Download Genetics of Diabetes and its Complications

Interactions and the Development of Type
2 Diabetes Among Mexican Americans
Susceptibility
Loci
NIDDM1
Calpain 10
Chr. 15
Calpain 3?
HNF-1α
Nongenetic Factors - Lifestyle and Environment
Type 2 Diabetes Mellitus
MODY
The Plot Thickens
Chr. 9 Chr. 10
Susceptibility
Loci
Modifier Loci
Chr. 11
NIDDM1
Chr. 3
Chr. 15
Chr. 7
HNF-1α
Chr. 21
Nongenetic Factors - Lifestyle and Environment
Type 2 Diabetes Mellitus
MODY
Genome Scans for Type 2 Diabetes
Study
Design
Reference/Status
Starr County, Texas 346 Affected Sib Pairs
Hanis et al., 1996/ Complete Scan
Eastern Finns
26 Pedigrees, Affected Members
Mahtani et al., 1996/ Complete Scan
GENNID
Affected Sib Pairs, 3 Ethnic Groups
ADA/Unpublished
FUSION
Affected Pairs, Pedigrees, Quantitative
Traits
Ghosh et al., 1999/ Nearing
Completion
San Antonio
Pedigrees, Quantitative Traits
Stern et al., 1996/ Near Completion
Utah
Pedigrees, Affected Pairs, Quantitative
Traits
Elbein et al., 1999/ Complete Scan
Pima Indians
Pedigrees, Affected Pairs, Quantitative
Traits
Hanson et al., 1998/ Complete Scan
Canadian Oji-Cree
49 Affected Sib Pairs
Hegele et al., 1999/ 20cM Scan
Old Order Amish
27 Pedigrees, Quantitative Traits
Hsueh et al., 1999 (Abstract)/
Complete Scan
Click for larger picture
Which Chromosome Next?
• All but 4 were picked by one or more groups!
• For us --- Chromosome 15
• Must pick region with greatest chance of
success in your data set
– What about replication?
Comp 1
Complications
Comp 2
Comp ?
Type 1 Diabetes
HLA
IDDM2
Others
Type 2 Diabetes
Calpain 10
Cs 15
Others
Familial Aggregation of
Retinopathy by Severity
Risk in Siblings
100%
90%
80%
70%
60%
50%
<= Mild
Moderate
Severe
Proband Retinopathy Status
Familial Aggregation of Vibratory
Perception Threshold
Risk in Siblings
0,5
0,4
0,3
0,2
0,1
0,0
< 20
20 +
Proband Vibratory Perception Status
Familial Aggregation of Proteinuria among Pima
Pettitt et al., Diabetologia 33:438-443, 1990
Proteinuria in
Offspring
100%
80%
60%
40%
20%
0%
Neither Parent
One Parent
Both Parents
Parents with Proteinuria
Familial Aggregation of Test-Strip
Microalbuminuria
Risk in Siblings
0,5
0,4
0,3
0,2
0,1
0,0
Negative
Positive
Proband Test-Strip Status
Familial Clustering of
Complications
Frequency
50%
40%
30%
20%
10%
0%
VPT
Micro-Alb
Complication
None to Mild
Either
Moderate +
Candidate Gene Association Studies
with Diabetic Retinopathy (92 References)
• Positive Associations
– Aldose Reductase
• Ko et al., 1995
– PAI1
• Nagi et al., 1997
– HLA (in type 2)
• Cruickshanks et al.,
1992
– IGM
• Hawrami et al., 1991
– TNF-
• Hawrami et al., 1996
• Lack of Association
– Aldose Reductase
• HMOs et al., 1997
– PAI1
• Mansfield et al., 1991
– HLA (in type 1)
• Hawrami et al., 1991
Falck et al., 1997
– Angiotensinogen
• Fogarty et al., 1996, Gutierrz et al., 1997
– Angiotensin I Converting Enzyme
• Marre et al., 1994,Tarnow et al., 1995
• Fujisawa et al., 1995, Nagi et al., 1995
Gutierrez et al., 1997
• Lack of Association
• Positive Associations
– Angiotensin I
Converting Enzyme
• Hadjadj et al., 2001,
Several Others
– Apo E
• Kimura et al., 1998
– Glut 1
• Grzeszczak et al., 2001
– Angiotensinogen
• Reviewed by Taal, 2001
– NOS2
• Johannesen et al., 2000
– Advanced Glycation Endproduct
• Poirier et al., 2001
– Angiotensinogen
• Hadjadj, et al., 2001
– Angiotensin I Converting Enzyme
• Marre et al., 1994Tarnow et al., 1995
• Fujisawa et al., 1995 Nagi et al., 1995
Gutierrez et al., 1997
– Aldose Reductase
• NG et al., 2001
– PON1
• Araki et al., 2001
– Glutathione S Transferase
• Fujita et al., 2000
– GNB3
• Zychma et al., 2000
Candidate Gene Association Studies
with Diabetic Neuropathy (14 Reports)
• Positive Associations • Lack of Association
– Aldose Reductase
• Heesom et al., 1998
– Aldose Reductase
• Ng et al., 2001
– Apo(a)
• Gazzaruso et al., 1998
Linkage: Diabetes vs Complications
Genes
Nephropathy Linkage on Chromosome 20
Imperatore et
al., Diabetes
47:821-830,
1998
Click for larger picture
Bowden et
al., Diabetes
46:8882-886,
1997
Click for larger picture
Epidemiology in the Era of
Diabetes Genes
• Design
– Screening followed by imposition of design
– Increased power through balance
• Interaction by design
– Genotype by environment
– Genotype by treatment
• Risk Prediction
Barriers to Incorporating Genes
• Identifying the Genes
–
–
–
–
More Genome Scanning - including pooling
Disequilibrium-based approaches
Human Genome Project
Animal Studies
• Appropriately phenotyped samples
– Remains the rate-limiting step
• Typing Technology
Which Paradigm?
• Disease Endpoints
– Definable
– Measurable
– Analyzable
• Concordant Pairs
• Discordant pairs
• Glycemic Control
– Difficult to define long
term
– Confounded by
Treatment
– Clinical Trials
• Response
– Closer to Biology
(genes)?
Age Structure of Starr County,
Texas and the U.S. Population
75
60
45
30
15
<5
0%
2%
4%
6%
8%
10%
12%
Intervention in the Presence of G x E
Interaction
Today
60%
0%
1900
2025
Year
William J.
Terry Bertin
Schull
Eric Boerwinkle Nancy
MacNaughton
Charles A.
Sara Barton
Garcia
Hsuan-Ho Chu David Martinez
David HewettEmmett
William
Mueller
Luiz Kubrusly
Denise
Kubrusly
Residents
Hilda Guerra
Collaborators
Jesusa Salmon
Graeme I. Bell
Alda Clarke
Nancy J. Cox
Myriam Muniz
Kenneth S.
Polonsky
Li Li
Leah
Patrick J.
Hernandez
Concannon
Kisoo Kil
Sylvia Hinojosa Richard S.
Spielman
Charles Huber Leticia
Ronald Klein
Gonzalez
Tommy Douglas Lisa Gonzalez
Victor H.
Gonzalez
Local
Community
Local
Physicians
Leaders
Physicians