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Abstract: TH-OR022

Genetic Variants Associated with Circulating Fibroblast Growth Factor-23 among Patients with CKD

Session Information

Category: Bone and Mineral Metabolism

  • 402 Bone and Mineral Metabolism: Clinical

Authors

  • Robinson-Cohen, Cassianne, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Perwad, Farzana, University of California San Francisco, San Francisco, California, United States
  • Akwo, Elvis A., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Lipworth, Loren, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Wolf, Myles, Duke University, Durham, North Carolina, United States
  • Kestenbaum, Bryan R., University of Washington, Seattle, Washington, United States
  • Hung, Adriana, VA & Vanderbilt University, Nashville, Tennessee, United States
  • Ikizler, Talat Alp, Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

Recent genome-wide association studies (GWAS) identified loci associated with differences in fibroblast growth factor 23 (FGF23) concentrations, near genes involved in vitamin D metabolism, ABO blood group system, and renal phosphate transport. These studies were conducted among individuals with preserved kidney function. It is possible that genetic contributions to circulating FGF23 may differ among individuals with mineral metabolism disturbances, such as those with chronic kidney disease (CKD), in whom the biologic implications and potential treatment options are most relevant.

Methods

We examined 5 SNPs previously identified in GWAS of FGF23 (index SNPs) and 44 putatively functional SNPs in the surrounding regions (±250kb) among unrelated individuals of European ancestry (n=1,666) who participated in the Chronic Renal Insufficiency Cohort (CRIC) Study. We additionally tested for interactions of eGFR on the SNP-FGF23 association.

Results

Two index SNPs were associated with FGF23, after adjustment for age, sex, eGFR and BMI: rs11741640 at 5q35.3/RGS14/SLC34A1 (beta for the G allele: 5.7% higher FGF23 95% CI: 3.6,13.9, p=0.001) and rs2769071 at 9q34.2/ABO (beta coefficient for the G allele: 7.3% higher FGF23, 95% CI: 2.8,11.8, p=0.001). When we expanded to surrounding functional variants, 9 SNPs were associated with FGF23 (false discovery rate ≤ 0.05), all within the 5q35.3 region. The strongest association was for rs4075958 in RGS14 (beta for the A allele: 7.3% lower FGF23, 95% CI: -11.3,-3.1, p=9x10-4). Statistically significant interaction by eGFR was noted for the association of rs17216707 at 20q13.2/CYP24A1 (p=0.019).

Conclusion

Our findings provide evidence that a subset of genetic variants associated with FGF23 under normal conditions are also associated in the setting of CKD. Larger, more comprehensive studies are needed to fully assess the generalizability of published GWAS findings and to identify potential novel associations in CKD. Both replication and lack of replication of published GWAS findings in CKD provide important information on the genetic etiology and on pathways influencing mineral metabolism disorders.

Funding

  • NIDDK Support