PMID- 36651668 OWN - NLM STAT- MEDLINE DCOM- 20230904 LR - 20230912 IS - 1462-0332 (Electronic) IS - 1462-0324 (Linking) VI - 62 IP - 9 DP - 2023 Sep 1 TI - Genetics of osteonecrosis in children and adults with systemic lupus erythematosus. PG - 3205-3212 LID - 10.1093/rheumatology/kead016 [doi] AB - OBJECTIVES: Genetics plays an important role in SLE risk, as well as osteonecrosis (ON), a significant and often debilitating complication of SLE. We aimed to identify genetic risk loci for ON in people with childhood-onset (cSLE) and adult-onset (aSLE) SLE. METHODS: We enrolled participants from two tertiary care centres who met classification criteria for SLE. Participants had prospectively collected clinical data and were genotyped on a multiethnic array. Un-genotyped single nucleotide polymorphisms (SNPs) were imputed, and ancestry was inferred using principal components (PCs). Our outcome was symptomatic ON confirmed by imaging. We completed time-to-ON and logistic regression of ON genome-wide association studies (GWASs) with covariates for sex, age of SLE diagnosis, five PCs for ancestry, corticosteroid use and selected SLE manifestations. We conducted separate analyses for cSLE and aSLE and meta-analysed results using inverse-variance weighting. Genome-wide significance was P < 5 x 10-8. RESULTS: The study included 940 participants with SLE, 87% female and 56% with cSLE. ON was present in 7.6% (n = 71). Median age of SLE diagnosis was 16.9 years (interquartile range [IQR]: 13.5, 29.3), with median follow-up of 8.0 years (IQR: 4.2, 15.7). Meta-GWAS of cSLE and aSLE time-to-ON of 4 431 911 SNPs identified a significant Chr.2 SNP, rs34118383 (minor allele frequency = 0.18), intronic to WIPF1 (hazard ratio = 3.2 [95% CI: 2.2, 4.8]; P = 1.0 x 10-8). CONCLUSION: We identified an intronic WIPF1 variant associated with a 3.2 times increased hazard for ON (95% CI: 2.2, 4.8; P = 1.0 x 10-8) during SLE follow-up, independent of corticosteroid exposure. The effect of the SNP on time-to-ON was similar in cSLE and aSLE. This novel discovery represents a potential ON risk locus. Our results warrant replication. CI - (c) The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com. FAU - Webber, Declan AU - Webber D AD - Division of Rheumatology, The Hospital for Sick Children, Toronto, ON, Canada. FAU - Cao, Jingjing AU - Cao J AD - Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada. FAU - Dominguez, Daniela AU - Dominguez D AD - Division of Rheumatology, The Hospital for Sick Children, Toronto, ON, Canada. FAU - Gladman, Dafna D AU - Gladman DD AD - Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada. FAU - Knight, Andrea AU - Knight A AD - Division of Rheumatology, The Hospital for Sick Children, Toronto, ON, Canada. AD - Department of Paediatrics, University of Toronto, Toronto, ON, Canada. AD - Neurosciences and Mental Health, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada. FAU - Levy, Deborah M AU - Levy DM AD - Division of Rheumatology, The Hospital for Sick Children, Toronto, ON, Canada. AD - Department of Paediatrics, University of Toronto, Toronto, ON, Canada. FAU - Liao, Fangming AU - Liao F AD - Division of Rheumatology, The Hospital for Sick Children, Toronto, ON, Canada. FAU - Ng, Lawrence AU - Ng L AD - Division of Rheumatology, The Hospital for Sick Children, Toronto, ON, Canada. FAU - Paterson, Andrew D AU - Paterson AD AD - Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada. FAU - Touma, Zahi AU - Touma Z AUID- ORCID: 0000-0001-5177-2076 AD - Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada. FAU - Wither, Joan AU - Wither J AD - Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada. AD - Department of Medicine, University of Toronto, Toronto, ON, Canada. FAU - Urowitz, Murray AU - Urowitz M AD - Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada. FAU - Silverman, Earl D AU - Silverman ED AD - Division of Rheumatology, The Hospital for Sick Children, Toronto, ON, Canada. AD - Department of Paediatrics, University of Toronto, Toronto, ON, Canada. FAU - Hiraki, Linda T AU - Hiraki LT AUID- ORCID: 0000-0002-6690-8148 AD - Division of Rheumatology, The Hospital for Sick Children, Toronto, ON, Canada. AD - Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada. AD - Department of Paediatrics, University of Toronto, Toronto, ON, Canada. LA - eng GR - CIHR/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Rheumatology (Oxford) JT - Rheumatology (Oxford, England) JID - 100883501 RN - 0 (WIPF1 protein, human) RN - 0 (Cytoskeletal Proteins) RN - 0 (Intracellular Signaling Peptides and Proteins) SB - IM MH - Adult MH - Humans MH - Child MH - Female MH - Adolescent MH - Male MH - *Genome-Wide Association Study MH - Age of Onset MH - *Lupus Erythematosus, Systemic/complications/genetics/diagnosis MH - Genotype MH - Severity of Illness Index MH - Cytoskeletal Proteins/genetics MH - Intracellular Signaling Peptides and Proteins/genetics OTO - NOTNLM OT - Osteonecrosis OT - SLE OT - epidemiology OT - genetics EDAT- 2023/01/19 06:00 MHDA- 2023/09/04 06:42 CRDT- 2023/01/18 08:13 PHST- 2022/08/23 00:00 [received] PHST- 2022/12/19 00:00 [accepted] PHST- 2023/09/04 06:42 [medline] PHST- 2023/01/19 06:00 [pubmed] PHST- 2023/01/18 08:13 [entrez] AID - 6991170 [pii] AID - 10.1093/rheumatology/kead016 [doi] PST - ppublish SO - Rheumatology (Oxford). 2023 Sep 1;62(9):3205-3212. doi: 10.1093/rheumatology/kead016.