genetics of diabetes and its complications: layers of complexity university of pittsburgh october...
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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 CandidatesBiological Candidates
Direct S
equ
encin
gPositional CandidatesPositional Candidates
Expressional
Candidates
Expressional
Candidates
Functional
Studies
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 USPHS
Hanis 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
mL
OD
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
SN
P-5
7
UC
SN
P-2
0
14 15 VNTR-2
(49136)
UC
SN
P-4
3,44
,45,
46U
CS
NP
-56
UC
SN
P-5
9U
CS
NP
-60
UC
SN
P-1
9
UC
SN
P-4
8
UC
SN
P-5
8
UC
SN
P-4
7
UC
SN
P-3
0
UC
SN
P-2
2,23
,24,
25,2
6
UC
SN
P-4
2
UC
SN
P-5
5U
CS
NP
-54
UC
SN
P-3
9
UC
SN
P-3
2
UC
SN
P-5
3U
CS
NP
-49,
50,5
1,52
UC
SN
P-3
8,40
UC
SN
P-4
1
UC
SN
P-3
6,37
UC
SN
P-3
5
UC
SN
P-3
4
UC
SN
P-2
7,28
,29
UC
SN
P-1
,2,3
,4
UC
SN
P-3
1
UC
SN
P-3
3
UC
SN
P-6
2U
CS
NP
-63
UC
SN
P-6
5
VNTR-1
Calpain 10 GPR35
Organization of the 31kb Calpain 10 Gene Region
1 2 3 4 5 6 7 8 9 10
11
12
13
UC
SN
P-5
7
UC
SN
P-2
0
14 15
UC
SN
P-4
3,44
,45,
46
UC
SN
P-5
6
UC
SN
P-5
9
UC
SN
P-6
0U
CS
NP
-19
UC
SN
P-4
8
UC
SN
P-5
8
UC
SN
P-4
7
UC
SN
P-3
0
UC
SN
P-4
2
UC
SN
P-3
2
UC
SN
P-6
2U
CS
NP
-63
UC
SN
P-6
5
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 10a
Calpain 10b
Calpain 10c
Calpain 10d
Calpain 10e
Calpain 10f
Calpain 10g
Calpain 10h
491
I II III T
Domain
SNP 43,19,63 Haplotype and Diabetes Risk
2,86 3,06
0
1
2
3
4
5
6
Odd
s R
atio
Starr 1 Starr 2
Population
OGTT Glucose Response by Genotype
100
125
150
175
200
0 30 60 90 120Time (minutes)
Glu
cose
(m
g/d
l)
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
0
1
2
3
4
5
6
Odd
s R
atio
Starr 1 Starr 2 Botnia Germany
Population
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