Genetics of Diabetes and Its Complications: Layers of Complexity
University of Pittsburgh
October 23, 2001
Craig L. Hanis, Ph.D.Human Genetics Center
The University of Texas Health Science Center at Houston
A Brief History of the Genetics of Diabetes
Nightmare
Headache
Heterogeneity
Complexity
Interactions
Linkage
Disequilibrium
Genetics of Diabetes Complications
Headaches from the Nightmares
&
Nightmares from the Headaches
Rising Interest in the Genetics of Diabetes and Its Complications
0
50
100
150
200
250
300
350Publications
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000
Complex Inheritance• Model Free Linkage Approaches
– Affected Pairs• Concordant Sib Pairs• Discordant Sib Pairs
• Association Based Mapping– Transmission Disequilibrium Testing
• Parent - Offspring Trios (pairs)– Traditional Associations
• SNP-based mapping
Fine Mapping
• Ultimately a Search for Association• Criteria for selecting samples
– Affected/Unaffected– Segregating/Non-segregating– Haplotype Determination
• enhanced by pedigrees?
Candidate Genes to Functional Variation
Biological Candidates
Direct Sequencing
Positional Candidates
Expressional Candidates
Functional
Studies
Diabetes Mortality in Texas
Type 2 Diabetes Among Mexican Americans in Starr County, Texas
4%1%1%
10%
4%2%
17%
4%4%
15%
6%6%
12%
6%5%
0%5%
10%15%20%25%30%
Prevalence
35-44 45-54 55-64 65-74 75+Age Category
Starr County Rancho Bernardo USPHSHanis et al. (1983). Am J Epidemiol 118:659-672
Type 2 Diabetes in 3 Ethnic Groups
0%10%20%30%40%50%60%70%
Prevalence
35-44 45-54 55-64 65-74 75+Age Category
Pima Indians Starr County USPHS
Genome Scan Results – Chromosome 2
-18-15-12
-9-6-3036
0 0,5 1 1,5 2 2,5 3
Position
mLO
D
1,6 1,2 2,8
Narrowing the NIDDM1 Region on Chromosome 2
300 cM – 300+ million base pairs
NIDDM1 maps near
D2S1405 – 10 million base pairs
150,000 base pairs
Direct Sequencing of 65,000 base pairs
Organization of the NIDDM1 Region
1 2 3 4 5 6 7 8 9 1011
1213
UC
SNP-
57
UC
SNP-
20
14 15 VNTR-2(49136)
UC
SNP-
43,4
4,45
,46
UC
SNP-
56U
CSN
P-59
UC
SNP-
60U
CSN
P-19
UC
SNP-
48U
CSN
P-58
UC
SNP-
47
UC
SNP-
30
UC
SNP-
22,2
3,24
,25,
26
UC
SNP-
42
UC
SNP-
55U
CSN
P-54
UC
SNP-
39
UC
SNP-
32
UC
SNP-
53U
CSN
P-49
,50,
51,5
2
UC
SNP-
38,4
0
UC
SNP-
41
UC
SNP-
36,3
7
UC
SNP-
35
UC
SNP-
34
UC
SNP-
27,2
8,29
UC
SNP
-1,2
,3,4
UC
SNP-
31
UC
SNP-
33
UC
SNP-
62U
CSN
P-63
UC
SNP-
65
VNTR-1
Calpain 10 GPR35
Organization of the 31kb Calpain 10 Gene Region
1 2 3 4 5 6 7 8 9 10
11
1213
UC
SNP-
57
UC
SNP-
20
14 15
UC
SNP-
43,4
4,45
,46
UC
SNP-
56U
CSN
P-59
UC
SNP-
60U
CSN
P-19
UC
SNP-
48
UC
SNP-
58
UC
SNP-
47
UC
SNP-
30
UC
SNP-
42
UC
SNP-
32
UC
SNP-
62U
CSN
P-63
UC
SNP-
65
Click for larger picture
Alternative Splicing of Calpain 10
ATG
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
TAAATG
Exon
6721 41 304Protease
544TGAag
517ATG TAA
513TGAATG
444ATG TGA ag
274ATG TGAgt
139TGAATG
138ATG TAA
Calpain 10aCalpain 10b
Calpain 10c
Calpain 10dCalpain 10eCalpain 10fCalpain 10gCalpain 10h
491
I II III TDomain
SNP 43,19,63 Haplotype and Diabetes Risk
2,86 3,06
0123456
Odd
s Rat
io
Starr 1 Starr 2Population
OGTT Glucose Response by Genotype
100
125
150
175
200
0 30 60 90 120Time (minutes)
Glu
cose
(mg/
dl)
G
AA
GG
AGAA
Mouse Pancreatic Islets in the Presence of Calpain Inhibitors
have an approximate 2-fold increased
Insulin Secretory Response
Sreenen et al. (2000). Diabetes 49 suppl 1:A62
Insulin and Glucose by Calpain 10 Genotype
Insulin
Glucose
Insulin
Glucose
St. Louis - N = 29 Utah - N = 38 Seattle - N = 29
Chicago - N = 32 Colorado - N = 44 Los Angeles - N = 8
0.00
20.00
40.00
60.00
80.00
100.00
120.00
0 30 60 90 120
80.00
100.00
120.00
140.00
160.00
180.00
200.00
0 30 60 90 120
0.00
20.00
40.00
60.00
80.00
100.00
120.00
0 30 60 90 120
80.00
100.00
120.00
140.00
160.00
180.00
200.00
0 30 60 90 120
0.00
20.00
40.00
60.00
80.00
100.00
120.00
0 30 60 90 120
80.00
100.00
120.00
140.00
160.00
180.00
200.00
0 30 60 90 120
0.00
20.00
40.00
60.00
80.00
100.00
120.00
0 30 60 90 120
80.00
100.00
120.00
140.00
160.00
180.00
200.00
0 30 60 90 120
0.00
20.00
40.00
60.00
80.00
100.00
120.00
0 30 60 90 120
80.00
100.00
120.00
140.00
160.00
180.00
200.00
0 30 60 90 120
0.00
20.00
40.00
60.00
80.00
100.00
120.00
0 30 60 90 120
80.00
100.00
120.00
140.00
160.00
180.00
200.00
0 30 60 90 120
FSIVGTT Insulin by Calpain 10 Genotype
Insulin - FSIVGTT
020
40
60
80
100
120
140
160
0 20 40 60 80 100 120 140 160
Time (minutes)
Insu
lin (u
U/m
L)
SNP 43,19,63 Haplotype and Diabetes Risk
2,86 3,062,57
5,52
01
23
4
56
Odd
s Rat
io
Starr 1 Starr 2 Botnia GermanyPopulation
Genome Scan Results – Chromosome 15
-18-15-12
-9-6-3036
0 0,2 0,4 0,6 0,8 1 1,2 1,4
Position
mL
OD
1,2 1,6 2,8