Nephropathy (NP) is a frequent, devastating consequence of non-insulin- dependent diabetes mellitus (NIDDM) and hypertension (HTN). The prevalence of NP is particularly high among African Americans (AAs). AA women with a history of gestational diabetes mellitus (GDM) are at high risk for NIDDM and HTN and probably NP. Persistent urinary albumin excretion,, microalbumnuria (MA), is the earliest clinical evidence of many cases of NP. MA may precede the onset of clinical diagnosis of NIDDM and/or HTN. The frequency of MA prior to the onset of these clinical disorders in this high risk population is unknown. The proposed study will estimate these rates. The factors which cause MA are uncertain. We propose to test the hypothesis that insulin resistance (IR) is a phenotype influenced by genes in or near the Major Histocompatibility Complex (MHC) that results in increased occurrence and rate of progression of kidney dysfunction and this relationship is in part independent of the relationship between IR and two of its hypothesized sequelae, HTN and dyslipidemia both of which have been hypothesized as causes of MA. We will test the hypothesis that IR and the hyperinsulinemia which it causes lead to elevated fibrinogen levels and impaired fibrinolytic activity which results in MA in combination with hyperglycemia, HTN and dyslipidemia. We propose to test the hypotheses in a longitudinal study of a well established cohort of AA women who presented with GDM (N=450) and an additional cohort of recent GDMs (N=100). We will assess their status with respect to the genetic phenotype IR and possible genetic markers of the phenotype and MA (HLA-DR and DQ). We also propose to assess its hypothesized biochemical and physiological sequelae HTN, dyslipidemia, (hyperinsulinemia, hyperfibrinogenemia, hyperplasminogen activator inhibitor-1 activity) as well as possible confounders, e.g. smoking and dietary protein intake. Urinary albumin excretion rate (UAER) and MA will be assessed. Kidney function will be assessed by a 24 hour creatinine clearance (CC). The women will be examined three times over five years. The statistical analyses are designed to determine the influence of IR and the relative contribution of each of its sequelae and their interaction in the occurrence of MA and the change in UAER and CC over time. The goal is to understand the role of these factors that lead to MA and ultimately to prevent NP.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK032767-11A2
Application #
2138865
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Project Start
1983-07-01
Project End
1999-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
11
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Giger, Joyce Newman; Strickland, Ora L; Weaver, Michael et al. (2005) Genetic predictors of coronary heart disease risk factors in premenopausal African-American women. Ethn Dis 15:221-32
Barton, E H; West, P A; Rivers, C A et al. (2001) Transferrin receptor-2 (TFR2) mutation Y250X in Alabama Caucasian and African American subjects with and without primary iron overload. Blood Cells Mol Dis 27:279-84
Acton, R T; Barton, J C; Bell, D S et al. (2001) HFE mutations in African-American women with non-insulin-dependent diabetes mellitus. Ethn Dis 11:578-84
Go, R C; Desmond, R; Roseman, J M et al. (2001) Prevalence and risk factors of microalbuminuria in a cohort of African-American women with gestational diabetes. Diabetes Care 24:1764-9
Rivers, C A; Barton, J C; Acton, R T (2001) A rapid PCR-SSP assay for the hemochromatosis-associated Tyr250Stop mutation in the TFR2 gene. Genet Test 5:131-4
Barton, J C; Sawada-Hirai, R; Rothenberg, B E et al. (1999) Two novel missense mutations of the HFE gene (I105T and G93R) and identification of the S65C mutation in Alabama hemochromatosis probands. Blood Cells Mol Dis 25:147-55
Barton, J C; Shih, W W; Sawada-Hirai, R et al. (1997) Genetic and clinical description of hemochromatosis probands and heterozygotes: evidence that multiple genes linked to the major histocompatibility complex are responsible for hemochromatosis. Blood Cells Mol Dis 23:135-45; discussion 145a-b
Acton, R T; Bell, D S; Collins, J et al. (1997) Genes within and flanking the major histocompatibility region are risk factors for diabetes, insulin resistance, hypertension, and microalbuminuria in African-American women. Transplant Proc 29:3710-2
Acton, R T (1997) Molecular genetic testing for adult-onset disorders: the evolving laboratory, physician, patient interface. J Clin Lab Anal 11:23-7
Barton, J C; Harmon, L; Rivers, C et al. (1996) Hemochromatosis: association of severity of iron overload with genetic markers. Blood Cells Mol Dis 22:195-204

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