Kidney Disease Research Updates
Fall 2008

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. The work was conducted by researchers at the National Institutes of Health (NIH) and by NIH-funded investigators at the Johns Hopkins University. The findings were published in the October issue of Nature Genetics.

Researchers studied nondiabetic kidney diseases that can lead to chronic kidney disease (CKD) and, in severe cases, kidney failure requiring long-term dialysis or a kidney transplant. One of these diseases, focal segmental glomerulosclerosis (FSGS), is a condition that leads to kidney failure over a period of about 10 years in more than half of those with the disease.

CKD 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 a transplant in the United States each year.

Using a type of genome association that relies on differences in the frequency of gene variants between populations, NIH researchers identified several variations in the MYH9 gene as major contributors to excess risk of kidney disease among African Americans. NIH researchers shared their discovery with Johns Hopkins scientists, who replicated the findings in participants from earlier kidney disease studies.

Both research teams found statistically significant associations of MYH9 variants with FSGS, HIV-associated FSGS, and all nondiabetic kidney failure. They also found these variants were much more frequent among people of African ancestry than among Caucasians. 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 Caucasians.

Though FSGS affects African Americans more than Caucasians, the rate of progression to kidney failure is believed to be 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 with other forms of kidney disease. FSGS often affects adolescents and young adults as well as older individuals.

“These two breakthrough genomic studies on kidney disease illustrate the importance of collaborations between scientists at the 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 health disorders.”

In the NIH study, 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. 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 multicenter genetic studies of kidney disease ever conducted, has been funded by the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (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, Ph.D., M.H.S., and Rulan S. Parekh, M.D., M.S., the lead and senior authors of the Johns 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.”

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 the National Center for Research Resources through its General Clinical Research Centers.

For more information about kidney disease, visit www.kidney.niddk.nih.gov.

NIH Publication No. 09–4531
December 2008

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