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 Obesity 2005; 29:67-77.
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 Disord 2005;29:449-57.
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;52:239-46.
Rich SS, Bowden DW, Haffner SM, Norris JM, Saad MF, Mitchell BD, Rotter JI, Langefeld CD, Hedrick CC, Wagenknecht LE, Bergman RN. A genome scan for fasting insulin and fasting glucose identifies a quantitative trait locus on chromosome 17p. The Insulin Resistance Athersclerosis Study (IRAS) Family Study. Diabetes 2005;54:290-295.
Emery LM, Babu S, Bugawan TL, Norris JM, Erlich H, Eisenbarth GS, Rewers M. Newborn HLA-DR,DQ Screening: Age- and Ethnicity-Specific Type 1 diabetes risk estimates. Pediatr Diabetes 2005;6:136-44.
Sutton BS, Weinert S, Langefeld CD, Williams AH, Campbell JK, Saad MF, Haffner SM, Norris JM, Bowden DW. Genetic analysis of adiponectin and obesity in Hispanic families: the IRAS Family Study. Hum Genet 2005; 117:107-118.
Guo X, Cui J, Wagenknecht LE, Norris JM, Haffner SM, Darwin C, Jinagouda S, Rotter JI, Saad MF. Cosegregation of albuminuria and blood pressure. The Insulin Resistance Atherosclerosis (IRAS) Family Study. Am J Hypertens 2005;18:823-7.
Schneider A, Lawrence EC, Barmada MM, Norris JM, Hamman RF, Marshall JA, Ferrell RE, Whitcomb DC. The SPINK1 N34S mutation is not associated with Type 2 diabetes mellitus in a population of the USA. Diabet Med 2005;22:744-8.
Steck AK, Bugawan TL, Valdes AM, Emery LM, Blair A, Norris JM, Redondo MJ, Babu SR, Erlich HA, Eisenbarth GS, Rewers MJ. Association of non-HLA genes with type 1 diabetes autoimmunity. Diabetes 2005;54:2482-6.
Sutton BS, Langefeld CD, Williams AH, Norris JM, Saad MF, Haffner SM, Bowden DW. Association of proopiomelanocortin gene polymorphisms with obesity in the IRAS Family Study. Obes Res 2005;13:1491-98
Aly TA, Ide A, Humphrey K, Barker JM, Steck A, Erlich HA, Yu L, Miao D, Redondo MJ, McFann K, Roberts CM, Babu SR, Norris JM, Eisenbarth GS, Rewers MJ. Genetic prediction of autoimmunity: initial oligogenic prediction of anti-islet autoimmunity amongst DR3/DR4-DQ8 relatives of patients with type 1A diabetes. J Autoimmunity 2005;25:40-45.
Sutton BS, Langefeld CD, Campbell JK, Haffner SM, Norris JM, Scherzinger AL, Wagenknecht LE, Bowden DW. Genetic mapping of a 17q chromosomal region linked to obesity phenotypes in the IRAS Family Study. Int J Obes 2006;30:1433-41.
Palmer ND, Langefeld CD, Campbell JK, Williams AH, Norris JM, Haffner SM, Saad M, Rotter JI, Wagenknecht L, Bergman RN, Rich SS, Bowden DW. Genetic mapping of disposition index and acute insulin response loci on chromosome 11q: The IRAS Family Study. Diabetes 2006;55:911-8.
Guo X, Saad MF, Langefeld CD, Williams AH, Cui J, Taylor KD, Norris JM, Jinagouda S, Darwin CH, Mitchell BD, Bergman RN, Sutton B, Chen Y-DI, Wagenknecht LE, Bowden DW, Rotter RI. Genome-wide linkage of plasma adiponectin reveals a major locus on chromosome 3q distinct from the adiponectin structural gene. Diabetes 2006;55:1723-30.
Aly TA, Ide A, Jahromi MM, Barker JM, Fernando MS, Babu SR, Yu L, Miao D, Erlich HA, Fain PR, Barriga KJ, Norris JM, Eisenbarth GS, Rewers MJ for the Diabetes Autoimmunity Study in the Young. Extreme genetic risk for type 1A diabetes. PNAS 2006;103:14074-9.
Nelson TL, Fingerlin TE, Moss L, Barmada MM, Ferrell RE, Norris JM. Association of the peroxisome proliferator-activated receptor-? gene (PPAR-?) with type 2 diabetes varies by physical activity among Non-Hispanic Whites from Colorado. Metabolism Clin Exp 2007;56:388-393.
Nelson TL, Fingerlin TE, Moss L, Barmada MM, Ferrell RE, Norris JM. The PPAR? Pro12Ala polymorphism is not associated with body mass index or waist circumference among Hispanics from Colorado. Ann Nutr Metab 2007 51:252-257.
Nelson TL, Fingerlin TE, Moss L, Barmada MM, Ferrell RE, Norris JM. The peroxisome proliferator-activated receptor gamma coactivator-1 alpha gene (PGC-1?) is not associated with type 2 diabetes mellitus among Hispanic or Non-Hispanic whites from Colorado. Exp Clin Endocrin Diab 2007;115:268-75.
Sale MM, Hsu FC, Palmer ND, Gordon CJ, Keene KL, Borgerink HM, Sharma AJ, Bergman RN, Taylor KD, Saad MF, Norris JM. The uncoupling protein 1 gene, UCP1, is expressed in mammalian islet cells and associated with acute insulin response to glucose in African American families from the IRAS Family Study. BMC Endocr Disord 2007; 7(1).
Baschal EE, Aly TA, Babu SR, Fernando MS, Yu L, Biao D, Barriga KJ, Norris JM, Noble JA, Erlich HA, Rewers MJ, Eisenbarth GS. HLA-DPB1*0402 protects against type 1A diabetic autoimmunity in the highest risk DR3-DQB1*0201/DR4-DQB1*0302 DAISY population. Diabetes 2007;56(9):2405-9.
Taylor KD, Norris JM, Rotter JI. Genome-wide association. Which do you want first: the good news, the bad news or the good news? Diabetes 2007;56:2844-2848.
Palmer ND, Lehtinen AB, Langefeld CD, Campbell JK, Haffner SM, Norris JM, Bergman R, Goodarzi MO, Rotter JI, Bowden DW. Association of TCF7L2 Gene Polymorphisms with Reduced Acute Insulin Response in Hispanic Americans J Clin Endocrinol Metab 2008: 93(1):304-9.
Torkko KC, van Bokhoven A, Mai P, Beuten J, Balic I, Byers TE, Hokanson JE, Norris JM, Baron AB, Lucia MS, Thompson IM, Leach RJ. VDR and SRD5A2 polymorphisms combine to increase risk for prostate cancer in non-Hispanic white and Hispanic white men. Clin Cancer Res 2008;14:3223-3229.
Palmer ND, Goodarzi MO, Langefeld CD, Ziegler J, Norris JM, Haffner SM, Bryer-Ash M, Bergman RN, Wagenknecht LE, Taylor KD, Rotter JI, Bowden DW. Quantitative trait analysis of T2D susceptibility loci identified from whole genome association studies in the IRAS Family Study. Diabetes 2008;57(4):1093-100.
Vehik K, Hamman RF, Lezotte D, Norris JM, Klingensmith G, Rewers M, Dabelea D. Trends in High-Risk HLA Susceptibility Genes Among Colorado Youth with Type 1 Diabetes. Diabetes Care 2008;31:1392-96.
Engelman CD, Fingerlin TE, Langefeld CD, Hicks PJ, Rich SS, Wagenknecht LE, Bowden DW, Norris JM. Genetic and environmental determinants of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in Hispanic and African Americans: the IRAS Family Study. J Clin Endocrinol Metab 2008;93:3381-3388.
Rich, SS, Norris JM, Rotter JI. As a Trickle becomes a Flood, Genes Associated with Risk of Type 2 Diabetes Identified by a Candidate-Wide Association Scan (CWAS) Diabetes 2008;57:2915-17.
