Alexander Teumer1,2, Giovanni Gambaro3, Tanguy Corre4,5, Murielle Bochud4, Peter Vollenweider6, Idris Guessous7, Marcus E Kleber8, Graciela E Delgado8, Stefan Pilz9, Winfried März10,11, Catriona L K Barnes12, Peter K Joshi12, James F Wilson12,13, Martin H de Borst14, Gerjan Navis14, Pim van der Harst15, Hiddo J L Heerspink16, Georg Homuth17, Karlhans Endlich18, Matthias Nauck2,19, Anna Köttgen20,21, Cristian Pattaro22, Pietro Manuel Ferraro3. 1. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. 2. DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany. 3. Divisione di Nefrologia, Fondazione Policlinico Universitario A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy. 4. Institute of Social and Preventive Medicine, Lausanne, Switzerland. 5. Department of computational biology, University of Lausanne, Lausanne, Switzerland. 6. CHUV, Internal Medicine, Lausanne, Switzerland. 7. Division of Primary Care Medicine, University Hospital of Geneva, Geneva, Switzerland. 8. Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 9. Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria. 10. Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany. 11. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Graz, Austria. 12. Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland. 13. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland. 14. Department of Internal Medicine, Division of Nephrology, Groningen, The Netherlands. 15. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 16. Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands. 17. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany. 18. Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany. 19. Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany. 20. Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany. 21. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. 22. Institute for Biomedicine, Eurac Research, Bolzano, Italy.
Abstract
Background: The kidney plays a central role in the regulation of vitamin D metabolism. It is not clear, however, whether vitamin D influences kidney function. Previous studies have reported conflicting results, which may have been influenced by reverse causation and residual confounding. We conducted a Mendelian randomization (MR) study to obtain unconfounded estimates of the association between genetically instrumented vitamin D metabolites and estimated glomerular filtration rate (eGFR) as well as the urinary albumin:creatinine ratio (UACR). Methods: We performed a two-sample MR study based on three single nucleotide variants associated with 25(OH)D levels: rs2282679, rs10741657 and rs12785878, related to the genes GC, CYP2R1 and DHCR7, respectively. Estimates of the allele-dependent effects on serum 25(OH)D and eGFR/UACR were obtained from summary statistics of published genome-wide association meta-analyses. Additionally, we performed a one-sample MR analysis for both 25(OH)D and 1,25(OH)2 D using individual-level data from six cohorts. Results: The combined MR estimate supported a negative causal effect of log transformed 25(OH)D on log transformed eGFR (β = -0.013, P = 0.003). The analysis of individual-level data confirmed the main findings and also revealed a significant association of 1,25(OH)2 D on eGFR (β = -0.094, P = 0.008). These results show that a 10% increase in serum 25(OH)D levels causes a 0.3% decrease in eGFR. There was no effect of 25(OH)D on UACR (β = 0.032, P = 0.265). Conclusion: Our study suggests that circulating vitamin D metabolite levels are negatively associated with eGFR. Further studies are needed to elucidate the underlying mechanisms.
Background: The kidney plays a central role in the regulation of vitamin D metabolism. It is not clear, however, whether vitamin D influences kidney function. Previous studies have reported conflicting results, which may have been influenced by reverse causation and residual confounding. We conducted a Mendelian randomization (MR) study to obtain unconfounded estimates of the association between genetically instrumented vitamin D metabolites and estimated glomerular filtration rate (eGFR) as well as the urinary albumin:creatinine ratio (UACR). Methods: We performed a two-sample MR study based on three single nucleotide variants associated with 25(OH)D levels: rs2282679, rs10741657 and rs12785878, related to the genes GC, CYP2R1 and DHCR7, respectively. Estimates of the allele-dependent effects on serum 25(OH)D and eGFR/UACR were obtained from summary statistics of published genome-wide association meta-analyses. Additionally, we performed a one-sample MR analysis for both 25(OH)D and 1,25(OH)2 D using individual-level data from six cohorts. Results: The combined MR estimate supported a negative causal effect of log transformed 25(OH)D on log transformed eGFR (β = -0.013, P = 0.003). The analysis of individual-level data confirmed the main findings and also revealed a significant association of 1,25(OH)2 D on eGFR (β = -0.094, P = 0.008). These results show that a 10% increase in serum 25(OH)D levels causes a 0.3% decrease in eGFR. There was no effect of 25(OH)D on UACR (β = 0.032, P = 0.265). Conclusion: Our study suggests that circulating vitamin D metabolite levels are negatively associated with eGFR. Further studies are needed to elucidate the underlying mechanisms.
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