BADERC-Jose C. Florez

Jose C. Florez, M.D., Ph.D.

Pharmacogenetics of Type 2 Diabetes

Dr. Florez’s research interests lie on the genetic determinants of type 2 diabetes and related metabolic traits, and how these variants may impact disease prediction and therapeutic choices. Thus his laboratory leads two parallel efforts in gene discovery and pharmacogenetics. With regard to the former, he is involved in the conduct, analysis and integration of genome-wide association studies for type 2 diabetes and related traits, in the Framingham Heart Study and elsewhere. His group currently participates in a large international consortium of cohorts that have collected similar phenotypes (MAGIC), where new loci that underlie quantitative measures of insulin secretion and action are being identified. These and other discoveries can then be applied to a clinical trial such as the Diabetes Prevention Program, where participants at high risk of developing diabetes were randomized to preventive interventions: in this manner, whether diabetes-associated genetic variants influence response to treatment can be assessed. He has also obtained funding to launch two pharmacogenetic studies: the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR MGH) intends to establish whether genetic variation at selected loci influences the acute response to a sulfonylurea, metformin or a glucose load; and the Patients with Hyperglycemia Assessed for Response to Medications by Genetics (PHARMGen) study will mine the electronic medical record to recruit patients who have failed monotherapy, to examine the genetic determinants for medication failure

References:

Florez JC, Burtt N, de Bakker PIW, Almgren P, Tuomi T, Homkvist J, Gaudet D, Hudson TJ, Schaffner SF, Daly MJ, Hirschhorn JN, Altshuler D. Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor (SUR1) and the islet ATP-sensitive potassium channel (Kir6.2) gene region. Diabetes 2004;53:1360-1368
Florez JC, Jablonski KA, Bayley N, Pollin TI, de Bakker PIW, Shuldiner AR, Knowler WC, Nathan DM, Altshuler D, for the Diabetes Prevention Program Research Group: TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med 2006;355:241-250.
Florez JC, Jablonski KA, Kahn SE, Franks PW, Dabelea D, Hamman RF, Knowler WC, Nathan DM, Altshuler D for the Diabetes Prevention Program Research Group. Diabetes-associated missense polymorphisms KCNJ11 E23K and ABCC8 A1369S influence progression to diabetes and response to interventions in the Diabetes Prevention Program. Diabetes 2007;56:531-536.
Florez JC, Jablonski KA, Sun MW, Kahn SE, Shamoon H, Hamman RF, Knowler WC, Nathan DM, Altshuler D for the Diabetes Prevention Program Research Group. Effects of the type 2 diabetes-associated missense polymorphism PPARG P12A on progression to diabetes and response to troglitazone. J Clin Endocrinol Metab 2007;92:1502-1509.
The Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University and Novartis Institutes for BioMedical Research. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007;316:1331-1336.
Florez JC, Manning AK, Dupuis J, Gianniny L, Irenze K, McAteer J, Mirel DB, Fox CS, Cupples LA, Meigs JB. A 100K genome-wide association scan for diabetes and related traits in the Framingham Heart Study: Replication and integration with other genome-wide datasets. Diabetes 2007;56:3063-3074.
Florez JC, Jablonski KA, McAteer JB, Sandhu MS, Wareham NJ, Barroso I, Franks PW, Altshuler D, Knowler WC for the Diabetes Prevention Program Research Group. Testing of diabetes-associated WFS1 polymorphisms in the Diabetes Prevention Program. Diabetologia 2008;51:451-457.
Stolerman ES, Manning AK, McAteer JB, Dupuis J, Fox CS, Cupples LA, Meigs JB, Florez JC. Haplotype structure of the ENPP1 gene and nominal association of the K121Q polymorphism with glycemic traits in the Framingham Heart Study. Diabetes 2008;57:1971-1977.
Moore AF, Jablonski KA, McAteer JB, Saxena R, Pollin TI, Franks PW, Hanson RL, Shuldiner AR, Knowler WC, Altshuler D, Florez JC for the Diabetes Prevention Program Research Group. Extension of type 2 diabetes genome-wide association scan results in the Diabetes Prevention Program. Diabetes 2008;57:2503-2510.
Meigs JB, Shrader P, Sullivan LM, McAteer JB, Fox CS, Dupuis J, Manning AK, Florez JC, Wilson PF, D’Agostino RB, Cupples LA. Genetic prediction of type 2 diabetes beyond common risk factors. N Engl J Med 2008;359:2208-2219.
Prokopenko I*, Langenberg C*, Florez JC*, Saxena R*, Soranzo N* et al. Variants in the melatonin receptor 1B gene (MTNR1B) influence fasting glucose levels. Nat Genet 2009;41:77-81.
Moore AF, Jablonski KA, Mason CC, McAteer JB, Arakaki RF, Goldstein BJ, Kahn SE, Kitabchi AE, Hanson RL, Knowler WC, Florez JC for the Diabetes Prevention Program Research Group. The association of ENPP1 K121Q with diabetes incidence is abolished by lifestyle modification in the Diabetes Prevention Program. J Clin Endocrinol Metab 2009;94:449-455.






			Jose C. Florez, M.D., Ph.D. Pharmacogenetics of Type 2 Diabetes Dr. Florez’s research interests lie on the genetic determinants of type 2 diabetes and related metabolic traits, and how these variants may impact disease prediction and therapeutic choices. Thus his laboratory leads two parallel efforts in gene discovery and pharmacogenetics. With regard to the former, he is involved in the conduct, analysis and integration of genome-wide association studies for type 2 diabetes and related traits, in the Framingham Heart Study and elsewhere. His group currently participates in a large international consortium of cohorts that have collected similar phenotypes (MAGIC), where new loci that underlie quantitative measures of insulin secretion and action are being identified. These and other discoveries can then be applied to a clinical trial such as the Diabetes Prevention Program, where participants at high risk of developing diabetes were randomized to preventive interventions: in this manner, whether diabetes-associated genetic variants influence response to treatment can be assessed. He has also obtained funding to launch two pharmacogenetic studies: the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR MGH) intends to establish whether genetic variation at selected loci influences the acute response to a sulfonylurea, metformin or a glucose load; and the Patients with Hyperglycemia Assessed for Response to Medications by Genetics (PHARMGen) study will mine the electronic medical record to recruit patients who have failed monotherapy, to examine the genetic determinants for medication failure References: Florez JC, Burtt N, de Bakker PIW, Almgren P, Tuomi T, Homkvist J, Gaudet D, Hudson TJ, Schaffner SF, Daly MJ, Hirschhorn JN, Altshuler D. Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor (SUR1) and the islet ATP-sensitive potassium channel (Kir6.2) gene region. Diabetes 2004;53:1360-1368 Florez JC, Jablonski KA, Bayley N, Pollin TI, de Bakker PIW, Shuldiner AR, Knowler WC, Nathan DM, Altshuler D, for the Diabetes Prevention Program Research Group: TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med 2006;355:241-250. Florez JC, Jablonski KA, Kahn SE, Franks PW, Dabelea D, Hamman RF, Knowler WC, Nathan DM, Altshuler D for the Diabetes Prevention Program Research Group. Diabetes-associated missense polymorphisms KCNJ11 E23K and ABCC8 A1369S influence progression to diabetes and response to interventions in the Diabetes Prevention Program. Diabetes 2007;56:531-536. Florez JC, Jablonski KA, Sun MW, Kahn SE, Shamoon H, Hamman RF, Knowler WC, Nathan DM, Altshuler D for the Diabetes Prevention Program Research Group. Effects of the type 2 diabetes-associated missense polymorphism PPARG P12A on progression to diabetes and response to troglitazone. J Clin Endocrinol Metab 2007;92:1502-1509. The Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University and Novartis Institutes for BioMedical Research. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007;316:1331-1336. Florez JC, Manning AK, Dupuis J, Gianniny L, Irenze K, McAteer J, Mirel DB, Fox CS, Cupples LA, Meigs JB. A 100K genome-wide association scan for diabetes and related traits in the Framingham Heart Study: Replication and integration with other genome-wide datasets. Diabetes 2007;56:3063-3074. Florez JC, Jablonski KA, McAteer JB, Sandhu MS, Wareham NJ, Barroso I, Franks PW, Altshuler D, Knowler WC for the Diabetes Prevention Program Research Group. Testing of diabetes-associated WFS1 polymorphisms in the Diabetes Prevention Program. Diabetologia 2008;51:451-457. Stolerman ES, Manning AK, McAteer JB, Dupuis J, Fox CS, Cupples LA, Meigs JB, Florez JC. Haplotype structure of the ENPP1 gene and nominal association of the K121Q polymorphism with glycemic traits in the Framingham Heart Study. Diabetes 2008;57:1971-1977. Moore AF, Jablonski KA, McAteer JB, Saxena R, Pollin TI, Franks PW, Hanson RL, Shuldiner AR, Knowler WC, Altshuler D, Florez JC for the Diabetes Prevention Program Research Group. Extension of type 2 diabetes genome-wide association scan results in the Diabetes Prevention Program. Diabetes 2008;57:2503-2510. Meigs JB, Shrader P, Sullivan LM, McAteer JB, Fox CS, Dupuis J, Manning AK, Florez JC, Wilson PF, D’Agostino RB, Cupples LA. Genetic prediction of type 2 diabetes beyond common risk factors. N Engl J Med 2008;359:2208-2219. Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N* et al. Variants in the melatonin receptor 1B gene (MTNR1B) influence fasting glucose levels. Nat Genet 2009;41:77-81. Moore AF, Jablonski KA, Mason CC, McAteer JB, Arakaki RF, Goldstein BJ, Kahn SE, Kitabchi AE, Hanson RL, Knowler WC, Florez JC for the Diabetes Prevention Program Research Group. The association of ENPP1 K121Q with diabetes incidence is abolished by lifestyle modification in the Diabetes Prevention Program. J Clin Endocrinol Metab 2009;94:449-455.