Interactions and the Development of Type 2 Diabetes Among Mexican Americans

1. Interactions and the Development of Type 2 Diabetes Among Mexican Americans Susceptibility Loci HNF-1α NIDDM1 Calpain 10 Chr. 15 Calpain 3? Nongenetic Factors - Lifestyle and Environment Type 2 Diabetes Mellitus MODY

2. The Plot Thickens Chr. 9 Chr. 10 Susceptibility Loci Chr. 11 Chr. 15 Chr. 7 HNF-1α NIDDM1 Modifier Loci Chr. 3 Chr. 21 Nongenetic Factors - Lifestyle and Environment Type 2 Diabetes Mellitus MODY

3. Genome Scans for Type 2 Diabetes Click for larger picture

4. 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?

5. Comp 1 Complications Comp 2 Comp ? Type 1 Diabetes Type 2 Diabetes HLA IDDM2 Others Calpain 10 Cs 15 Others

6. Familial Aggregation of Retinopathy by Severity

7. Familial Aggregation of Vibratory Perception Threshold

8. Familial Aggregation of Proteinuria among PimaPettitt et al., Diabetologia 33:438-443, 1990

9. Familial Aggregation of Test-Strip Microalbuminuria

10. Familial Clustering of Complications

11. 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 Candidate Gene Association Studieswith Diabetic Retinopathy (92 References)

12. 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 Lack of Association 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

13. Positive Associations Aldose Reductase Heesom et al., 1998 Lack of Association Aldose Reductase Ng et al., 2001 Apo(a) Gazzaruso et al., 1998 Candidate Gene Association Studieswith Diabetic Neuropathy (14 Reports)

14. Linkage: Diabetes vs Complications Genes

15. 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

16. 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

17. 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

18. 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)? Which Paradigm?

19. Age Structure of Starr County, Texas and the U.S. Population

20. Intervention in the Presence of G x E Interaction Today