1 / 24

Genetics of type 1 diabetes in Japanese (similarity to and difference from Caucasian populations)

IDS8, Awaji Yumebutai （ October 8, 2005 ）. Genetics of type 1 diabetes in Japanese (similarity to and difference from Caucasian populations). Hiroshi IKEGAMI Osaka University Graduate School of Medicine. Japanese 3.8% ( l s > 100). Ikegami H et al. Endocrine J 1996.

corbin
Download Presentation

Genetics of type 1 diabetes in Japanese (similarity to and difference from Caucasian populations)

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

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

  2. Japanese 3.8% (ls > 100) Ikegami H et al. Endocrine J 1996 Familiar clustering of type 1 diabetes General population Sibling ? Caucasian 0.4 % Caucasian 6% (ls = 15) Japanese 0.01～0.02%

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

  4. Association of DRB1 alleles with type 1 diabetes Type 1 diabetesControls OR P (n=264) (n=314) DRB1*040533.7% 17.2%2.45 <0.00001 *0901 25.4% 13.1% 2.26 0.0002 *15021.9% 14.6% 0.11 <0.0000001 Kawabata Y et al. Diabetes 51:545-551, 2002

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

  6. Different haplotypes are associated with type 1 diabetes in Japanese and Caucasian populations Japanese Caucasian DRB1-DQB1Type 1 diabetes HF1)Type 1 diabetes HF haplotypesusceptibilitysusceptibility DRB1*0405-DQB1*0401susceptible present unknown rare DRB1*0901-DQB1*0303susceptible present unknown rare DRB1*0301-DQB1*0201 unknown rare susceptible present DRB1*0401-DQB1*0302 unknown rare susceptible present DRB1*1501-DQB1*0602protective present protective present • HF: Haplotype frequency, http://square.umin.ac.jp/JSHI/frame.html

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

  8. 23.1 1.0 Kawabata Y et al. Diabetes 51:545-551, 2002 Disease-associated genotypes in Japanese （DRB1*0405 vs. DRB1*0901 haplotype） Odds Ratio DRB1*0405 / DRB1*04052.1 DRB1*0405 / X 2.8 DRB1*0901 /DRB1*0901 DRB1*0901 / Y

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

  10. HLA haplotypes associated with type 1 diabetes Japanese DRB1*0405-DQB1*0401 (DR4) DRB1*0901-DQB1*0303 (DR9) Caucasians DRB1*0301-DQB1*0201 (DR3) DRB1*0401-DQB1*0302 (DR4) Korean DRB1*0301-DQB1*0201 (DR3) DRB1*0405-DQB1*0401 (DR4) DRB1*0901-DQB1*0303 (DR9)

  11. DR9 homozygosity confers susceptibility to type 1 diabetes :homo 20 :hetero Odds ratio 10 1 Japanese Korean Japanese Korean DR4 DR9 Kawabata Y et al. Diabetes 51:545-551, 2002

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

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

  14. Frequency of class I INS-VNTR tended to be higher in type 1 diabetes than in controls ControlsCasesOdds ratio France1 55% 84% 4.2 UK2 59% 76% 2.2 Japan3 94% 99% 1 Lucassen et al. Nature Genet 4:305, 1993 2 Bennet et al. Nature Genet 9:284, 1995 3 Kawaguchi et al. BBRC233:283, 1997

  15. Susceptibility genes for type 1 diabetes Major gene： HLA (IDDM1) b-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 disease 1.51 (1.31-1.75) Hashimoto thyroiditis 1.45 (1.17-1.80) Type 1 diabetes 1.14 (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 diabetes N. American1 1.83 (1.28-2.60) Italian1 2.31 (0.93-5.82) UK2 1.78 (1.54-2.06) Caucasian3 (C/T) 1.7 (1.3-2.3) (T/T) 3.4 (1.3-8.9) Graves's disease2 1.43 (1.17-1.76) RA4 1.74 (1.27-2.38) SLE5 (C/T) 1.37 (1.07-1.75) (T/T) 4.37 (1.98-9.65) 1Nat Genet 36:337, 2004, 2Diabetes 53:3020, 2004, 3Diabetes 54:906, 2005 4Am J Hum Genet 75:330, 2004, 5 Am J Hum Genet 75:504, 2004

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

  20. SUMO4（M55V）is associated with type 1 diabetes (Japanese and Koreans) Cases Controls OR (95%CI) p (n=541) (n=743) Japanese 59% 50% Koreans 58% 44% 1.46 (1.17-1.83) 0.0008* *Mantel-Haenszel test Noso S et al. Poster #098 Diabetes ( in press)

  21. Meta-analysis Caucasian, Guo et al. 2004 Asian, Guo et al. 2004* UK, Smyth et al. 2005* Canadian, Paterson et al. 2005 Korean, Park et al. 2005 Japanese, Noso et al. 2005 Korean, Noso et al. 2005 0.5 0.7 1.0 1.2 1.5 2.0 3.0

  22. Meta-analysis Caucasian, Guo et al. 2004 UK, Smyth et al. 2005* Canadian, Paterson et al. 2005 Summary OR:1.02 (95%CI: 0.98-1.07) p = 0.25 (NS) Caucasian (n=23,431) Asian, Guo et al. 2004* p value against homogeneity 0.16 (NS) Korean, Park et al. 2005 Japanese, Noso et al. 2005 Korean, Noso et al. 2005 Asian (n=4720) Summary OR:1.29 [95%CI: 1.15-1.44] p = 4.0 x 10-7 Total (n=28,151) 0.5 0.7 1.0 1.2 1.5 2.0 3.0

  23. SUMO4 M55V is associated with type 1 diabetes in Asians, but not in Caucasians. 95%CI （Caucasian) 95%CI （Asian) Meta-analysis Caucasian, Guo et al. 2004 UK, Smyth et al. 2005* Canadian, Paterson et al. 2005 Summary OR:1.02 (95%CI: 0.98-1.07) p = 0.25 (NS) Caucasian (n=23,431) Asian, Guo et al. 2004* Korean, Park et al. 2005 Japanese, Noso et al. 2005 Korean, Noso et al. 2005 Asian (n=4720) Summary OR:1.29 [95%CI: 1.15-1.44] p = 4.0 x 10-7 Total (n=28,151) 0.5 0.7 1.0 1.2 1.5 2.0 3.0 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 HLA yes yesallele difference INS yes yesallele frequency CTLA4 yesrestricted clinical subtype PTPN22 yes unknown allele absent SUMO4 ? yes heterogeneity?

More Related