Jill Norris, Ph.D.
Genetics of non-insulin dependent diabetes mellitus (NIDDM)
Since 1993, we have been conducting a family study in Colorado to search for the genes for type 2 diabetes. We have two study clinics in Colorado where we study the individuals with diabetes as well as other family members, including parents, siblings and children of the diabetic individuals. One study clinic is in Alamosa, Colorado, where we are studying Hispanic-American families from a rural population in the San Luis Valley. We are also studying caucasian, African-American and Hispanic-American families in the urban population of Denver, Colorado. Both the American Diabetes Association and the National Institutes of Health are supporting us in this effort.
Our research seeks to use what we know about the environmental component in type 2 diabetes to help us find susceptibility genes. The general framework for our research is the family study. The family design can directly assess the effect of transmission of the gene with transmission of the trait, thereby allowing a robust estimate of causality of the candidate. Acknowledging that many genes may appear to have small effects because of the presence of gene-environment interaction, we have designed a strategy of data collection and analysis that will enable us to detect genes with small effects better than affected sibling pair approaches. This strategy involves collecting data on parents and affected offspring (e.g. trios), using the transmission-disequilibrium test to detect linkage and association, and conditional logistic regression analyses to account for behavioral risk factors such as diet and physical activity. In addition, our study design and analysis approach will allow us to narrow the region of linkage so that sequencing and identification of mutations are more feasible.
Our research is built on an already impressive and unique resource of the San Luis Valley population for searching for the genetic and environmental risk factors for type 2 diabetes. The San Luis Valley Genetics Studies have a sufficient amount of family data to do parametric and non-parametric linkage analyses for type 2 diabetes. In addition, the separately-funded San Luis Valley Diabetes Study cohort provides a population-based longitudinal cohort to do association studies for diabetes genes using longitudinal measures of phenotypes and environmental exposures. We are currently working on increasing the power of this resource by adding a population of nuclear families in which to do fine scale mapping and family-based gene-environment studies. One unique aspect of our populations is the collection of dietary and physical activity data on all individuals that we genotype. In the search for the genes for a complex disease such as type 2 diabetes, a battery of study designs will likely be necessary.
Publications
Yu MS, Norris JM, Mitchell CM, Butler-Simon N, Groshek M, Follansbee D, Erlich H, Rewers M, Klingensmith GJ. The impact on maternal parenting stress of receipt of genetic information regarding risk of diabetes in newborns. Am J Med Genet 1999;86:219-226.
Merriwether DA, Huston S, Iyengar S, Hamman RF, Norris JM, Shetterly SM, Kamboh MI, Ferrell RE. Mitochondrial versus nuclear admixture estimates demonstrates a past history of directional mating. Am J Phys Anthropol 1997;102:153-159.
Rewers M, Bugawan TL, Norris JM, Blair A, Beaty B, Hoffman M, McDuffie R, Hamman RF, Klingensmith G, Eisenbarth GS, Erlich HA. Newborn Screening for HLA markers associated with IDDM: Diabetes Autoimmunity Study in the Young (DAISY). Diabetologia 1996;39:807-12.
Raffel LJ, Robbins DC, Norris JM, Boerwinkle E, DeFronzo RA, Elbein SC, Fujimoto W, Hanis CL, Kahn SE, Mulivor R, Permutt MA, Chiu KC, Cruz J, Ehrmann DA, Robertson RP, Rotter JI, Buse J. The GENNID study: A resource for mapping the genes that cause NIDDM. Diabetes Care 1996;19:864-72.
Wingrove KJ, Norris J, Hagerman R, Lindsay Barton P. Experiences and Attitudes concerning genetic testing and insurance in a Colorado population: A survey of families diagnosed with Fragile X syndrome. Am J Med Genet 1996;64:378-381.
Kostraba JN (aka Norris JM), Cruickshanks KJ, Lawler-Heavner J, Rewers MJ, Gay EC, Chase HP, Klingensmith G, Hamman RF. Early exposure to cow's milk and solid foods in infancy, genetic susceptibility and risk of insulin-dependent diabetes mellitus. Diabetes 1993;42:288-295.
Langefeld CD, Wagenknecht LE, Saad MF, Hokanson JE, Rotter JI, Williams AH, Haffner S, Norris JM, Rich SS, Mitchell BD. Linkage of the metabolic syndrome to 1q23-q31 in Hispanic Families. The IRAS Family Study. Diabetes 2004; 53:1170-1174.
Bensen JT, Hsu F-C, Brown WM, Sutton BS, Norris JM, Tracy RP, Jenny NS, Bowden DW, Langefeld CD, Saad MF, Haffner S. Association analysis of the plasminogen activator inhibitor-1 4G/5G polymorphism in Hispanics and African-Americans: The IRAS Family Study. Hum Hered 2004;57:128-137.
Rich SS, Bowden DW, Haffner SM, Norris JM, Saad MF, Mitchell BD, Rotter JI, Langefeld CD, Wagenknecht LE, Bergman RN. Identification of QTLs for glucose homeostasis: The IRAS Family Study. Diabetes 2004; 53:1866-75.
Parra EJ, Hoggart CJ, Bonilla C, Dios S, Norris JM, Marshall JA, Hamman RF, Ferrell RE, McKeigue PM, Shriver MD. Relation of type 2 diabetes to individual admixture and candidate gene polymorphisms in the Hispanic-American population of San Luis Valley, Colorado. J Med Genet 2004;41:e116.
Norris JM, Langefeld CD, Scherzinger AL, Rich SS, Bookman E, Beck SR, Saad MF, Haffner SM, Bergman RN, Bowden DW, Wagenknecht LE. Quantitative Trait Loci for Abdominal Fat and BMI in Hispanic-Americans and African-Americans: The IRAS Family Study. Int J Obes Relat Metab Disorder 2004 Nov 09 (epub)
Palmer ND, Bento JL, Mychaleckyj JC, Langefeld CD, Campbell JK, Norris JM, Haffner SM, Bergman RN, Bowden DW. Association of protein tyrosine phosphatase 1B gene polymorphisms with measures of glucose homeostasis in Hispanic Americans: The IRAS Family Study. Diabetes 2004; 53: 3013-19.
Lange LA, Norris JM, Langefeld CD, Nicklas B, Wagenknecht LE, Saad MF, Bowden DW. Association of adipose tissue deposition and beta-2 adrenergic receptor variants: The IRAS Family Study. Int J Obes Relat Metab Disorder 2005 (in press)
Ferucci ED, Majka DS, Parrish LA, Moroldo MB, Ryan M, Passo M, Thompson
SD, Deane KD, Rewers M, Arend WP, Glass DN, Norris JM, Holers VM. Antibodies
against cyclic citrullinated pepetid (CCP) are associated with HLA-DR4
in simplex and multiplex polyarticular juvenile rheumatoid arthritis.
Arthritis and Rheumatism 2005 (in press)
