Abstract
Background
Genome-wide association studies (GWAS) in healthy populations have identified variants associated with erythrocyte traits, but genetic causes of hemoglobin variation in children with CKD are incompletely understood.
Methods
The Pediatric Investigation of Genetic Factors Linked with Renal Progression (PediGFR) Consortium comprises three pediatric CKD cohorts: Chronic Kidney Disease in Children (CKiD), Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE), and Cardiovascular Comorbidity in Children with CKD (4C). We performed cross-sectional and longitudinal association studies of single-nucleotide polymorphisms (SNPs) in 1125 patients.
Results
Children of European (n = 725) or Turkish (n = 400) ancestry (EA or TA) were included. In cross-sectional analysis, two SNPs (rs10758658 and rs12718597) previously associated with RBC traits were significantly associated with hemoglobin levels in children of EA and TA. In longitudinal analysis, SNP rs2540917 was nominally associated with hemoglobin in EA and TA children.
Conclusions
SNPs associated with erythrocyte traits in healthy populations were marginally significant for an association with hemoglobin. Further analyses/replication studies are needed in larger CKD cohorts to investigate SNPs of unknown significance associated with hemoglobin. Functional studies will be required to confirm that the observed associations between SNPs and clinical phenotype are causal.
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Acknowledgements
The CKiD Study is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), with additional funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Heart, Lung, and Blood Institute (U01-DK-66143, U01-DK-66174, U01DK-082194, and U01-DK-66116). The CKID website is located at http://www.statepi.jhsph.edu/ckid. The ESCAPE trial and the 4C Study were conducted by the ESCAPE Clinical Research Network. The ESCAPE Trial was supported by grants from the European Commission Fifth Framework Programme (QLRT-2001-00908), Boehringer Ingelheim Foundation, Kuratorium für Dialyse und Nierentransplantation e.V., and the Baxter Extramural Grant Program. Support for the 4C Study was received from the ERA-EDTA Research Programme, the KfH Foundation for Preventive Medicine and the German Federal Ministry of Education and Research (reference number: 01EO0802). The genotyping data utilized for the PediGFR Consortium studies (CKiD, 4C, and ESCAPE) were supported by NIDDK Grant No. RO1-DK-082394. Additional support was provided by the EU 7th Framework Programme (EURenOmics, Grant 2012-305608). M.A.A. was supported by the National Institutes of Health (NIH)/NIDDK (K23-DK-084116). The work of M.W. and A.K was supported by the CRC 1140 of the German Research Foundation. M.A.A. and S.L.F. were supported by an unrestricted grant from Amgen, Inc.
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M.A.A participated in the analysis and interpretation of data, drafted and revised the article providing intellectual content of critical importance to the work, and approved the final draft. R.X. participated in the analysis and interpretation of the data, revised the article providing intellectual content of critical importance to the work, and approved the final draft. A.K. participated in the conception and design of the analysis and the interpretation of data, revised the article and provided intellectual content of critical importance to the work, and approved the final draft. E.W. participated in the conception and design of the analysis and in the analysis and interpretation of data, revised the article and provided intellectual content of critical importance to the work, and approved the final draft. C.S.W. participated in the conception and design of the analysis and in the analysis and interpretation of data, revised the article and provided intellectual content of critical importance to the work, and approved the final draft. M.W. participated in the conception and design of the analysis and in the analysis and interpretation of data, revised the article and provided intellectual content of critical importance to the work, and approved the final draft. A.K.B. participated in the design of the analysis, revised the article for critical intellectual content, and approved the final draft. S.Ç. participated in the design of the analysis, revised the article for critical intellectual content, and approved the final draft. B.A.W. participated in the conception and design of the analysis and in the interpretation of data, revised the article and provided intellectual content of critical importance to the work, and approved the final draft. F.S. participated in the conception and design of the analysis and in the interpretation of data, revised the article and provided intellectual content of critical importance to the work, and approved the final draft. S.L.F. participated in the conception and design of the analysis and in the interpretation of data, revised the article and provided intellectual content of critical importance to the work, and approved the final draft.
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Atkinson, M.A., Xiao, R., Köttgen, A. et al. Genetic associations of hemoglobin in children with chronic kidney disease in the PediGFR Consortium. Pediatr Res 85, 324–328 (2019). https://doi.org/10.1038/s41390-018-0148-z
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DOI: https://doi.org/10.1038/s41390-018-0148-z
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