Genetic Markers for Focal Segmental Glomerulosclerosis

Glomerulonephritis is a disease which affect the kidneys. Occasionally these diseases can progress to a loss of kidney function in some patients. Glomerulosclerosis or focal segmental glomerulosclerosis (FSGS) is one form of glomerulonephritis.

The cause of FSGS is unknown and often occurs on its own (idiopathic), or it can be associated with HIV (Human Immunodeficiency Virus). FSGS occurs more commonly among black patients than Caucasian or Hispanic patients. Researchers believe that environmental factors may interact with genetic mutations to cause FSGS, at least in some patients.

This study will attempt to identify genetic factors associated with the development of FSGS. The study population will be made up of 600 total subjects divided into 3 groups. Group one will be 200 African-Americans with FSGS. Group two will be 200 African-Americans with HIV but without FSGS. Group three will be 200 non-African-Americans with FSGS.

Study participation requires that researchers obtain 20 ml (2 tubes of blood). The genetic material (DNA) will be prepared from the white blood cells and analyzed. The results of each group will be compared with the results from the other groups to determine if one or more genes predisposes to FSGS. In the long run, studies that demonstrate a genetic basis for FSGS may help us identify patients earlier and may lead to improved therapies....

Focal segmental glomerulosclerosis (FSGS) and a related condition, collapsing glomerulopathy, are chronic renal diseases affecting the glomerular podocytes. Currently, over thirteen genetic mutations are associated with FSGS. We are interested in expanding our understanding of these and other genes that may cause FSGS and collapsing glomerulopathy. We will study individuals with affected family members. We will also study sporadic cases; the rationale for studying this population is that FSGS and collapsing glomerulopathy are significantly more common among individuals of African descent. The latter observation suggests that particular FSGS-susceptibility alleles may be more common among African Americans. In the present study, we are addressing the hypothesis that genetic variation contributes to the pathogenesis of idiopathic FSGS and collapsing glomerulopathy, both idiopathic and HIV associated variants.

We are studying the following groups:

1. African-Americans with idiopathic or HIV-associated collapsing glomerulopathy. We will exclude post-adaptive FSGS, associated with glomerular hyperfiltration, and medication associated FSGS.
2. Other patients with idiopathic FSGS< TAB>
3. African Americans with HIV and without kidney disease (hyper-normal controls)
4. African descent controls (controls).< TAB>
5. Healthy European and Asian descent controls (controls).< TAB>
6. Relatives of patients with familial FSGS< TAB>
7. Kidney donors
8. Tamils

We are taking three methodologic approaches. First, we are examining known FSGS risk genes or candidate genes, looking for disease-causing mutations and for disease-susceptibility haplotypes. Second, we have undertaken a genome scan, in the African descent population. We may also undertake a whole genome scan in European and Asian descent. Evidence of linkage disequilibrium among these markers will be sought between patients with and without FSGS. Third, when we identify families with multiple affected individuals and which lack known genetic mutations affecting FSGS genes, we will pursue positional cloning.

• Focal Segmental Glomerulosclerosis
• HIV-Associated Focal Segmental Glomerulosclerosis

• Cantor ES, Kimmel PL, Bosch JP. Effect of race on expression of acquired immunodeficiency syndrome-associated nephropathy. Arch Intern Med. 1991 Jan;151(1):125-8.
• Rappaport J, Kopp JB, Klotman PE. Host virus interactions and the molecular regulation of HIV-1: role in the pathogenesis of HIV-associated nephropathy. Kidney Int. 1994 Jul;46(1):16-27. Review.
• Stephens JC, Briscoe D, O'Brien SJ. Mapping by admixture linkage disequilibrium in human populations: limits and guidelines. Am J Hum Genet. 1994 Oct;55(4):809-24.

• INCLUSION CRITERIA:

All patients with idiopathic FSGS and idiopathic and HIV-associated collapsing glomerulopathy, and kidney donors are eligible.

AFRICAN-AMERICANS WITH FSGS:

Renal biopsy showing FSGS or collapsing glomerulopathy, including HIV-associated collapsing glomerulopathy (HIV-associated nephropathy).

We will include adult and pediatric patients.

OTHER PATIENTS WITH FSGS:

Renal biopsy showing FSGSor collapsing glomerulopathy, including HIV-associated collapsing glomerulopathy (HIV-associated nephropathy).

We will include adult and pediatric patients.

AFRICAN AMERICANS WITH HIV AND WITHOUT KIDNEY DISEASE (CONTROLS):

We will include adult patients who have had serologically confirmed HIV-1 infection for at least 8 years and lack clinical renal disease, as evidenced by normal creatinine and urine protein/creatinine ratio less than 0.5 or 24 hour urine protein excretion less than 500 mg/d.

AFRICAN AMERICAN BLOOD DONORS (CONTROLS):

We will include adults only.

HEALTHY CAUCASIAN CONTROLS (CONTROLS):

These samples represent DNA already obtained.

RELATIVES OF PATIENTS WITH FSGS:

In selected families (in which a patient has been found to have a mutation in a FSGS risk gene whose pathologic role has not been established), we will obtain individual histories of renal disease (hematuria, proteinuria, hypertension,nehrolithiasis) and will measure serum creatinine and urine protein excretion. We will include adults with and without renal disease and children with renal disease. We will evaluate children less than 18 years by obtaining a urine sample; if urinalysis and urine protein excretion are normal, we will not a request a blood sample.

KIDNEY DONORS:

We will include NIH kidney donors only. We will obtain individual histories that provide information as to age, sex, race, surgical and medical histories, and family history. Dr. Cho, as part of another protocol, will measure urinary albumin and kidney size (which by comparison with radiologic studies done at the time of kidney donation will allow determination of kidney hypertrophy following donation). Our purpose is to examine whether particular genetic variants, including those in MYH9, influence the ability of the kidney to undergo hypertrophy following renal donation or the propensity to manifest albuminuria as a sign of glomerular stress. These findings have the potential to extend our understanding of the biology of MYH9 and might have clinical relevance for selecting kidney donors.

EXCLUSION CRITERIA:

AFRICAN-AMERICANS WITH FSGS:

We will exclude patients with hyperfiltration FSGS (reduced renal mass, chronic interstitial nephritis, sickle cell anemia, obesity with BMI greater than 40 kg/m(2)).

OTHER PATIENTS WITH FSGS:

No patients with hyperfiltration FSGS (reduced renal mass, chronic interstitial nephritis, sickle cell anemia, obesity with BMI greater than 40 kg/m(2)).

AFRICAN AMERICAN BLOOD DONORS (CONTROLS):

HIV-1 infection.

Renal disease.

HEALTHY CAUCASIAN CONTROLS (CONTROLS):

Patients will not be recruited as part of the present study.