Hiroshi IKEGAMI Osaka University Graduate School of Medicine Genetics of type 1 diabetes in Japanese...

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 population Sibling

Japanese 0.01～ 0.02%

Caucasian 0.4 % Caucasian 6% (s = 15)

?

Familiar clustering of type 1 diabetes

Japanese 3.8% (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 diabetes Controls OR P(n=264) (n=314)

DRB1 *0405 33.7% 17.2% 2.45 <0.00001

*0901 25.4% 13.1% 2.26 0.0002

*1502 1.9% 14.6% 0.11 <0.0000001

Kawabata Y et al. Diabetes 51:545-551, 2002

Japanese DRB1*0405-DQB1*0401 (DR4)

DRB1*0901-DQB1*0303 (DR9)

Caucasians DRB1*0301-DQB1*0201 (DR3)

DRB1*0401-DQB1*0302 (DR4)

Disease susceptible HLA-haplotypes

Japanese Caucasian

DRB1-DQB1 Type 1 diabetes HF1) Type 1 diabetes HF haplotype susceptibility susceptibility

DRB1*0405-DQB1*0401 susceptible present unknown rare

DRB1*0901-DQB1*0303 susceptible present unknown rare

DRB1*0301-DQB1*0201 unknown rare susceptible present

DRB1*0401-DQB1*0302 unknown rare susceptible present

DRB1*1501-DQB1*0602 protective present protective present

Different haplotypes are associated with type 1 diabetes inJapanese and Caucasian populations

1) HF: Haplotype frequency, http://square.umin.ac.jp/JSHI/frame.html


DRB1*0901-DQB1*0303 (DR9)


DRB1*0401-DQB1*0302 (DR4)

Very high risk genotype

DRB1*0301 /0401 (DR3/4)

High risk genotypes for type 1 diabetes (Caucasians)


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）


DRB1*0901-DQB1*0303 (DR9)


DRB1*0401-DQB1*0302 (DR4)

Very high risk genotype（ Japanese）

DRB1*0901 /0901 (DR9/9)

High risk genotypes for type 1 diabetes (Japanese)


DRB1*0901-DQB1*0303 (DR9)


DRB1*0401-DQB1*0302 (DR4)

HLA haplotypes associated with type 1 diabetes

Korean DRB1*0301-DQB1*0201 (DR3)

DRB1*0405-DQB1*0401 (DR4)

DRB1*0901-DQB1*0303 (DR9)

DR9 homozygosity confers susceptibility to type 1 diabetes

DR4 DR9

1

10

20

Odd

s ra

tio

:homo

:hetero

Japanese Korean Japanese Korean






SUMO4 (IDDM5)

Association of INS-VNTR with type 1 diabetes

-596VNTR

-23HphI

4.1 kb region of IDDM2

Class III haplotype Class III protective

Class I haplotype Class I ＋ susceptible

TH INS IGF2VNTR

Type 1 diabetes susceptibility

Frequency of class I INS-VNTR tended to be higher in type 1 diabetes than in controls

Controls Cases Odds ratio

France1 55% 84% 4.2

UK2 59% 76% 2.2

Japan3 94% 99%

1 Lucassen et al. Nature Genet 4:305, 19932 Bennet et al. Nature Genet 9:284, 19953 Kawaguchi et al. BBRC 233:283, 1997





PTPN22

SUMO4 (IDDM5)

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

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

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)

1 Nat Genet 36:337, 2004, 2 Diabetes 53:3020, 2004, 3 Diabetes 54:906, 20054 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>G M55V 438C>T frequency

Haplotype A G A C 49.6%

Haplotype B A G T 35.9%

Haplotype C A A C 14.4%

-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

Cases Controls OR (95%CI) p(n=541) (n=743)

Japanese 59% 50%

Koreans 58% 44% 1.46 (1.17-1.83) 0.0008*

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

0.5 0.7 1.0 1.2 1.5 2.0 3.0

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

0.5 0.7 1.0 1.2 1.5 2.0 3.0








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)

0.5 0.7 1.0 1.2 1.5 2.0 3.0

95%CI （ Caucasian)

95%CI （ Asian)

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)

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

HLA yes yes allele difference

INS yes yes allele frequency

CTLA4 yes restricted clinical subtype

PTPN22 yes unknown allele absent

SUMO4 ? yes heterogeneity?

Hiroshi IKEGAMI Osaka University Graduate School of Medicine Genetics of type 1 diabetes in Japanese...

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