|Newly Identified Gene Variations Account
for Increased Burden of Kidney Disease among African-Americans
For the first time, researchers have identified variations in
a single gene that are strongly associated with kidney diseases
disproportionately affecting African-Americans. This work was conducted
by researchers at the National Institutes of Health (NIH) and by
NIH-funded investigators at the Johns Hopkins University. The findings
are published online today in two papers in Nature Genetics and
will be published in the October print issue.
"These two breakthrough genomic studies on kidney disease
illustrate the importance of collaborations between scientists
at NIH and NIH-funded investigators at Johns Hopkins," said NIH
Director Elias A. Zerhouni, M.D. "This type of government-academic
collaboration moves translational research forward and provides
the knowledge base for developing new therapies for these chronic
The researchers studied nondiabetic kidney diseases that can lead
to chronic kidney disease and, in severe cases, to kidney failure
requiring long-term dialysis or a kidney transplant. One of these
diseases, focal segmental glomerulosclerosis (FSGS), is a kidney
disease that leads to kidney failure in more than half of those
with the disease over a period of about 10 years. Chronic kidney
disease is caused by many different diseases and conditions and
affects 26 million Americans. More than 106,000 individuals develop
kidney failure and more than 485,000 receive dialysis or transplantation
in the United States each year.
Using a type of genome association that relies on differences
in the frequency of gene variants between populations, the NIH
researchers identified several variations in the MYH9 gene
as major contributors to excess risk of kidney disease among African-Americans.
The NIH researchers shared their discovery with the Johns Hopkins
scientists, who replicated the findings in participants from earlier
studies of kidney disease.
Both research teams found statistically significant associations
of MYH9 variants with FSGS, HIV-associated FSGS, and all
nondiabetic kidney failure. They also found that these variants
were much more frequent among people of African ancestry than among
whites. The increased risk among African-Americans with these variants
is more than 300 percent for FSGS, more than 500 percent for HIV-associated
FSGS, and more than 100 percent for all nondiabetic kidney failure.
Sixty percent of African-Americans carry the risk variants in contrast
to 4 percent of whites.
Though FSGS affects African-Americans more than whites, the rate
of progression to kidney failure is believed to the same for both
populations. FSGS associated with HIV infection is almost exclusively
found in individuals of African descent and, without treatment,
progresses more rapidly to kidney failure compared to other forms
of kidney disease. FSGS often affects adolescents and young adults
as well as older individuals.
In the NIH study, the researchers scanned the genome of 190 African-Americans
known to have FSGS, including the form associated with HIV infection,
and 222 who did not have FSGS and replicated these findings in
additional cases. The Johns Hopkins researchers, members of the
Family Investigation of Nephropathy and Diabetes (FIND) consortium,
studied more than 2,100 participants of the FIND study and the
Choices for Healthy Outcomes in Caring for ESRD (CHOICE) study.
FIND, one of the largest multi-center genetic studies of kidney
disease ever conducted, has been funded by the NIDDK since 1999.
"MYH9 genetic variations account for some of the
excess risk of kidney disease due to hypertension, and much of
the excess risk due to FSGS, and HIV-associated FSGS in African-Americans," said
Jeffrey B. Kopp, M.D., a kidney specialist and lead author of the
NIH study. “We hope this finding will lead to personalized medical
therapy that will reduce the burden of chronic kidney disease.”
Though diabetes is one of the leading causes of kidney failure,
both research teams found no association between the MYH9 variants
and diabetes-related kidney failure in African-Americans. “This
finding suggests that the mechanisms leading from onset of chronic
kidney disease to kidney failure may differ based on the inciting
cause,” said W.H. Linda Kao, M.H.S., Ph.D., and Rulan S. Parekh,
M.D., M.S., the lead and senior authors of the Hopkins study. “Therefore,
understanding the role that MYH9 plays in kidney failure
may ultimately lead to development of drug therapies that target
more specific, rather than common, genetic pathways to prevent
kidney disease progression more effectively.”
“These two studies are important not only because the MYH9 risk
variants account for nearly all the excess burden of FSGS and HIV-associated
kidney disease in African-Americans, but also because MYH9 is
the first kidney disease gene identified that explains an important
health disparity and involves common forms of kidney disease,"said
Cheryl Winkler, Ph.D., principal scientist with the National Cancer
Institute, senior author of the NIH intramural study, and a co-author
of the Johns Hopkins study. “In addition, the MYH9 gene’s
estimated relative risk is higher than that observed for nearly
all genetic factors discovered by genome-wide scans, including
those for prostate cancer, diabetes, cardiovascular disease, breast
cancer, and hypertension."
The different frequencies of genetic variants between African
Americans and European Americans have potential implications for
future screening strategies for African-Americans with hypertension.
It remains unclear whether hypertension is particularly likely
to damage the kidney in individuals with these MYH9 variants,
and further research will be needed to determine whether individuals
identified as having hypertensive kidney disease actually have
The variants found in these studies are markers indicating that
the MYH9 gene is the location of the disease-causing variations,
but the specific variants have not yet been definitively identified.
Further studies will be needed to identify the specific causal
variants. Most individuals with the gene variants do not develop
kidney disease, suggesting that additional genetic or environmental
factors contribute to causing kidney disease in particular individuals
with the MYH9 variants.
This research also was supported by the National Cancer Institute,
the National Heart Lung and Blood Institute, the Agency for Healthcare
Research and Quality, and by the National Center for Research Resources
through its General Clinical Research Centers.
For more information on FSGS and kidney failure, visit http://kidney.niddk.nih.gov/kudiseases/pubs/glomerular/index.htm.
For more technical information on glomerular disease, visit http://intramural.niddk.nih.gov/research/glomerular_diseases/normal_kidney.asp
NIDDK conducts and supports research in diabetes and other endocrine
and metabolic diseases; digestive diseases, nutrition, and obesity;
and kidney, urologic, and hematologic diseases. Spanning the full
spectrum of medicine and afflicting people of all ages and ethnic
groups, these diseases encompass some of the most common, severe,
and disabling conditions affecting Americans. For more information
about NIDDK and its programs, see www.niddk.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov.
References: Kopp, J.B. et al. "MYH9 is
major-effect risk gene for focal segmental glomerulosclerosis," Nature
Genetics, September 14, 2008.
Kao, W.H. Linda et al. “MYH9 is associated with nondiabetic
end-stage renal disease in African-Americans,” Nature Genetics,
September 14, 2008.