAAC14.4% -504A>G D’: 1.0 for single pair of SNPs SUMO4 SNPs identified by re-sequencing in Japanese

20 SUMO4 （ M55V ） is associated with type 1 diabetes (Japanese and Koreans) *Mantel-Haenszel test CasesControlsOR(95%CI)p (n=541)(n=743) Japanese59% 50% Koreans58%44%1.46 (1.17-1.83)0.0008* Noso S et al. Poster #098 Diabetes ( in press)

21 0.50.71.01.21.52.03.0 Asian, Guo et al. 2004* Korean, Park et al. 2005 Japanese, Noso et al. 2005 Korean, Noso et al. 2005 Caucasian, Guo et al. 2004 UK, Smyth et al. 2005* Canadian, Paterson et al. 2005 Meta-analysis

22 0.50.71.01.21.52.03.0 Asian, Guo et al. 2004* Korean, Park et al. 2005 Japanese, Noso et al. 2005 Korean, Noso et al. 2005 Caucasian, Guo et al. 2004 UK, Smyth et al. 2005* Canadian, Paterson et al. 2005 Total (n=28,151) Meta-analysis Asian (n=4720) Caucasian (n=23,431) Summary OR:1.29 [95%CI: 1.15-1.44] p = 4.0 x 10 -7 Summary OR:1.02 (95%CI: 0.98-1.07) p = 0.25 (NS) p value against homogeneity 0.16 (NS)

23 0.50.71.01.21.52.03.0 95%CI （ Caucasian) 95%CI （ Asian) Total (n=28,151) Meta-analysis Asian, Guo et al. 2004* Korean, Park et al. 2005 Japanese, Noso et al. 2005 Korean, Noso et al. 2005 Asian (n=4720) Caucasian, Guo et al. 2004 UK, Smyth et al. 2005* Canadian, Paterson et al. 2005 Caucasian (n=23,431) Summary OR:1.29 [95%CI: 1.15-1.44] p = 4.0 x 10 -7 Summary OR:1.02 (95%CI: 0.98-1.07) p = 0.25 (NS) SUMO4 M55V is associated with type 1 diabetes in Asians, but not in Caucasians. Noso S et al. Poster #098 Diabetes ( in press)

24 Reasons for apparent differences in susceptibility alleles for type 1 diabetes between Japanese and Caucasian populations Association Reasons for apparent Caucasian Japanese difference HLAyesyes allele difference INSyesyes allele frequency CTLA4yesrestricted clinical subtype PTPN22yes unknown allele absent SUMO4? yes heterogeneity?

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