Jarcy Zee1, Michelle T McNulty2, Jeffrey B Hodgin3, Olga Zhdanova4, Sangeeta Hingorani5, Jonathan Ashley Jefferson6, Keisha L Gibson7, Howard Trachtman8, Alessia Fornoni9, Katherine M Dell10, Heather N Reich11, Serena Bagnasco12, Larry A Greenbaum13, Richard A Lafayette14, Debbie S Gipson15, Elizabeth Brown16, Matthias Kretzler17, Gerald Appel18, Kamalanathan K Sambandam19, Katherine R Tuttle20,21, Dhruti Chen7, Meredith A Atkinson22, Marie C Hogan23, Frederick J Kaskel24, Kevin E Meyers25, John O'Toole26, Tarak Srivastava27, Christine B Sethna28, Michelle A Hladunewich29, J J Lin30, Cynthia C Nast31, Vimal K Derebail7, Jiten Patel19, Suzanne Vento8, Lawrence B Holzman32, Ambarish M Athavale33, Sharon G Adler34, Kevin V Lemley35, John C Lieske23, Jonathan J Hogan32, Crystal A Gadegbeku36, Fernando C Fervenza23, Chia-Shi Wang13, Raed Bou Matar10,37, Pamela Singer28, Jeffrey B Kopp38, Laura Barisoni39, Matthew G Sampson40,41,42. 1. Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine and Children's Hospital of Philadelphia, 423 Guardian Drive, Philadelphia, PA, 19104, USA. Jarcy.Zee@Pennmedicine.upenn.edu. 2. Division of Pediatric Nephrology, Boston Children's Hospital, Enders 509 (Mail Stop BCH3100), 300 Longwood Ave, Boston, MA, 02115, USA. 3. Department of Pathology, University of Michigan, Ann Arbor, MI, USA. 4. Division of Nephrology, New York University Langone Health, New York, NY, USA. 5. Department of Pediatrics, University of Washington and Division of Nephrology, Seattle Children's, Seattle, WA, USA. 6. Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA, USA. 7. University of North Carolina Kidney Center at Chapel Hill, Chapel Hill, NC, USA. 8. Division of Nephrology, Department of Pediatrics, New York University Langone Health, New York, NY, USA. 9. Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA. 10. Department of Pediatrics, Cleveland Clinic Children's, Cleveland, OH, USA. 11. Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, ON, USA. 12. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 13. Division of Pediatric Nephrology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA. 14. Division of Nephrology, Department of Medicine, Stanford University, Stanford, CA, USA. 15. Division of Nephrology, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA. 16. Division of Nephrology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA. 17. Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. 18. Division of Nephrology at Columbia University Medical Center, New York, NY, USA. 19. Division of Nephrology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA. 20. Providence Medical Research Center, Providence Health Care, Spokane, WA, USA. 21. Kidney Research Institute, Nephrology Division, and Institute for Translational Health Sciences, University of Washington, Seattle, WA, USA. 22. Division of Pediatric Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 23. Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA. 24. Division of Nephrology, Department of Pediatrics, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, USA. 25. Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 26. Department of Nephrology, Cleveland Clinic, Cleveland, OH, USA. 27. Section of Nephrology, Children's Mercy Hospital and University of Missouri at Kansas City, Kansas City, MO, USA. 28. Pediatric Nephrology, Cohen Children's Medical Center of New York, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA. 29. Division of Nephrology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, USA. 30. Division of Pediatric Nephrology, Brenner Children's Hospital, Wake Forest University, Winston Salem, NC, USA. 31. Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 32. Renal-Electrolyte & Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 33. Division of Nephrology, Core Faculty, Internal Medicine Residency Program, Cook County Health, Chicago, IL, USA. 34. Division of Nephrology and Hypertension, Lundquist Research Institute at Harbor-UCLA, Torrance, CA, USA. 35. Department of Pediatrics, USC Keck School of Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA. 36. Division of Nephrology, Temple University School of Medicine, Philadelphia, PA, USA. 37. Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA. 38. Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA. 39. Department of Pathology, Duke University, Durham, NC, USA. 40. Division of Pediatric Nephrology, Boston Children's Hospital, Enders 509 (Mail Stop BCH3100), 300 Longwood Ave, Boston, MA, 02115, USA. matthew.sampson@childrens.harvard.edu. 41. Harvard Medical School, Boston, MA, USA. matthew.sampson@childrens.harvard.edu. 42. Broad Institute, Cambridge, MA, USA. matthew.sampson@childrens.harvard.edu.
Abstract
BACKGROUND: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging. METHODS: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. RESULTS: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features. CONCLUSIONS: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.
BACKGROUND: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging. METHODS: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. RESULTS: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features. CONCLUSIONS: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.
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Authors: Lijun Ma; Gregory S Shelness; James A Snipes; Mariana Murea; Peter A Antinozzi; Dongmei Cheng; Moin A Saleem; Simon C Satchell; Bernhard Banas; Peter W Mathieson; Matthias Kretzler; Ashok K Hemal; Lawrence L Rudel; Snezana Petrovic; Allison Weckerle; Martin R Pollak; Michael D Ross; John S Parks; Barry I Freedman Journal: J Am Soc Nephrol Date: 2014-07-10 Impact factor: 10.121
Authors: Xiqian Lan; Aakash Jhaveri; Kang Cheng; Hongxiu Wen; Moin A Saleem; Peter W Mathieson; Joanna Mikulak; Sharon Aviram; Ashwani Malhotra; Karl Skorecki; Pravin C Singhal Journal: Am J Physiol Renal Physiol Date: 2014-06-04