You are here

Article Text

Article menu

Download PDFPDF

Abstracts
1501 Genetics of age at systemic lupus erythematosus diagnosis
  1. Raffaella Carlomagno1,
  2. Fangming Liao1,
  3. Jingjing Cao2,
  4. Daniela Dominguez1,
  5. Dafna D Gladman3,
  6. Mariko Ishimori4,
  7. Caroline Jefferies4,
  8. Diane L Kamen5,
  9. Sylvia Kamphuis6,
  10. Marisa S Klein-Gitelman7,
  11. Andrea M Knight1,
  12. Chia-Chi J Lee4,
  13. Deborah M Levy1,
  14. Karen B Onel8,
  15. Andrew D Paterson2,
  16. Christine A Peschken9,
  17. Janet E Pope10,
  18. Zahi Touma3,
  19. Murray B Urowitz3,
  20. Daniel J Wallace4,
  21. Declan Webber1,
  22. Joan E Wither3,
  23. Earl D Silverman1, 11 and
  24. Linda T Hiraki1, 2
  1. 1Division of Rheumatology
  2. 2Genetics and Genome Biology, Research Institute, The Hospital for Sick Children
  3. 3Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, Toronto, Canada
  4. 4Division of Rheumatology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles
  5. 5Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, USA
  6. 6Department of Pediatric Rheumatology, Sophia Children’s Hospital, Erasmus University Medical Center, Rotterdam, Netherlands
  7. 7Division of Rheumatology, Department of Pediatrics, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago
  8. 8Pediatric Rheumatology, Hospital for Special Surgery, New York, USA
  9. 9Departments of Medicine and Community Health Sciences, University of Manitoba, Winnipeg
  10. 10Department of Medicine, University of Western Ontario, St. Joseph’s Health Centre, London
  11. 11Division of Translational Medicine Research Institute, The Hospital for Sick Children, Toronto, Canada

Abstract

Background Genome wide association studies (GWAS) have identified >100 SNPs associated with systemic lupus erythematosus (SLE) risk. There may be additional loci impacting the age of diagnosis. The purpose of this study was to identify genetic variants associated with age of SLE diagnosis.

Methods Our cohort included patients from tertiary care centres who met ACR and/or SLICC SLE classification criteria. We censored patients missing age at diagnosis. Patients were genotyped on the Illumina Multiethnic Array (MEGA) or Global Screen Array (GSA). Ungenotyped SNPs were imputed using the TopMed reference. We restricted to SNPs with a minor allele frequency (MAF) ≥ 0.01 and imputation quality R2≥ 0.3. Ancestry was genetically inferred using principal components (PCs) and ADMIXTURE in reference to 1000 Genome Project. We completed genome-wide linear regression of log-transformed age at SLE diagnosis with GENESIS (significance P<5x10-8). Multivariate models adjusted for sex and 5 PCs. We also conducted a GWAS of childhood-onset SLE (cSLE) patients, defined as diagnosis <18 years of age, vs. adult-onset SLE (aSLE), using logistic regression, and adjusted for the same covariates. We conducted sensitivity analyses where we stratified GWAS by cSLE and aSLE, then meta-analyzed results using inverse variance weighting, as well as ancestry-stratified analyses (Europeans, East Asians, Africans, Amerindians and Admixed).

Results Our cohort included 1489 patients, 761 (51%) cSLE, 1306 (88%) female. Median age at diagnosis was 17.7 years (IQR 14, 31) in the total cohort, 14.1 years (IQR 11.8, 15.8) in cSLE, and 31.2 years (IQR 24.7, 42) in aSLE. In the total cohort, 576 (39%) were of European ancestry, 278 (19%) East Asian, and 253 (17%) Admixed. We included 11.7M SNPs in GWAS. In the age of SLE diagnosis GWAS, 2 loci on chr16 were genome-wide significantly associated with younger age at diagnosis (top SNP rs11641349, Beta -0.03y, SE 0.15y, P=4.33x10-8, MAF 0.2). Both SNPs were intronic to CCDC113, a component of centriolar satellites. These loci were also the most significant in the GWAS of cSLE (top SNP rs16959933, OR 1.75 [95% CI: 1.43, 2.14, P=5.45 x10-8]). Sensitivity analyses showed similar results, yet they did not reach genome-wide significance with top SNPs rs11641349 (P=3.84x10-7) and rs16959933 (P=4.50x10-7) in the age group model, and rs11641349 (P=3.52x10-7) and rs16959933 (P=4.22x10-7) in the ancestry model.

Conclusion In our multiethnic cSLE and aSLE cohort, we identified genome-wide significant loci associated with age at diagnosis and cSLE risk, intronic to CCDC113. Our study requires independent validation.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

http://dx.doi.org/10.1136/lupus-2021-lupus21century.84

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.