The National Institute of Diabetes & Digestive & Kidney Diseases

The escalating rates of obesity and type 2 diabetes are primarily attributed to changes in the environment, coupled with changes in lifestyle. However, in most developed countries, food is now plentiful and lifestyle is generally sedentary, but not all people become obese, and furthermore, most obese people do not develop type 2 diabetes. Multiple studies have shown that heritable factors underlie a significant portion of the variation in risk for obesity and type 2 diabetes, and it is generally believed that expression of this genetic susceptibility is influenced by environmental variables. The Pima Indians of Arizona have the highest reported prevalence of type 2 diabetes of any population in the world. They are also a very obese population. The goal of my lab is to identify and characterize susceptibility genes for type 2 diabetes and obesity among this Native American population.

Our recent genetic studies have utilized genome-wide approaches to identify potential susceptibility loci for type 2 diabetes and obesity. We have completed two genome-wide association studies (GWASs) that utilized a 100,000 SNP and a 1 million SNP platform to identify common variants associated with type 2 diabetes, obesity, or pre-diabetes/pre-obesity traits in Pima Indians. A few variants associated with these diseases in GWASs from other ethnic groups showed similar associations in Pima Indians, however, several strong and reproducible associations were identified that were not reported in other GWASs, suggesting ethnic specific heterogeneity in risk factors for these common diseases. Follow-up fine mapping and functional studies for several of these new susceptibility variants is ongoing. We are also pursuing the hypothesis that multiple rare variants may underlie a proportion of the variance of these common diseases. Whole exome sequencing was recently completed on 180 Pima Indians, and whole genome sequencing was recently completed on 11 Pima Indians. Whole genome sequence data on additional Pima samples is anticipated in the coming year. We also have genome-wide expression data (1M exons) from human skeletal muscle and adipose biopsies from more than 200 non-diabetic Pima Indians who had been characterized for metabolic traits related to diabetes and obesity. These data are being used to identify expression profiles that may predict the onset of diabetes. Expression data are also being merged with GWAS genotypic data and whole genome sequence data to identify cis and trans acting factors that may contribute to these polygenic diseases.  

It is our hope that understanding and quantifying specific genetically-determined susceptibility factors could lead to prevention by identifying individuals “at risk” for these diseases and lead to improved treatment by identifying novel therapeutic targets or personalized targets.

Ma L, Hanson RL, Que LN, Cali AMG, Fu M, Mack JL, Infante AM, Kobes S, International Type 2 Diabetes 1q Consortium, Bogardus C, Shuldiner AR, and Baier LJ. (2007) "Variants in ARHGEF11, a candidate gene for the linkage to type 2 diabetes mellitus on chromosome 1q, are nominally associated with insulin resistance and type 2 diabetes mellitus in Pima Indians.” Diabetes 56:1454-1459.

                Guo T, Traurig M, Muller YL, Ma L, Mack J, Hanson RL, Knowler WC, Bogardus C, and Baier LJ. (2007) “TCF7L2 is not a susceptibility gene for type 2 diabetes in Pima Indians.” Diabetes 56:3082-3088.

                Muller YL, Hanson RL, Zimmerman C, Harper I, Sutherland J, Kobes S, The International Type 2 Diabetes 1q Consortium, Knowler WC, Bogardus C and Baier LJ. (2007) “Variants in the Ca_v2.3 (α1E) subunit of voltage-activated Ca²⁺ channels are associated with insulin resistance and type 2 diabetes in Pima Indians.”  Diabetes 56:3089-3094.

                Hanson RL, Bogardus C, Duggin D, Kobes S, Knowlton M, Infante AM, Marovich L, Benitez D, Baier LJ, Knowler WC. (2007) “A search for variants associated with young-onset type 2 diabetes in American Indians in a 100k genotyping array.” Diabetes 56:3045-3052.

                Ma L, Hanson RL, Que LN, Guo Y, Kobes S, Bogardus C, Baier LJ. (2008) “PCLO variants are nominally associated with early onset type 2 diabetes and insulin resistance in Pima Indians.” Diabetes 57:3156-3160.

                Krakoff J, Ma L, Kobes S, Knowler WC, Hanson RL, Bogardus C, Baier LJ. (2008) “Lower metabolic rate in individuals heterozygous for either a frameshift or a functional missense MC4R variants.” Diabetes 57:3267-3272.

Rong R, Hanson RL, Ortiz D, Wiedrich C, Kobes S, Knowler WC, Bogardus C, Baier LJ. (2009) “Association analysis of FTO, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, OC387761 and CDKN2B with type 2 diabetes and pre-diabetic traits in Pima Indians.” Diabetes 58:478-488.       

                Traurig M, Mack J, Hanson RL, Ghoussaini M, Meyre D,  Knowler WC, Kobes S, Froguel P, Bogardus C, Baier LJ. (2009) “Common variation in SIM1 is reproducibly associated with body mass index in Pima Indians.” Diabetes 58:1682-1689.

                Bian L, Muller YL, Ma L, Hanson RL, Kobes S, Bogardus C, Baier LJ. (2010) “Variants in the acyl-coenzyme A dehydrogenase 10 (ACAD10) gene are associated with type 2 diabetes, insulin resistance and decreased lipid oxidation in Pima Indians.” Diabetologia 53:1349-1353.

                Bian L, Hanson RL, Ossowski V, Wiedrich K, Mason C, Traurig M, Muller YL, Kobes S, Knowler WC, Baier LJ, Bogardus C. (2010) “Variants in ASK1 are associated with skeletal muscle mRNA expression, in vivo insulin resistance, and type 2 diabetes in Pima Indians.” Diabetes 59:1276-1282.

Muller YL, Hanson RL, Bian L, Mack J, Shi X, Pakyz R, Shuldiner AR, Knowler WC, Bogardus C, Baier LJ. (2010) “Functional variants in MBL2 are associated with type 2 diabetes and pre-diabetic traits in Pima Indians and the Old Order Amish.” Diabetes 59:2080-2085.

                Acuña-Alonzo V, Flores-Dorantes T, Kruit JK, Villarreal-Molina T, Arellano-Campos O, Hünemeier T, Moreno-Estrada A, Ortiz-López MG, Villamil-Ramírez H, León-Mimila P, Villalobos-Comparan M, Jacobo-Albavera L, Ramírez-Jimenez S, Sikora M, Zhang L-H, Pape TD, de Angeles Granados-Silvestre M, Montufar-Robles I, Tito AM, Zurita C, Bustos-Arriaga J, Cedillo-Barrón L, Gómez-Trejo C, Barquera-Lozano R, Vieira-Filho JP, Granados J, Romero-Hidalgo S, Huertas-Vázquez A, González-Martín A, Gorostiza A, Bonatto SL, Rodríguez-Cruz A, Li Wang L, Tusié-Luna T, Aguilar-Salinas CA, Moisés RS, Menjivar M, Salzano FM, Knowler WC, Cátira Bortolini M, Hayden MR, Baier LJ, Canizales-Quinteros S. (2010) “A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans.” Human Molecular Genetics 19:2877-2885

Ma L, Traurig MT, Hanson RL, Muller YL, Kaur BP, Perez JM, Meyre D, Fu M, Körner A, Franks PW, Kiess W, Kobes S. Knowler WC, Kovacs P, Froguel P, Shuldiner AR, Bogardus C, Baier LJ. (2010) “Evaluation of A2BP1 as an obesity gene.” Diabetes 59:2837-2845.

Williams RC, Muller YL, Knowler WC, Mason CC, Bian L, Ossowski V, Wiedrich K, Chen Y-F, Marcovina S, Hahnke J, Hanson RL, Nelson RG, Baier LJ, Bogardus C. (2011) “HLA-DRB1 reduces the risk of type 2 diabetes mellitus by increased insulin secretion.” Diabetalogia, 54:1684-1692.

Malhotra A, Kobes S, Knowler WC, Baier LJ, Bogardus C, Hanson RL. (2011) “A genome-wide association study of body mass index in American Indians.” Obesity, in press

Marie S Thearle MS, Muller YL, Hanson RL, Mullins M, AbdusSamad M, Tran J, Knowler WC, Bogardus C, Krakoff J, Baier LJ. (2011) “Greater impact of Melanocortin-4 Receptor deficiency on rates of growth and risk of type 2 diabetes mellitus during childhood compared with adulthood in Pima Indians.”  Diabetes, in press

Dong Y, Guo T, Traurig M,  Mason CC, Kobes S, Perez J, Knowler WC, Bogardus C, Hanson RL, Baier LJ (2011) “SIRT1 is Associated with a Decrease in Acute Insulin Secretion and a Sex Specific Increase in Risk for Type 2 Diabetes in Pima Indians.” Molecular Genetics and Metabolism, in press