Hiroshi IKEGAMI

1
Genetics of type 1 diabetes in Japanese
(similarity to and difference from Caucasian
populations)
IDS8, Awaji Yumebutai ( October 8, 2005 )

• Hiroshi IKEGAMI
• Osaka University Graduate School of Medicine

2
Familiar clustering of type 1 diabetes
General population
Sibling
?
Caucasian 0.4
Caucasian 6 (ls 15)
Japanese 0.010.02
3
Susceptibility genes for type 1 diabetes
Major gene HLA (IDDM1) b-cell specificity INS (I
DDM2) negative regulator CTLA4 (IDDM12) SUMO4 (I
DDM5) PTPN22
4
Association of DRB1 alleles with type 1 diabetes
Type 1 diabetes Controls OR P (n264) (n314)
DRB1 0405 33.7 17.2 2.45 lt0.00001 0901 25.4
13.1 2.26 0.0002 1502 1.9 14.6 0.11 lt0.00000
01
Kawabata Y et al. Diabetes 51545-551, 2002
5
Disease susceptible HLA-haplotypes
Japanese DRB10405-DQB10401 (DR4) DRB10901-DQB
10303 (DR9) Caucasians DRB10301-DQB10201
(DR3) DRB10401-DQB10302 (DR4)
6
Different haplotypes are associated with type 1
diabetes in Japanese and Caucasian populations
Japanese Caucasian DRB1-DQB1 Type 1
diabetes HF1) Type 1 diabetes HF haplotype
susceptibility susceptibility
DRB10405-DQB10401 susceptible present
unknown rare DRB10901-DQB10303 susceptible
present unknown rare DRB10301-DQB10201 unkno
wn rare susceptible present DRB10401-DQB10302
unknown rare susceptible present DRB11501-DQB1
0602 protective present protective present

• HF Haplotype frequency, http//square.umin.ac.jp/
  JSHI/frame.html

7
High risk genotypes for type 1 diabetes
(Caucasians)
Japanese DRB10405-DQB10401 (DR4) DRB10901-DQB
10303 (DR9) Caucasians DRB10301-DQB10201
(DR3) DRB10401-DQB10302 (DR4)
Very high risk genotype DRB10301 /0401 (DR3/4)
8
Disease-associated genotypes in
Japanese (DRB10405 vs. DRB10901 haplotype)

Odds Ratio DRB10405 / DRB10405
2.1 DRB10405 / X
2.8 DRB10901 / DRB10901 DRB10901
/ Y
9
High risk genotypes for type 1 diabetes (Japanese)
Japanese DRB10405-DQB10401 (DR4) DRB10901-DQB
10303 (DR9) Caucasians DRB10301-DQB10201
(DR3) DRB10401-DQB10302 (DR4)
Very high risk genotype(Japanese) DRB10901 /0901
(DR9/9)
10
HLA haplotypes associated with type 1 diabetes
Japanese DRB10405-DQB10401 (DR4) DRB10901-DQB
10303 (DR9) Caucasians DRB10301-DQB10201
(DR3) DRB10401-DQB10302 (DR4)
Korean DRB10301-DQB10201 (DR3) DRB10405-DQB1
0401 (DR4) DRB10901-DQB10303 (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 51545-551, 2002
12
Susceptibility genes for type 1 diabetes
Major gene HLA (IDDM1) b-cell specificity INS (I
DDM2) negative regulator CTLA4 (IDDM12) SUMO4 (I
DDM5)
13
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
Controls Cases Odds ratio France1 55 84 4.2
UK2 59 76 2.2 Japan3 94 99
1 Lucassen et al. Nature Genet 4305, 1993 2
Bennet et al. Nature Genet 9284, 1995 3
Kawaguchi et al. BBRC 233283, 1997
15
Susceptibility genes for type 1 diabetes
Major gene HLA (IDDM1) b-cell specificity INS (I
DDM2) negative regulator CTLA4 (IDDM12) PTPN22
SUMO4 (IDDM5)
16
NATURE VOL 423 29 MAY 2003 www.nature.com/natu
re
17
Association of CTLA4 with autoimmune diseases
(Caucasian populations)
Odds ratio (95 CI) Gravess
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 6230GgtA (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 (95CI) 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 36337, 2004, 2 Diabetes 533020,
2004, 3 Diabetes 54906, 2005 4 Am J Hum Genet
75330, 2004, 5 Am J Hum Genet 75504, 2004
19
SUMO4 SNPs identified by re-sequencing in Japanese
2176bp
SUMO4
Exon 6
Exon 7
M55V
438CgtT
-504AgtG
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 (95CI) p (n541) (n743) Ja
panese 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 OR1.02 (95CI 0.98-1.07) p 0.25 (NS)
Caucasian (n23,431)
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 (n4720)
Summary OR1.29 95CI 1.15-1.44 p 4.0 x 10-7
Total (n28,151)
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.

• Meta-analysis

95CI (Caucasian)
95CI (Asian)
Caucasian, Guo et al. 2004
UK, Smyth et al. 2005
Canadian, Paterson et al. 2005
Summary OR1.02 (95CI 0.98-1.07) p 0.25 (NS)
Caucasian (n23,431)
Asian, Guo et al. 2004
Korean, Park et al. 2005
Japanese, Noso et al. 2005
Korean, Noso et al. 2005
Asian (n4720)
Summary OR1.29 95CI 1.15-1.44 p 4.0 x 10-7
Total (n28,151)
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 yes al
lele difference INS yes yes allele
frequency CTLA4 yes restricted clinical subtype
PTPN22 yes unknown allele absent SUMO4 ? yes
heterogeneity?