0560: Genetic Determinants of Lupus Nephritis and Kidney Function in Systemic Lupus Erythematosus

Magdalena Riedl Khursigara¹, Nicholas Gold², Thai-Son Tang³, Daniela Dominguez², Marisa Klein-Gitelman⁴, Dafna Gladman⁵, Daniel Goldman⁶, Elizabeth Harvey², Mariko Ishimori⁷, Caroline Jefferies⁷, Diane L. Kamen⁸, Sylvia Kamphuis⁹, Andrea Knight², Chia-Chi Lee⁷, Deborah Levy², Damien Noone², Karen Onel¹⁰, Christine Peschken¹¹, Michelle Petri⁶, Janet Pope¹², Eleanor Pullenayegum², Earl Silverman¹³, Zahi Touma¹, Murray Urowitz¹⁴, Daniel Wallace⁷, Joan Wither¹⁵ and Linda Hiraki², ¹University of Toronto, Toronto, ON, Canada, ²The Hospital for Sick Children, Toronto, ON, Canada, ³University of Toronto, Mississauga, ON, Canada, ⁴Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, ⁵Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, Department of Medicine, University of Toronto, Toronto, ON, Canada, ⁶Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, Timonium, MD, ⁷Cedars-Sinai Medical Center, Los Angeles, CA, ⁸Medical University of South Carolina, Charleston, SC, ⁹Sophia Children’s Hospital, Rotterdam, Netherlands, ¹⁰Hospital for Special Surgery, New York, NY, ¹¹University of Manitoba, Winnipeg, MB, Canada, ¹²University of Western Ontario, London, ON, Canada, ¹³Silverman, Toronto, ON, Canada, ¹⁴Schroeder Arthritis Institute, Krembil Research Institute; University of Toronto Lupus Clinic; Division of Rheumatology, Toronto, ON, Canada, ¹⁵University Health Network, Toronto, ON, Canada

Background/Purpose: Lupus nephritis (LN) is one of the most common and severe manifestation of SLE. Risk factors for lupus nephritis and renal function decline are not well understood. We completed a genome wide association study (GWAS) of LN in a multi-ethnic cohort of children and adults with SLE.

Methods: We included SLE patients from dedicated Lupus clinics and the SLICC cohort. All patients met ACR and/or SLICC SLE classification criteria and were genotyped on a multi-ethnic Illumina array. Ungenotyped SNPs were imputed to TopMed, and principal components for ancestral estimation were generated using both 1000 Genomes and GRAF-pop. LN was defined by SLE criteria and confirmed on kidney biopsy in 75%. Kidney function (estimated glomerular filtration rate, eGFR) was calculated using the Schwartz Bedside formula for measures < 18 years and CKD-EPI (without race) for >18 years of age and collected longitudinally over time. Wilcoxon rank sum or Chi-square tests were used to compare characteristics between LN and Non-LN patients. We completed GWAS of LN in marginal and multivariable adjusted regression models with principal components for ancestry, sex and cohort site.

Results: The study included 2981 patients with SLE, 88% female, 46% of European ancestry and 27% childhood-onset SLE. LN was present in 45%. People with LN were younger at diagnosis, and more likely of African American or East Asian ancestry than those without LN. People with LN had significantly lower within-person mean eGFR, greater eGFR variability and slope over time compared to those without LN (Table). GWAS of LN demonstrated a peak on chromosome 8, intronic to ATP6V1C1, yet did not reach a genome-wide significance (p < 5x10^-8).

Conclusion: A GWAS of LN in a multiethnic cohort of children and adults with SLE, did not identify a significant locus. The top signal was on chromosome 8, intronic to ATP6V1C1. We will complete GWAS of repeated eGFR measures, as it is a more informative outcome that we expect will improve power for detecting genetic loci for LN.






M. Riedl Khursigara: None; N. Gold: None; T. Tang: None; D. Dominguez: None; M. Klein-Gitelman: None; D. Gladman: AbbVie, 2, 5, Amgen, 2, 5, Bristol Myers Squibb, 2, Celgene, 2, 5, Eli Lilly, 2, 5, Galapagos, 2, Gilead Sciences, 2, Janssen, 2, 5, Novartis, 2, 5, Pfizer Inc, 2, 5, UCB, 2, 5; D. Goldman: None; E. Harvey: None; M. Ishimori: None; C. Jefferies: None; D. Kamen: None; S. Kamphuis: None; A. Knight: Pfizer, 6; C. Lee: None; D. Levy: None; D. Noone: None; K. Onel: None; C. Peschken: AstraZeneca, 2, 5, GSK, 2, 5, Roche, 1, 2; M. Petri: Alexion, 1, Amgen, 1, AnaptysBio, 1, Annexon Bio, 1, Argenx, 1, Arhros-Focus Med/Ed, 6, AstraZeneca, 1, 5, Aurinia, 1, 5, 6, Axdev, 1, Biogen, 1, Boxer Capital, 2, Cabaletto Bio, 2, Caribou Biosciences, 2, CVS Health, 1, Eli Lilly, 1, 5, Emergent Biosolutions, 1, Exagen, 5, Exo Therapeutics, 2, Gilead Biosciences, 2, GlaxoSmithKlein(GSK), 1, 5, 6, Horizon Therapeutics, 2, Idorsia Pharmaceuticals, 2, IQVIA, 1, Janssen, 1, 5, Kira Pharmaceuticals, 2, MedShr, 6, Merck/EMD Serono, 1, Momenta Pharmaceuticals, 2, Nexstone Immunology, 2, Nimbus Lakshmi, 2, Proviant, 2, Sanofi, 2, Sinomab Biosciences, 2, Thermofisher, 5, UCB, 2; J. Pope: AbbVie, 1, 2; E. Pullenayegum: None; E. Silverman: None; Z. Touma: AstraZeneca, 2, GSK, 2; M. Urowitz: None; D. Wallace: None; J. Wither: AstraZeneca, 1, 6, Pfizer, 12, Indirect salary support through a Chair award to the Division of Rheumatology at the University of Toronto; L. Hiraki: None.