Abstract

Fewer than 30 percent of diabetic patients get irreversible nephropathy. For diabetic relatives of patients with nephropathy the risk is 3.5 to 10-fold higher than the general population. Thus, genetic susceptibility appears to distinguish those diabetic patients destined to develop nephropathy. We propose to map diabetes susceptibility genes using an approach that combines nonparametric sib pair analysis of concordant and discordant sibs, allelic association, and quantitative trait analysis in families with multiple diabetic siblings. Linkage will be tested in 150 sib pairs concordant for diabetes and 75 discordant for diabetes. Linkage and association will first be tested for known genes and proposed loci that influence risk of Type 2 diabetes, hypertension, nephropathy in other populations or animal models, and glycemic effects including aldose reductase. A 10 cM genome scan will be conducted to map novel genes. Potential nephropathy loci will be tested for association in 200 unrelated patients with nephropathy, and tested in an additional 100 concordant and 50 discordant sib pairs. Additional studies will map the quantitative trait locus controlling albumin excretion in diabetic patients using a variance component approach to linkage. Finally, transformed lymphocytes from diabetic and nondiabetic members of familial diabetes pedigrees will be studied under euglycemic and hyperglycemic conditions to search for preclinical markers of nephropathy. These studies will be conducted in families for which a genome search for diabetes susceptibility is in progress. Sorbitol accumulation and aldose reductase expression will be examined and tested for linkage to the aldose reductase locus. Sodium hydrogen exchange will be measured and tested for correlation with sodium hydrogen exchanger 1 message. A genome scan will be undertaken to map the quantitative trait locus controlling sodium hydrogen exchange, and to determine whether this locus leads to nephropathy. These studies will identify genes and chromosomal regions containing genes that predispose to nephropathy, and will lead to an improved understanding better management of diabetic nephropathy.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054636-04
Application #
6381264
Study Section
Special Emphasis Panel (ZDK1-GRB-4 (M1))
Program Officer
Kimmel, Paul,
Project Start
1998-08-14
Project End
2003-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
4
Fiscal Year
2001
Total Cost
$217,966
Indirect Cost

  Institution

Name
University of Arkansas for Medical Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Little Rock
State
AR
Country
United States
Zip Code
72205

  Publications

Craig, Rebekah L; Chu, Winston S; Elbein, Steven C (2007) Retinol binding protein 4 as a candidate gene for type 2 diabetes and prediabetic intermediate traits. Mol Genet Metab 90:338-44
Wang, Hua; Elbein, Steven C (2007) Detection of allelic imbalance in gene expression using pyrosequencing. Methods Mol Biol 373:157-76
Elbein, Steven C; Wang, Xiaoqin; Karim, Mohammad A et al. (2006) Role of a proline insertion in the insulin promoter factor 1 (IPF1) gene in African Americans with type 2 diabetes. Diabetes 55:2909-14
Elbein, Steven C; Wang, Xiaoqin; Karim, Mohammad A et al. (2006) Analysis of coding variants in the betacellulin gene in type 2 diabetes and insulin secretion in African American subjects. BMC Med Genet 7:62
Karim, Mohammad A; Craig, Rebekah L; Wang, Xiaoqin et al. (2006) Analysis of FOXO1A as a candidate gene for type 2 diabetes. Mol Genet Metab 88:171-7
Wang, Hua; Zhang, Zhengxian; Chu, Winston et al. (2005) Molecular screening and association analyses of the interleukin 6 receptor gene variants with type 2 diabetes, diabetic nephropathy, and insulin sensitivity. J Clin Endocrinol Metab 90:1123-9
Karim, Mohammad A; Wang, Xiaoqin; Hale, Terri C et al. (2005) Insulin Promoter Factor 1 variation is associated with type 2 diabetes in African Americans. BMC Med Genet 6:37
Wang, Hua; Chu, Winston; Wang, Xiaoqin et al. (2005) Evaluation of sequence variants in the pre-B cell leukemia transcription factor 1 gene: a positional and functional candidate for type 2 diabetes and impaired insulin secretion. Mol Genet Metab 86:384-91
Karim, Mohammad A; Wang, Xiaoqin; Zhang, Zhengxian et al. (2004) Association of an insulin gene promoter insertion polymorphism with type 2 diabetes and diabetic nephropathy in African Americans. Mol Genet Metab 83:344-6
Elbein, Steven C; Zheng, Hailing; Jia, Yiwen et al. (2004) Molecular screening of the human glutamine-fructose-6-phosphate amidotransferase 1 (GFPT1) gene and association studies with diabetes and diabetic nephropathy. Mol Genet Metab 82:321-8

Showing the most recent 10 out of 11 publications