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Abstract: TH-PO188

Genome-Wide Association Study Reveals That Distinct Genetic Factors Regulate Intact and C-Terminal FGF23 Levels in Humans

Session Information

Category: Bone and Mineral Metabolism

  • 402 Bone and Mineral Metabolism: Clinical


  • Barrington, William T., UCLA, Los Angeles, California, United States
  • Hanudel, Mark R., UCLA, Los Angeles, California, United States
  • Pereira, Renata C., University of California, Los Angeles, California, United States
  • Charugundla, Sarada, UCLA, Los Angeles, California, United States
  • Laakso, Markku Hs, University of Eastern Finland, Kuopio, Finland
  • Lusis, Aldons J., UCLA, Los Angeles, California, United States
  • Salusky, Isidro B., UCLA, Los Angeles, California, United States

Elevated fibroblast growth factor 23 (FGF23) levels have been associated with chronic kidney disease (CKD) progression, cardiovascular disease (CVD) and increased mortality. FGF23 also directly induces cardiac myocyte hypertrophy. Recently, non-mineral factors such as iron, anemia, inflammation and erythropoietin (EPO) have been identified in FGF23 production. Such factors are also associated with CKD progression, CVD and mortality. Thus, several lines of evidence suggest that FGF23 could play an important link. However, no studies have examined genetic factors underlying FGF23 levels in humans. We conducted the first-ever genome-wide association study (GWAS) study of FGF23.


We measured both the active, intact form (iFGF23), and the total amount of FGF23 as measured by c-terminal form (cFGF23) via ELISA in a population of 1,400 Finnish men aged 58+7 (SD) yrs. and eGFR 85+15 ml/min/1.73 m2. We performed GWAS mapping using a linear mixed model removing, SNPs with less than 5% minor allele frequency.


We identified suggestive loci for cFGF23 on chromosomes 3 (p = 4.3 x 10-7) and 21 (p = 8.9 x 10-8), and suggestive for iFGF23 levels on chromosomes 7 (p = 3.6x10-6), 12 (p = 3.6x10-6) and chromosome 18 (p = 4.5x10-6). The locus influencing iFGF23 levels on chromosome 7 is near the erythropoietin (EPO) gene, which stimulates hematopoiesis and is deregulated in CKD patients. It is known that serum EPO and recombinant EPO administration are associated with FGF23 levels. Genetic manipulation of FGF23 has been shown to regulate erythropoiesis through EPO, indicating that regulation of EPO and FGF23 is complex. Our results show that genetic variants near EPO regulate iFGF23, raising the possibility that iFGF23 is genetically controlled by EPO. In contrast, the cFGF23 levels were not associated with the locus near EPO possibly due interindividual variation in FGF23 cleavage.


Our results improve the understanding of the complex regulation between FGF23 and EPO. Our results provide evidence that complex and distinct genetic factors are involved in the regulation iFGF23 and cFGF23 that may help identify populations with different FGF23 levels at similar GFR, and indicate that natural genetic variation near EPO is involved in the regulation of FGF23.


  • Other NIH Support