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Anatomy of a Genetic Breakthrough
Established academic leaders in nephrology—the field of medicine that deals with kidney disease—bought into the conventional wisdom that high blood pressure was the major culprit causing kidney disease in African-Americans. That changed in 2010, when Freedman and his fellow researchers reported that variants in the apolipoprotein L1 (APOL1) gene were the true cause of this disease.
“Two coding changes in this single gene fully explained the excess risk of non-diabetic kidney disease we saw in African-Americans, compared to European-Americans,” says Freedman, chief of nephrology and the John H. Felts III Distinguished Professor of Internal Medicine at Wake Forest Baptist Medical Center.
“The kidney disease in African-Americans that was once blamed on high blood pressure actually turned out to be related to this gene.”
The work took nearly 20 years, a commitment to teamwork across disciplines at Wake Forest Baptist, collaboration with the National Institutes of Health, Harvard University and others, and the cooperation of more than 18,000 people who shared their blood for research studies at Wake Forest Baptist.
This major breakthrough is expected to transform the screening process for kidney donors around the world—and lead to an increase in successful kidney transplants.
As a young investigator, Freedman questioned the conventional wisdom of how kidney disease developed.
“I thought, why do some patients with extremely high blood pressure and poorly controlled diabetes not develop kidney disease, whereas others with mild hypertension and controlled diabetes end up on dialysis?” he says. “It just didn’t seem like a reasonable explanation. It wasn’t fair.”
He noticed a strong pattern, in which patients who lacked kidney disease but had both diabetes and high blood pressure also had no family history of kidney disease—whereas many patients with severe kidney disease had close relatives who shared
Freedman suspected that genes were responsible, and he set out to develop a research team to prove it. Many early efforts to publish this research met with harsh resistance and intense criticism.
Building a Team
“I was able to work with senior geneticists who listened to what I had to say, supported the research and were eager to jump on board and work with me to create a clinical/basic science team,” he says. At PHS, he found some of the best statisticians and statistical geneticists in the country.
“We were able to recruit the patients, do the genetic analysis and the statistical analysis all in one place, with world-leading groups,” Freedman says. “That’s when I realized how special this place was.”
In the process, Freedman says nephrology became a hub of research activity within the Medical Center, working with many other departments.
“Without the support of the leaders that we have here in geriatrics and gerontology, infectious diseases, lipid sciences, radiology, genetics, statistics and diabetes, we’d be nowhere,” he says. “It’s really a team.”
The cross-disciplinary effort serves as a model that spans basic research, clinical trials and education, and integrates it all into enhanced patient care, according to John D. McConnell, MD, chief executive officer of Wake Forest Baptist.
“There is probably no finer example of how a team of individuals united around a single goal—in this case to improve the outcome of patients with kidney disease—allows us to accelerate change and to be one of the leading institutions in America in this important area,” McConnell says.
The Work Goes On
“I think the instant that our findings are replicated by another group, testing for APOL1 gene variants in African ancestry kidney donors will become the standard of care in transplant medicine,” he says. “This is going to change the way we practice medicine across the United States and anywhere there are African ancestry populations.”
Despite the team’s discovery, which he describes as a “game-changer” and “one of the most important breakthroughs in medical genetics of common disease,” Freedman didn’t pause in his work for long. Almost immediately after the gene discovery, he started work on his next grant application to secure further research funding.
“We think there are also important genes that contribute to risk of stroke, heart attack and diabetes, and we’re actively searching for them,” he says. “We don’t stop to celebrate—we keep pushing forward.”
He’s “very optimistic” that in the next 20 years, research advances to prevent APOL1-associated, non-diabetic kidney failure in African-Americans will be at hand. Finding this major gene was only the start of his journey; curing kidney disease is his ultimate goal.
Says Freedman, “I feel a strong obligation to my patients and their family members who participated in these research projects.”
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