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

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 Candidates Direct Sequencing Positional Candidates Expressional Candidates Functional Studies

Diabetes Mortality in Texas

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

Type 2 Diabetes in 3 Ethnic Groups

Genome Scan Results – Chromosome 2

Narrowing the NIDDM1 Region on Chromosome 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

Organization of the NIDDM1 Region UCSNP-57UCSNP VNTR-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

Organization of the 31kb Calpain 10 Gene Region UCSNP-57 UCSNP 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

Alternative Splicing of Calpain 10 ATG TAAATG Exon 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

SNP 43,19,63 Haplotype and Diabetes Risk

OGTT Glucose Response by Genotype GG AG AA

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

FSIVGTT Insulin by Calpain 10 Genotype Insulin - FSIVGTT Time (minutes) Insulin (uU/mL)

SNP 43,19,63 Haplotype and Diabetes Risk

Genome Scan Results – Chromosome 15