Family Investigation of Nephropathy and Diabetes (F.I.N.D.)

The Family Investigation of Nephropathy and Diabetes (FIND) is a multicenter study designed
to identify genetic determinants of diabetic kidney disease. FIND is conducted in eleven
centers and in many ethnic groups throughout the United States. Two different strategies are
used to localize genes predisposing to kidney disease: a family-based genetic
linkage/association study and a case-control study that uses admixture linkage
disequilibrium. The center based at the Phoenix office of the National Institute of Diabetes
and Digestive and Kidney Diseases (NIDDK-Phoenix) conducts family-based linkage/association
studies among American Indian populations in the southwestern United States, and in the
indigenous Micronesian populations of the Territory of Guam and the Commonwealth of the
Northern Mariana Islands (CNMI).

Participants (index cases) with diabetes and kidney disease are recruited, and their parents
and siblings are also invited to participate. Members of target populations who are not
related to index cases are also included and offered screening for diabetes and kidney
disease; this will facilitate association studies. Genetic material from these participants
is used to genotype markers throughout the genome. Linkage and association analyses are
conducted to identify particular chromosomal regions containing genes that influence
susceptibility to diabetic kidney disease. Linkage and association analyses are also used to
identify genes influencing traits related to diabetic kidney disease, such as serum
creatinine, urinary protein excretion, plasma glucose levels, blood pressure and blood lipid
levels. Genome-wide and candidate gene association studies are also conducted. Regions that
show evidence for linkage or association are then examined in more detail, with both genetic
linkage and association studies, to attempt to identify the specific genes that influence
diabetic kidney disease, or related traits.

The identification of genes that influence susceptibility to diabetic kidney disease will
lead to a better understanding of how kidney disease develops. In the long run, this may lead
to improved treatment and prevention of diabetic kidney disease.

- INCLUSION CRITERIA:

Index Cases:

Individuals with diabetes and diabetic nephropathy who are at least 18 years of age.

Potential index cases must have at least one sibling, or both parents available as
potential study participants.

Potential index cases must also have diabetic nephropathy. An index case must have
nephropathy that is more severe than microalbuminuria. An index case must meet one of the
following criteria:

1. Biopsy proven diabetic nephropathy (by medical record review):

1. Nodular and/or diffuse increases in the mesangial matrix accumulation; and

2. Thickened glomerular basement membranes and/or arteriolar hyalinization; and

3. Absence of mesangial immunoglobulin or paraprotein deposits by immunoflorecscence
microscopy, absence of amyloid deposits by Congo Red staining or electron
microscopy, absence of electron dense deposits within the glomerular basement
membrane or glomerular capillary subendothelial space; and

4. Overt proteinuria, defined as ACR greater than or equal to 300 mg/g, urinary
protein creatinine ratio greater than or equal to 0.5 g/g, urinary albumin
excretion greater than or equal to 300 mg/24 hr, or urinary protein excretion
greater than or equal to 0.5 g/24 hr.

2. ESRD (including transplant) from presumed diabetic nephropathy:

Diabetes present for at least 5 years prior to the initiation of replacement therapy
and retinopathy at any time;

or Diabetes present for at least 5 years prior to the initiation of replacement
therapy and either greater than or equal to 3 gm protein/24 hours, or a urine protein
(mg)/creatinine (mg) greater than or equal to 3.0 or urinary ACR greater than or equal
to 3000 mg/g or urinary albumin excretion greater than or equal to 3000 mg/24 hours
(historical data acceptable);

or retinopathy and either greater than or equal to 3 gm protein/24 hours, or a urine
protein (mg)/creatinine (mg) greater than 3.0 or urinary ACR greater than or equal to
3000 mg/g or urinary albumin excretion greater than 3000 mg/24 hours (historical data
acceptable).

3. Patient with presumed diabetic nephropathy but not ESRD:

Patient has diabetic retinopathy and either greater than or equal to 1 gram proteinuria/24
hours or a urine protein (mg)/creatinine (mg) greater than or equal to 1.0 or urinary ACR
greater than or equal to 1000 mg/g or urinary albumin excretion greater than or equal to
1000 mg/24 hours (historical data acceptable);

or first detection of either greater than or equal to 3 gram protein/24 hours or a urine
protein (mg)/creatinine (mg) greater than or equal to 3.0 gram or urinary ACR greater than
or equal to 3000 mg/g or urinary albumin excretion greater than or equal to 3000 mg/24
hours at DM duration greater than or equal to 10 years (historical data acceptable).

Recruitment of Family Members:

Any available parent or sibling who is at least 18 years of age will be recruited as a
potential participant and will use the same criteria as above.

DNA for individuals in informative families will be submitted to the genotyping laboratory.
An informative family is defined as one for which DNA specimens are available for the
following individuals:

1. The index case and both parents, or

2. The index case and at least one other affected sibling who has diabetes and renal
disease, or

3. The index case and at least one unaffected sibling, defined as an individual who has
had diabetes for at least 10 years and who has no renal disease (based on evidence
obtained from the medical record and from the FIND examination.