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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Finns 26 Pedigrees, Affected Members Mahtani et al., 1996/ Complete Scan GENNID Affected Sib Pairs, 3 Ethnic Groups ADA/Unpublished FUSION Affected Pairs, Pedigrees, Quantitative Traits Ghosh et al., 1999/ Nearing Completion San Antonio Pedigrees, Quantitative Traits Stern et al., 1996/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