Genetics of Diabetes and Its Complications: Layers of Complexity

1
Genetics of Diabetes and Its Complications
Layers of Complexity
Craig L. Hanis, Ph.D. Human Genetics Center The
University of Texas Health Science Center at
Houston
University of Pittsburgh October 23, 2001
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A Brief History of the Genetics of Diabetes
Nightmare
Disequilibrium
Headache
Linkage
Interactions
Heterogeneity
Complexity
3
Genetics of Diabetes Complications
Headaches from the Nightmares Nightmares from
the Headaches
4
Rising Interest in the Genetics of Diabetes and
Its Complications
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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

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Fine Mapping

• Ultimately a Search for Association
• Criteria for selecting samples
• Affected/Unaffected
• Segregating/Non-segregating
• Haplotype Determination
• enhanced by pedigrees?

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Candidate Genes to Functional Variation
Biological Candidates
Direct Sequencing
Functional Studies
Positional Candidates
Expressional Candidates
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Diabetes Mortality in Texas
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(No Transcript)
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Type 2 Diabetes Among Mexican Americans in Starr
County, Texas
Hanis et al. (1983). Am J Epidemiol 118659-672
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Type 2 Diabetes in 3 Ethnic Groups
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Genome Scan Results Chromosome 2
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Narrowing the NIDDM1 Region on Chromosome 2
300 cM 300 million base pairs
NIDDM1 maps near D2S140
5 10 million base pairs
150,000 base pairs
Direct Sequencing of 65,000 base pairs
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Organization of the NIDDM1 Region
UCSNP-57
UCSNP-20
1
2
3
4
5
6
7
8
9
10
12
14
15
VNTR-2
VNTR-1
11
13
(49136)
Calpain 10
GPR35
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Organization of the 31kb Calpain 10 Gene Region
Click for larger picture
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Alternative Splicing of Calpain 10
Exon
Domain
I
II
III
T
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Calpain 10a
Protease
672
1
41
304
491
TAA
ATG
Calpain 10b
544
ATG
TGA
ag
Calpain 10c
517
ATG
TAA
Calpain 10d
513
TGA
ATG
Calpain 10e
444
ATG
TGA
ag
Calpain 10f
274
gt
ATG
TGA
Calpain 10g
139
TGA
ATG
Calpain 10h
138
ATG
TAA
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SNP 43,19,63 Haplotype and Diabetes Risk
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OGTT Glucose Response by Genotype
GG
AG
AA
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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 1A62
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Insulin and Glucose by Calpain 10 Genotype
120.00
100.00
80.00
60.00
40.00
20.00
0.00
0
30
60
90
120
200.00
180.00
160.00
140.00
120.00
100.00
80.00
0
30
60
90
120
90
120
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FSIVGTT Insulin by Calpain 10 Genotype
Insulin - FSIVGTT
160
140
120
100
Insulin (uU/mL)
80
60
40
20
Time (minutes)
0
0
20
40
60
80
100
120
140
160
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SNP 43,19,63 Haplotype and Diabetes Risk
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Genome Scan Results Chromosome 15