Mapping CKD Complications to Unexpected Genetic Locations

New meta-analysis integrates seven genome-wide association studies to explain FGF23 elevations.

A patient’s individual response to chronic kidney disease (CKD) depends on a multitude of genetic risk factors, but connections between risk factors aren’t always clear.

Well-documented CKD complications include elevated levels of fibroblast growth factor 23 (FGF23). The bone-derived hormone regulates phosphorus and vitamin D metabolism. High levels can cause mineral and bone disorders in CKD patients, and research also suggests FGF23 is an emerging cardiovascular risk factor.

“Most people don’t realize it, but when you have chronic kidney disease, you’re more likely to develop a cardiovascular event than you are to go on dialysis and have kidney complications,” said Cassianne Robinson-Cohen, Ph.D., assistant professor of medicine at Vanderbilt University Medical Center, and an expert on genetics of mineral metabolism.

As an epidemiologist, Robinson-Cohen has identified genetic mechanisms that underlie FGF23 levels in different patient populations. “The first step is cataloguing genetic association data so that we and others can start pointing to different pathways that are implicated in FGF23 regulation.”

Digging into Genome-Wide Studies

In a recent meta-analysis published in the Journal of the American Society of Nephrology, Robinson-Cohen and 26 other researchers integrated genetic data from seven genome-wide association studies (GWAS), looking for single nucleotide polymorphisms (SNPs) that significantly alter FGF23 levels.

The first-of-its-kind analysis included circulating FGF23 levels from 16,624 healthy participants of European ancestry. After controlling for age, sex, study site, and more specific ancestry, the researchers found 154 SNPs associated with FGF23—none of which were in the FGF23 gene itself. The researchers confirmed the top five SNPs in 4,443 people of African descent.

The SNP most strongly associated with elevated FGF23 levels lies 37 kilobases upstream of CYP24A1 (the primary catabolic enzyme for the active form of vitamin D). According to the analysis, a SNP in this region is associated with five percent higher FGF23 blood levels—which could impact CKD risk. Said Robinson-Cohen, “We now have direct evidence that the vitamin D breakdown is important for FGF23 regulation.”

Other SNPs identified are closely linked with parathyroid hormone concentration, including enzymes, transporters, and receptors involved in vitamin D metabolism and phosphate regulation. These SNPs are in five genomic regions not previously associated with FGF23. The regions are located on chromosomes 5, 9, 16, and 20.

GWAS Analyses to Inform Drug Design

“We need to take pause and be sure we aren’t moving too quickly in development of these drugs.”

Since so many different genes are involved in controlling FGF23 levels, current drugs aimed at the hormone may not be as effective as previously thought, Robinson-Cohen said.

“Many drugs, including those for osteoporosis have been developed that target and inhibit the FGF23 gene. We found this gene actually isn’t fully responsible for levels of FGF23. We need to take pause and be sure we aren’t moving too quickly in development of these drugs.”

Additional studies are needed to confirm genetic associations with risk factors—like FGF23—before drug designers start targeting genes. With the availability of GWAS data, such follow up research may not require large, randomized, controlled trials.

Said Robinson-Cohen, “We have this incredible data resource in front of us. Let’s use what we have now to better prioritize future effort.”