Researchers developed a polygenic risk score for chronic kidney disease (CKD) that performed well across ancestrally diverse populations.
The risk score combines risk from APOL1 gene variants — which confer high risk of CKD among Black persons — as well as small risks from thousands of other gene variants.
The APO1 and polygenic effects were additive.
The score was tested in 15 large cohorts of people of African, Asian, European, and LatinX descent.
In each of the ancestries, people with risk scores in the top 2% had a threefold higher risk of CKD compared to people with lower risk scores, which is similar to the increased risk of CKD from having a family history of kidney disease.
The study by Atlas Khan, PhD, instructor in medical sciences, and senior author Krzysztof Kiryluk, MD, assistant professor from the Division of Nephrology, Department of Medicine, Columbia University, New York, and colleagues, was published recently in Nature Medicine.
Despite certain limitations, “our study demonstrates that [a clinically] meaningful polygenic prediction of CKD is within reach,” Khan and Kiryluk summarize in a research briefing, also published in Nature Medicine.
“Additional refinements of the risk score are needed but should only improve its current performance,” they add.
“Inherited variants in APOL1 (a well-established gene for kidney disease with large effect in individuals of African ancestry) are also accounted for in the risk score equation that includes thousands of other variants with smaller effects that were discovered in GWAS [genome-wide association studies],” Kiryluk explained to Medscape Medical News in an email.
Patients would provide a blood or saliva sample for DNA testing, from which a CKD risk score would be determined, he noted.
For now, this is only being done in a research setting.
The research was performed as part of the Electronic Medical Records and Genomics-IV (eMERGE-IV) study, a National Institutes of Health–funded nationwide study that started recruiting 20,000 participants to prospectively test risk scores for 10 common diseases.
The “key questions,” Kiryluk said, “are (1) if the genetic testing helps to detect early kidney disease that would otherwise be undetected, and (2) if the positive test triggers adoption of protective lifestyle modifications by the patients that can help to prevent the development of kidney disease.”
The risk score could also potentially help with the selection of kidney donors.
Building a Clinically Meaningful Polygenic Risk Score for CKD
“Our study aimed to test if existing knowledge on APOL1 and polygenic contributions to kidney function is sufficient to build a clinically meaningful polygenic risk score for CKD with reproducible performance across ancestrally diverse populations,” Khan and Kiryluk write.
They combined APOL1 risk genotypes with GWAS for kidney function and designed, optimized, and validated a genome-wide polygenic score for CKD.
They then tested the score in 15 independent cohorts, including three cohorts of European ancestry (with a total of 97,050 people), six cohorts of African ancestry (14,544 people), four cohorts of Asian ancestry (8625 people), and two admixed Latinx cohorts (3625 people).
The prospective eMERGE-IV cohort will provide evidence of whether genetic screening for CKD is indeed clinically effective.
“Important Study,” “More Work Needs to Be Done”
“This is an important study,” Madhav C. Menon, MBBS, MD, associate professor and nephrology and director of research in kidney transplantation, Yale School of Medicine, who was not involved with this research, told Medscape Medical News in an email.
It uses robust sample sizes, he noted, with multiple representative ancestries to develop a quantitative and continuous risk score using several genetic variants across the genome.
A key finding is that it confirms the unique risk of kidney disease in people of African ancestry who have two copies of variants in the APOL1 gene (G1 and G2).
“I think this could be helpful for clinicians to know the risk likelihood for CKD to advise their patients,” Menon said.
“However, as the authors admit,” he continued, “since their data did not capture the family history of kidney disease well from the medical records, whether the score will be an improvement over this knowledge in predicting CKD risk is not known from this work.”
The researchers do point out, he noted, “that in other diseases, such as diabetes, polygenic risk scores are better than family history.
“I think that over the coming years, genetic information could become an integral part of all medical records,” Menon speculated.
This information might be used in transplant scenarios. However, at this stage, “such an extrapolation is still premature,” he cautioned.
Logistic, ethical, and insurance problems would need to be surmounted.
“The major downside,” according to Menon, “is that the [CKD risk] score is a bit like a black box.”
The authors know the exact genetic loci — which are likely numerous — that are involved in the makeup of the score, he continued, but the weight of the individual contributions is not yet understood. The mechanisms that operate when a score leads to CKD are also unknown.
“Most importantly,” Menon said, is that it is not known what a physician should specifically do when a risk score carrier in the top 2% has been identified.
“Hence, while [this is] an important advance, a lot of work still needs to be done.”
The authors and Menon have disclosed no relevant financial relationships.
Nat Med. Published online June 16 and June 23, 2022. Abstract, Research briefing
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