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Genetic Determinants of Diabetic Nephropathy: The Family Investigation of Nephropathy and Diabetes (FIND)

Correspondence to Dr. Robert C. Elston, Genetic Analysis and Data Coordinating Center, Family Investigation of Nephropathy and Diabetes, Case Western Reserve University, Department of Epidemiology and Biostatistics, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109. Phone: 216-778-4526; Fax: 216-778-3280;

	Abstract

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ABSTRACT. Diabetes mellitus is the leading cause of ESRD in the United States. Family-based studies and segregation analyses suggest that inherited factors play a major role in susceptibility to diabetic renal complications, including albuminuria and chronic kidney failure. The Family Investigation of Nephropathy and Diabetes (FIND) study is a multicenter consortium established by the National Institute of Diabetes, Digestive and Kidney Diseases to identify the gene(s) responsible for diabetic nephropathy. Eight participating centers will enroll nearly 10,000 individuals by September 2004. Two independent strategies to detect causative genes will be used. These include family-based linkage analyses in African-American, American-Indian, Mexican-American, and European-American families (predominantly affected and discordant relative pair analyses) and mapping by admixture linkage disequilibrium (MALD) in African and Mexican Americans. Cell lines are being created from participants, and a repository containing stored urine and serum samples has been developed. This paper describes the enrollment criteria and methods used in FIND to allow for the detection of gene(s) predisposing to diabetic nephropathy. E-mail: sialacci@darwin.epbi.cwru.edu

	Introduction

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Diabetic nephropathy (DN) is the most common cause of ESRD in the United States (1). African-Americans, Mexican-Americans, and American-Indians have a disproportionate burden of ESRD. Familial aggregation occurs in diverse populations with either type 1 or type 2 diabetes (2–4). These findings are consistent with the hypothesis that genetic factors influence susceptibility to DN. Analyses of familial aggregation and family transmission of DN (5) indicate that some genetic determinants have sufficiently large effects to be detected by conventional genetic techniques.

The National Institutes of Health created a multicenter consortium entitled "Family Investigation of Nephropathy and Diabetes" (FIND). FIND is charged with localizing and identifying genetic factors that modulate susceptibility to DN. FIND is being conducted in eight clinical centers and a Genetic Analysis and Data Coordinating Center. To assess potential genetic heterogeneity, FIND is recruiting European-Americans, African-Americans, Mexican-Americans, and American-Indians. Strategies include genome-wide linkage analyses and mapping by admixture linkage disequilibrium (MALD).

Genetic studies commonly use two major strategies to identify disease-causing alleles: (1) a functional candidate gene approach focusing on genes that code for proteins with a suspected pathophysiologic role; and (2) a positional candidate gene approach focusing on regions demonstrating linkage on genome-wide scans. These two strategies can be incorporated into the following approaches: (1) association studies that test for associations of particular alleles with disease frequency in a population; (2) linkage studies that test for cosegregation of a genetic marker with the disease among families (6); and (3) MALD, which uses the association of alleles that can distinguish one of the founding populations as a tool to map susceptibility alleles (7,8). The combined use of family-based linkage and MALD strategies enhances our power to detect DN-susceptibility genes and genetic-ethnic interactions. To identify chromosomal regions harboring DN genes, we will use linkage analysis on the basis of sibling pairs concordant or discordant for DN. The transmission disequilibrium test (9) will be used to facilitate fine mapping and the investigation of functional and positional candidate genes. The MALD approach will be used to study Mexican- and African-American subpopulations. In addition to performing linkage and MALD analyses, we will investigate selected functional candidate genes.

	Materials and Methods

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The methods are described briefly here. A detailed description will be published elsewhere (10). Participants can be entered into one of two studies: family and MALD. The family study ascertains DN probands with a diabetic sib(s) for linkage analysis. The MALD study uses a case-control design and enrolls individuals with African-American or Mexican-American ancestry and DN.

Participants provide medical histories and urine, plasma, and serum samples for determination of glycosylated hemoglobin, serum and urine creatinine concentration, and urinary albumin : creatinine ratio (UAC). Lymphocytes from eligible participants are immortalized and a repository kept for serum, plasma, and urine samples.

Family Study
The family study is recruiting multiplex diabetic families identified by a proband with overt nephropathy or ESRD attributed to diabetes mellitus. Family eligibility is determined by at least one additional diabetic sibling either with nephropathy (urine UACR 0.03 mg/mg) or without nephropathy (UACR <0.03 mg/mg and normal serum creatinine concentration) after a 10-yr diabetes duration. Available parents, other diabetic siblings and at least one nondiabetic sibling are recruited in eligible families.

Each clinical center ships biologic samples to the Laboratory of Genetic Diversity, National Cancer Institute. After transformation, the B cell pellets are shipped to the molecular laboratory at the Genetic Analysis and Data Coordinating Center. DNA is extracted from the B cell pellets and will be made available for centralized and clinical center-specific genotyping. Genotyping for a genome-wide scan will be performed for the family-based linkage study by the Center for Inherited Disease Research.

We will fine map regions that demonstrate evidence for linkage. The entire region will be saturated with microsatellite markers 1 cM apart and then examined for adjacent markers demonstrating linkage disequilibrium. When a sufficiently small (1 Mb) region has been identified we will pursue positional candidate genes. Functional and positional candidate genes will be evaluated for functional sequence variants that may be associated with DN.

MALD Study
The MALD study will use a case-control design and recruit African and Mexican Americans. African-American diabetic and nondiabetic renal disease triads, consisting of probands with nephropathy, spouses without nephropathy, and a child, are recruited. African- and Mexican American hypernormal controls (individuals with long-standing diabetes mellitus and no evidence of nephropathy), and Mexican Americans with overt nephropathy or ESRD attributed to diabetes are also recruited.

Microsatellites, short diallelic insertion deletion polymorphisms, and single nucleotide polymorphisms (SNP) dispersed throughout the genome have been identified that can distinguish between the ancestral founders of African Americans and Mexican Americans (11,12). These markers will be genotyped in the MALD study and tested for association with DN.

Functional Candidate Genes
In addition to performing linkage and MALD analyses, we will investigate the association of DN with selected functional candidate genes. These may include genes involved in the renin-angiotensin system; apolipoprotein E; aldose reductase; paraoxonase 1; nitric oxide synthase; IL-1 receptor antagonist; growth factor cascades (TGF- 1, 2, and 3, platelet-derived growth factor, epidermal growth factor, tumor necrosis factor and ); endothelin; tissue kallikrein; plasma kallikrein; and sodium/hydrogen exchangers.

Timeline
This 5-yr study was funded in the fall of 1999. A 3-mo pilot study began in August 2000 during which we tested recruitment, shipping specimens, and bioinformatics. The full-scale study began in February 2001. Recruitment will continue through September 2004. This will be followed by completion of the genome scans and data analyses.

	Discussion

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Genetics is likely to make important contributions to understanding the biochemical perturbations that predispose to DN. With large numbers of families and unrelated individuals from four ethnic groups, FIND will provide a valuable resource for genetic analyses. Creation of cell lines from participants ensures adequate sources of DNA. The storage of serum, urine, and plasma samples in a repository will allow for measurement of the products of renal failure susceptibility genes. Novel causative pathways predisposing to the development of diabetes mellitus and kidney disease may be detected using these molecular genetic approaches.

Members of the FIND Research Group (in alphabetical order according to center)
Coordinating Center (Robert C. Elston, Katrina Goddard, Sudha Iyengar, Jane M. Olson)

Case Western Reserve University (John R. Sedor, Jeffrey R. Schelling)

Johns Hopkins University (Michael Klag, Josef Coresh, Rulan Parekh)

NIDDK Bethesda (Paul Kimmel, Rebekah Rasooly, Josephine Briggs)

NIDDK Phoenix (William C. Knowler, Robert Hanson, Robert Nelson)

UCLA Cedars Sinai (Mohammed Saad, Xiuqing Guo, Jerome I. Rotter, Kent Taylor)

UCLA Harbor (Sharon Adler, Madeline Pahl, Michael Seldin)

University of New Mexico (Philip Zager, Marina Scavini, Vallabh Shah, Christine Stidley, Jean MacCluer)

University of Texas at San Antonio Health Science Center (Hanna Abboud, Nedal Arar, B.S. Kasinath, Rosemarie Plaetke)

Wake Forest University (Barry I. Freedman, Don Bowden, Stephen Rich, Scott Satko)

	Footnotes

 
This paper was prepared by Philip G. Zager, William C. Knowler, and Barry I. Freedman on behalf of the FIND Research Group. Members of the FIND Research Group are listed at the end of this paper.

	References

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1. U.S. Renal Data System: USRDS 2001 Annual Data Report. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2001
2. Seaquist ER, Goetz FC, Rich S, Barbosa J: Familial clustering of diabetic kidney disease: Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 320: 1161–1165, 1989[Abstract]
3. Borch-Johnsen K, Nørgaard K, Hommel E, Mathiesen ER, Jensen JS, Deckert T, Parving H-H: Is diabetic nephropathy an inherited complication? Kidney Int 41: 719–722, 1992[Medline]
4. Quinn M, Angelico MC, Warram JH, Krolewski AS: Familial factors determine the development of diabetic nephropathy in patients with IDDM. Diabetologia 39: 940–945, 1996[Medline]
5. Imperatore G, Knowler WC, Pettitt DJ, Kobes S, Bennett PH, Hanson RL: Segregation analysis of diabetic nephropathy in Pima Indians. Diabetes 49: 1049–1056, 2000[Abstract]
6. Elston RC, Guo X, Williams LV: Two-stage global search designs for linkage analysis using pairs of affected relatives. Genet Epidemiol 13: 535–558, 1996[CrossRef][Medline]
7. Stephens JC, Briscoe D, O’Brien SJ: Mapping by admixture linkage disequilibrium in human populations: limits and guidelines. Am J Hum Genet 55: 809–824, 1994[Medline]
8. McKeigue PM: Mapping genes that underlie ethnic differences in disease risk: Methods for detecting linkage in admixed populations, by conditioning on parental admixture. Am J Hum Genet 63: 241–251, 1998[CrossRef][Medline]
9. Spielman RS, Ewens WJ: The TDT and other family-based tests for linkage disequilibrium and association [editorial]. Am J Hum Genet 59: 983–989, 1996[Medline]
10. The Family Investigation of Nephropathy and Diabetes Research Group: The Family Investigation of Nephropathy and Diabetes (FIND): Design and Methods, in preparation.
11. Smith MW, Lautenberger JA, Doo Shin H, Chretien J, Shrestha S, Gilbert DA, O’Brien SJ: Markers for mapping by admixture linkage disequilibrium in African-American and Hispanic populations. Am J Hum Genet 69: 1080–1094, 2001[CrossRef][Medline]
12. Collins-Schramm HE, Phillips CM, Operario DJ, Lee JS, Weber JL, Hanson RL, Knowler WC, Cooper R, Li H, Seldin MF: Ethnic-difference markers for use in mapping by admixture linkage disequilibrium. Am J Hum Genet 70: 737–750, 2002[CrossRef][Medline]

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