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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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 ）

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

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

Association of DRB1 alleles with type 1 diabetes Type 1 diabetesControlsORP (n=264)(n=314) DRB1 * %17.2%2.45 < * %13.1% * %14.6%0.11 < Kawabata Y et al. Diabetes 51: , 2002

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

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,

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)

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

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)

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)

DR9 homozygosity confers susceptibility to type 1 diabetes DR4DR Odds ratio :homo :hetero JapaneseKorean JapaneseKorean Kawabata Y et al. Diabetes 51: , 2002

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

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

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, Bennet et al.Nature Genet 9:284, Kawaguchi et al. BBRC 233:283, 1997

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

NATURE |VOL 423 | 29 MAY 2003 |

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

Arg620Trp (R620W) of PTPN22 was consistently reported to be associated with autoimmune diseases in Caucasian populations Odds ratio (95%CI) Type 1 diabetesN. American ( ) Italian ( ) UK ( ) Caucasian 3 (C/T)1.7( ) (T/T)3.4( ) Graves's disease ( ) RA ( ) SLE 5 (C/T)1.37 ( ) (T/T)4.37 ( ) 1 Nat Genet 36:337, 2004, 2 Diabetes 53:3020, 2004, 3 Diabetes 54:906, Am J Hum Genet 75:330, 2004, 5 Am J Hum Genet 75:504, 2004

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

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 ( )0.0008* Noso S et al. Poster #098 Diabetes ( in press)

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

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

%CI （ Caucasian) 95%CI （ Asian) Total (n=28,151) Meta-analysis Asian, Guo et al. 2004* Korean, Park et al Japanese, Noso et al Korean, Noso et al Asian (n=4720) Caucasian, Guo et al UK, Smyth et al. 2005* Canadian, Paterson et al Caucasian (n=23,431) Summary OR:1.29 [95%CI: ] p = 4.0 x Summary OR:1.02 (95%CI: ) 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)

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?