1. 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

2. A Brief History of the Genetics of Diabetes Nightmare Headache Heterogeneity Complexity Interactions Linkage Disequilibrium

3. Genetics of Diabetes Complications Headaches from the Nightmares & Nightmares from the Headaches

4. Rising Interest in the Genetics of Diabetes and Its Complications

5. 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

6. Fine Mapping Ultimately a Search for Association Criteria for selecting samples –Affected/Unaffected –Segregating/Non-segregating –Haplotype Determination enhanced by pedigrees?

7. Candidate Genes to Functional Variation Biological Candidates Direct Sequencing Positional Candidates Expressional Candidates Functional Studies

8. Diabetes Mortality in Texas

10. Type 2 Diabetes Among Mexican Americans in Starr County, Texas Hanis et al. (1983). Am J Epidemiol 118:659-672

11. Type 2 Diabetes in 3 Ethnic Groups

12. Genome Scan Results – Chromosome 2

13. 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

14. Organization of the NIDDM1 Region 12345678910 11 12 13 UCSNP-57UCSNP-20 1415VNTR-2 (49136) UCSNP-43,44,45,46 UCSNP-56 UCSNP-59UCSNP-60 UCSNP-19UCSNP-48UCSNP-58UCSNP-47UCSNP-30 UCSNP-22,23,24,25,26 UCSNP-42 UCSNP-55UCSNP-54UCSNP-39UCSNP-32 UCSNP-53 UCSNP-49,50,51,52 UCSNP-38,40 UCSNP-41 UCSNP-36,37 UCSNP-35UCSNP-34 UCSNP-27,28,29 UCSNP -1,2,3,4 UCSNP-31 UCSNP-33 UCSNP-62 UCSNP-63 UCSNP-65 VNTR-1 Calpain 10GPR35

15. Organization of the 31kb Calpain 10 Gene Region 12345678910 11 12 13 UCSNP-57 UCSNP-20 1415 UCSNP-43,44,45,46 UCSNP-56 UCSNP-59UCSNP-60 UCSNP-19UCSNP-48UCSNP-58UCSNP-47UCSNP-30UCSNP-42 UCSNP-32 UCSNP-62 UCSNP-63 UCSNP-65 Click for larger picture

16. Alternative Splicing of Calpain 10 ATG 1 23456789101112131415 TAAATG Exon 672 141304 Protease 544 TGAag 517 ATGTAA 513 TGAATG 444 ATGTGAag 274 ATGTGA gt 139 TGAATG 138 ATGTAA Calpain 10a Calpain 10b Calpain 10c Calpain 10d Calpain 10e Calpain 10f Calpain 10g Calpain 10h 491 I IIIII T Domain

17. SNP 43,19,63 Haplotype and Diabetes Risk

18. OGTT Glucose Response by Genotype GG AG AA

19. 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

20. Insulin and Glucose by Calpain 10 Genotype 90120 0.00 20.00 40.00 60.00 80.00 100.00 120.00 0306090120 80.00 100.00 120.00 140.00 160.00 180.00 200.00 0306090120

21. FSIVGTT Insulin by Calpain 10 Genotype Insulin - FSIVGTT 0 20 40 60 80 100 120 140 160 020406080100120140160 Time (minutes) Insulin (uU/mL)

22. SNP 43,19,63 Haplotype and Diabetes Risk

23. Genome Scan Results – Chromosome 15